Dr. Kanwaljeet Anand graduated from M.G.M. Medical College, Indore (India). As a Rhodes Scholar at University of Oxford, he received the D.Phil. degree, followed by post-doctoral fellowship at Harvard Medical School, Pediatrics residency training at Boston Children’s Hospital and a Critical Care Medicine fellowship at the Massachusetts General Hospital, Boston.
His research was recognized by the Dr. Michael Blacow Award from British Paediatric Association (1986), Pediatric Resident Research Award from American Academy of Pediatrics (1992), the inaugural Young Investigator Award in Pediatric Pain from International Association for Study of Pain (IASP, 1994), the Jeffrey Lawson Award for Children’s Advocacy from American Pain Society (2000), the Windermere Honorary Lectureship Award from Royal College of Paediatrics & Child Health (2004), Joan M. Cranmer “Mentor of the Year” Award (2007) from University of Arkansas, the Nils Rosén von Rosenstein Award* from the Swedish Academy of Medicine (2009), Top Mentor Award, School of Graduate Studies, University of Arkansas for Medical Sciences (2011), the 9th Annual “In Praise of Medicine” Public Address at Erasmus University (2014), the Journées Nationales de Néonatologie 2015 Address at The Pasteur Institute (Paris, France), the Nightingale Excellence Award (2016) from Stanford Children’s Healthcare, and an Honorary Doctorate from University of Örebro, Sweden (2019). Dr. Anand founded the Harmony Health Clinic, the largest charitable medical & dental clinic in Little Rock and worked to remove inter-faith conflict throughout the state of Arkansas. He received the Father Joseph Biltz Award (2007) from the National Conference for Community & Justice (NCCJ) and the Dr. Martin Luther King “Salute to Greatness” Individual Award (2008) from the Governor of Arkansas for his commitments to community service.
Dr. Anand is currently Professor of Pediatrics, Anesthesiology, Perioperative & Pain Medicine at Stanford University School of Medicine; he directs the Pain/Stress Neurobiology Lab, the Jackson Vaughan Critical Care Research Fund, and serves as Editor for the journal Pediatric Research. He is considered a world authority on pain/stress in newborns and pain management in infants.

Clinical Focus

  • Pediatric Critical Care Medicine

Academic Appointments

Administrative Appointments

  • Division Chief, Pediatric Critical Care, Department of Pediatrics, School of Medicine (2015 - 2017)
  • Director, Child Wellness Lab, Maternal & Child Health Research Institute (2016 - Present)
  • Co-Chair, Ideal Village Conferences at Stanford, Stanford University (2017 - Present)
  • Director, Jackson Vaughan Critical Care Research Fund, Critical Care Medicine Division, Department of Pediatrics (2018 - Present)

Honors & Awards

  • Dr. Michael Blacow Award, British Paediatric Association (1986)
  • Pediatric Resident Research Award, American Academy of Pediatrics (1992)
  • Young Investigator Award in Pediatric Pain, International Association for the Study of Pain, Special Interest Group for Pain in Children (1994)
  • Jeffrey Lawson Award for Advocacy in Children’s Pain Relief, American Pain Society (2000)
  • Morris & Hettie Oakley Endowed Chair for Critical Care Medicine, University of Arkansas for Medical Sciences (2001)
  • Joan M. Cranmer “Mentor of the Year” Award, Department of Pediatrics, University of Arkansas for Medical Sciences (2007)
  • “Salute to Greatness” Individual Award, Dr. Martin Luther King Commission, State of Arkansas (2008)
  • The Nils Rosén von Rosenstein Award, Swedish Academy of Medicine & Swedish Paediatric Society (2009)
  • St. Jude Chair of Pediatric Critical Care Medicine, University of Tennessee Health Science Center and St. Jude Children’s Research Hospital (2010)
  • 9th Annual “In Praise of Medicine” Public Address, Erasmus University 100th Anniversary Celebrations (2013)
  • Journées Nationales de Néonatologie Keynote Address, The Pasteur Institute, Paris, France (2015)
  • Nightingale Excellence Award for Physicians, Stanford Children’s Healthcare System (2016)
  • Chief Guest, Inaugural Function of the 37th Annual Meeting of National Neonatology Forum, National Neonatology Forum, India (2017)
  • Co-Chair, Annual International Conferences on the Ideal Village Program, Stanford University School of Medicine (2017, 2018, 2019)
  • Chair, SBIB-H82 Study Section, Clinical Fetal & Pediatric Applications, NIH/Center for Scientific Review (2018)
  • Honorary Doctorate, Doctor of Medicine, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden (2019)

Boards, Advisory Committees, Professional Organizations

  • Member, Scientific Advisory Board, Sadhguru Center for a Conscious Planet (2021 - Present)
  • Member, Scientific Advisory Board, Riaan Research Initiative (2021 - Present)
  • Member, Trust Advisory Committee, NAS Monitoring Trust (2021 - Present)
  • Advisor, Board of Trustees, The Sikh Foundation International (2016 - Present)
  • Chair, Selection Committee, Distinguished Investigator Award in Pediatric Pain, International Association for the Study of Pain (2014 - 2015)
  • Chair, Promotion & Tenure Committee, Department of Pediatrics, University of Tennessee Health Science Center (2013 - 2014)
  • Dean’s Faculty Advisory Committee, College of Medicine, University of Tennessee Health Science Center (2013 - 2014)
  • Member, Executive Council, Special Interest Group on Pain in Children, International Association for the Study of Pain (2011 - 2014)
  • Chair, Selection Committee, Distinguished Investigator Award in Pediatric Pain, International Association for the Study of Pain (2011 - 2012)
  • Board Member, Critical Care Educational & Research Foundation, Society for Critical Care Medicine (2008 - 2010)
  • Founder & President, Board of Directors, Harmony Health Clinic, Little Rock AR (2008 - 2010)
  • Expert Consultant, Institute of Laboratory Animal Research, The National Academy of Sciences (2008 - 2009)
  • Member, Sub-Board of Critical Care Medicine, American Board of Pediatrics (2007 - 2013)
  • Chair, Research Committee, Society for Critical Care Medicine (2006 - 2008)
  • Chair, Special Task Force for Anesthesia & Analgesia Drugs, National Institute for Child Health & Human Development (2006 - 2008)
  • Member, ALSDAC Advisory Committee of the FDA, U.S. Public Health Service, Department of Health & Human Services (2006 - 2008)
  • Chair, Neonatal Pain Task Force, FDA/NICHD Newborn Drug Development Initiative (2003 - 2005)

Professional Education

  • Board Certification: American Board of Pediatrics, Pediatric Critical Care Medicine (1994)
  • Fellowship: Massachusetts General Hospital Pediatric Critical Care Fellowship (1993) MA
  • Residency: Boston Childrens Hospital Pediatric Residency (1991) MA
  • Internship: Boston Childrens Hospital Pediatric Residency (1989) MA
  • Fellowship: Boston Children's Hospital Dept of Anesthesiology (1988) MA
  • Medical Education: Mahatma Gandhi Memorial Medical College (1981) India

Current Research and Scholarly Interests

Dr. Anand is a translational clinical researcher who pioneered research on the endocrine-metabolic stress responses of infants undergoing surgery and developed the first-ever scientific rationale for pain perception in early life. This provided a framework for newer methods of pain assessment, numerous clinical trials of analgesia/anesthesia in newborns, infants and older children. His research focus over the past 30+ years has contributed fundamental knowledge about pediatric pain/stress, long-term effects of pain in early life, management of pain, mechanisms for opioid tolerance and withdrawal. Current projects in his laboratory are focused on developing biomarkers for repetitive pain/stress in critically ill children and the mechanisms underlying sedative/anesthetic neurotoxicity in the immature brain. He designed and directed many randomized clinical trials (RCT), including the largest-ever pediatric analgesia trial studying morphine therapy in ventilated preterm neonates. He has extensive experience in clinical and translational research from participating in collaborative networks funded by NIMH, NINDS, or NICHD, a track-record of excellent collaboration across multiple disciplines, while achieving success with large research teams like the Collaborative Pediatric Critical Care Research Network (CPCCRN). He played a leadership roles in CANDLE (Condition Affecting Neuro-Development & Learning in Early infancy) and other activities of the Urban Child Institute and UT Neuroscience Institute. More recently, he led the NeoOpioid Consortium funded by the European Commission, which collected data from 243 NICUs in 18 European countries.

Clinical Trials

  • Electronic Application of a Severe Sepsis Screening Tool and Management Bundle Recruiting

    Thousands of children die from Sepsis following routine infections. Many of these deaths can be prevented with earlier recognition and focused management. No tools are currently available to recognize the signs of early sepsis in children. The investigators have developed a electronic health record-based tool that will recognize children with sepsis early and trigger an alert to their hospital caregivers. The caregivers will be prompted to launch a focused management bundle that can stabilize these children, prevent further deterioration and reduce their chances of sepsis related complications and death. The proposed study will test the validity and effectiveness of this electronic tool in reducing sepsis mortality rates.

    View full details

  • Assessment of Pain in Newborns and Older Infants (Infant Pain Assessment Study = Not Recruiting

    Pain assessments in non-verbal, critically ill infants represent an important clinical challenge. Older children or adults can easily express their pain, but infants lack that capability. They frequently experience repetitive acute pain during routine ICU care, but their analgesic management flounders on the horns of a dilemma: (a) failure to treat infant pain leads to immediate clinical instability and potentially long-term physical, behavioral, and cognitive sequelae, vs. (b) strong analgesics may increase risks for medical complications and/or impaired brain growth. Bedside nurses currently assess pain using pain scores, before taking action to ameliorate pain. Pain scores increase nursing workload and provide subjective assessments, rather than objective data for evaluating infant pain. Consequently, infants exposed to skin-breaking procedures, surgery, or other painful conditions often receive variable and inconsistent pain management in the ICU. The investigators aim to develop a multimodal pain assessment system, using sensor fusion and novel machine learning algorithms to provide an objective measure of pain that is context-dependent and rater-independent. This will enhance the quality of pain management in ICUs and allow continuous pain monitoring in real-time.

    Stanford is currently not accepting patients for this trial. For more information, please contact Spectrum Child Health, 650-724-1175.

    View full details


  • Measuring Childhood Wellness in Preschool Children, Stanford University School of Medicine (October 30, 2017 - June 1, 2023)

    We are looking to engage healthy preschool children (aged 9 to 72 months) for research on measuring wellness in early childhood. We have worked with hundreds of families to date and want to partner with families and individuals with preschool children! We are studying the positive and negative experiences of young children by measuring hormones, proteins, or other molecules present in the hair samples that are painlessly obtained from children and their parents. To minimize the possibility of transmitting the COVID-19 virus, our “contact-free” study enrollment will guide participants how to:
    •Give informed consent using electronic signatures on the IRB-approved consent form;
    •Obtain a hair sample (pain-free method using a trimmer) from parent(s) and children;
    •Measure and record each child’s height and weight; and
    •Complete online questionnaires telling us about the parent(s) and their children.
    As a token of our gratitude, we will provide every child with a “Junior Scientist Certificate” and parents receive Gift Cards of $50 (for each child) and $25 for parent hair samples. All sessions can take place via Zoom, phone, or in-person at a location suitable to the parents/family. If anyone is interested in this research, either click on:, or email us at:, or call us at: (650) 687-7329.


    1701 Page Mill Road, Palo Alto, CA 94304

  • Reducing the Effects of Chronic Stress, Discrimination, and Poverty on Health Outcomes in Adolescents, Stanford University School of Medicine (October 10, 2021 - October 31, 2022)

    Adolescents are motivated by sensation- or novelty-seeking behaviors, peer relationships, and social status, associated with heightened emotional instability and stress responsivity, sleep and circadian rhythm changes, and impaired judgements due to an underdeveloped prefrontal cortex. We are testing an evidence-based biopsychosocial intervention designed to build social-emotional skills, self-mastery, and resilience, thus enhancing prosocial behaviors, emotional control, conflict resolution, and healthy behaviors. This includes a mind-body-lifestyle curriculum, daily breathing practices, and individual student supports, to promote self-esteem and protect against the effects of poverty or racism.
    We will test whether this SKY Schools Program reduces perceived stress, anxiety, depression, and risky behaviors, while improving self-esteem, school discipline, and healthy behaviors as compared to pre-intervention values. We will investigate the mechanisms of these effects by studying if children with greater perceived stress, anxiety, and risky behaviors will show higher stress hormones, whereas those with greater emotional regulation and self-esteem will show higher socializing hormones.
    7th Grade students (aged 11-14 years) will be enrolled from a school that has high numbers of children from socially disadvantaged and/or minority families. Students, parents, and teachers will complete surveys at the school start (October), after Winter Break (January), and when the school year ends (June); hair samples will be obtained painlessly from the enrolled students at these time-points. The SKY Schools Program will be delivered after Winter Break via daily 1-hour sessions for 4 weeks in January, followed by weekly refresher sessions, and individual student support until the school year ends. By comparing their risk factors, behaviors and outcomes before and after the proposed program, we will develop scientific insights into chronic stress and social isolation as causative factors for youth risk-taking, test the effectiveness of an evidence-based biopsychosocial intervention designed to counteract these behaviors, and ultimately help to improve the health, wellbeing, and academic outcomes of all socially disadvantaged adolescents.


    1701 Page Mill Road, Palo Alto, CA 94304

2023-24 Courses

Stanford Advisees

Graduate and Fellowship Programs

  • Pediatric Critical Care Medicine (Fellowship Program)

All Publications

  • Stress Symptoms Among Children and Their Parents After ICU Hospitalization. Journal of intensive care medicine Daughtrey, H. R., Lee, J., Boothroyd, D. B., Burnside, G. M., Shaw, R. J., Anand, K. J., Sanders, L. M. 2023: 8850666231201836


    Objective: Child survival after intensive care unit (ICU) hospitalization has increased, yet many children experience acute stress that may precipitate mental/behavioral health comorbidities. Parents report stress after their child's hospitalization. Little is known about the individual and family characteristics that may moderate intergenerational relationships of acute stress. Design: Following ICU admission at a large academic medical center, a prospective cross-sectional cohort study assessed the associations between intergenerational characteristics and acute stress among children and families. Patients: Parent-child dyads (N = 88) were recruited from the pediatric ICU and pediatric cardiovascular ICU (CVICU) following ICU discharge. Eligible children were between 8 and 18 years old with ICU stays longer than 24 hours. Children with developmental delays were excluded. Caregivers were proficient in English or Spanish. Surveys were collected before hospital discharge. Measurements/Main Results: The primary outcome was "child stress" defined as a score≥17, measured by the Children's Revised Impact of Events Scale (CRIES-8). "Parent stress" was defined as an elevated composite score on the Stanford Acute Stress Reaction Questionnaire. We used validated scales to assess the child's clinical and family social characteristics. Acute stress was identified in 34 (39.8%) children and 50 (56.8%) parents. In multivariate linear regression analyses adjusting for social characteristics, parent stress was associated with increased risk of child stress (adjusted odds ratio 2.58, 95% confidence interval 0.69, 4.46, p < .01). In unadjusted analyses, Hispanic ethnicity was associated with greater child stress. In adjusted analyses, race, income, ICU length of stay, and language were not associated with child stress and did not moderate the parent-child stress relationship. Conclusions: Parent stress is closely correlated with child stress during ICU hospitalization. Hispanic ethnicity may be associated with increased risk for child stress, but further studies are required to define the roles of other social and clinical measures.

    View details for DOI 10.1177/08850666231201836

    View details for PubMedID 37743757

  • Linear hair growth rates in preschool children. Pediatric research Ruiz, M. O., Rovnaghi, C. R., Tembulkar, S., Qin, F., Truong, L., Shen, S., Anand, K. J. 2023


    Human scalp hair is a validated bio-substrate for monitoring various exposures in childhood including contextual stressors, environmental toxins, prescription or non-prescription drugs. Linear hair growth rates (HGR) are required to accurately interpret hair biomarker concentrations.We measured HGR in a prospective cohort of preschool children (N = 266) aged 9-72 months and assessed demographic factors, anthropometrics, and hair protein content (HPC). We examined HGR differences by age, sex, race, height, hair pigment, and season, and used univariable and multivariable linear regression models to identify HGR-related factors.Infants below 1 year (288 ± 61 μm/day) had slower HGR than children aged 2-5 years (p = 0.0073). Dark-haired children (352 ± 52 μm/day) had higher HGR than light-haired children (325 ± 50 μm/day; p = 0.0019). Asian subjects had the highest HGR overall (p = 0.016). Younger children had higher HPC (p = 0.0014) and their HPC-adjusted HGRs were slower than older children (p = 0.0073). Age, height, hair pigmentation, and HPC were related to HGR in multivariable regression models.We identified age, height, hair pigment, and hair protein concentration as significant determinants of linear HGRs. These findings help explain the known hair biomarker differences between children and adults and aid accurate interpretation of hair biomarker results in preschool children.Discovery of hair biomarkers in the past few decades has transformed scientific disciplines like toxicology, pharmacology, epidemiology, forensics, healthcare, and developmental psychology. Identifying determinants of hair growth in children is essential for accurate interpretation of hair biomarker results in pediatric clinical studies. Childhood hair growth rates define the time-periods of biomarker incorporation into growing hair, essential for interpreting the biomarkers associated with environmental exposures and the mind-brain-body connectome. Our study describes age-, sex-, and height-based distributions of linear hair growth rates and provides determinants of linear hair growth rates in a large population of children. Age, height, hair pigmentation, and hair protein content are determinants of hair growth rates and should be accounted for in child hair biomarkers studies. Our findings on hair protein content and linear hair growth rates may provide physiological explanations for differences in hair growth rates and biomarkers in preschool children as compared to adults.

    View details for DOI 10.1038/s41390-023-02791-z

    View details for PubMedID 37667034

    View details for PubMedCentralID 8630179

  • Prevalence of burnout and its relation to the neuroendocrine system among pediatric residents during the early Covid-19 pandemic: A pilot feasibility study. Comprehensive psychoneuroendocrinology Tawfik, D. S., Rovnaghi, C., Profit, J., Cornell, T. T., Anand, K. J. 2023; 14: 100174


    Background: Measuring burnout relies on infrequent and subjective surveys, which often do not reflect the underlying factors or biological mechanisms that promote or prevent it. Burnout correlates with cortisol levels and dysregulation of the hypothalamic-pituitary-adrenal axis, but the chronology and strength of this relationship are unknown.Objective: To determine the prevalence and feasibility of studying burnout in pediatric residents using hair cortisol and hair oxytocin concentrations.Design: /Methods: Longitudinal observational cohort study of pediatric residents. We assessed burnout using the Stanford Professional Fulfillment Index and hair cortisol (HCC), and hair oxytocin concentrations (HOC) at four 3-month intervals from January 2020-January 2021. We evaluated test-retest reliability, sensitivity to change using Pearson product-moment correlations, and relationships between burnout and hair biomarkers using hierarchical mixed-effects linear regression.Results: 17 Pediatrics residents provided 78 wellness surveys and 54 hair samples. Burnout symptoms were present in 39 (50%) of the surveys, with 14 (82%) residents reporting burnout in at least one time point. The lowest (41%) and highest (60%) burnout prevalence occurred in 04/2020 and 01/2021, respectively. No significant associations between burnout scores and HCC (beta -0.01, 95%CI: 0.14-0.13), HOC (beta 0.06, 95%CI: 0.06-0.19), or the HCC:HOC ratio (beta -0.04, 95%CI: 0.09-0.02) were noted in separate analyses. Intra-individual changes in hair cortisol concentration were not associated with changes in burnout score.Conclusions: Burnout was prevalent among Pediatrics residents, with highest prevalence noted in January 2021. This pilot longitudinal study demonstrates the feasibility of evaluating burnout with stress and resilience biomarkers in Pediatrics residents.

    View details for DOI 10.1016/j.cpnec.2023.100174

    View details for PubMedID 36742128

  • Performance effectiveness of vital parameter combinations for early warning of sepsis-an exhaustive study using machine learning JAMIA OPEN Rangan, E., Pathinarupothi, R., Anand, K. S., Snyder, M. P. 2022; 5 (4): ooac080


    To carry out exhaustive data-driven computations for the performance of noninvasive vital signs heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), and temperature (Temp), considered both independently and in all possible combinations, for early detection of sepsis.By extracting features interpretable by clinicians, we applied Gradient Boosted Decision Tree machine learning on a dataset of 2630 patients to build 240 models. Validation was performed on a geographically distinct dataset. Relative to onset, predictions were clocked as per 16 pairs of monitoring intervals and prediction times, and the outcomes were ranked.The combination of HR and Temp was found to be a minimal feature set yielding maximal predictability with area under receiver operating curve 0.94, sensitivity of 0.85, and specificity of 0.90. Whereas HR and RR each directly enhance prediction, the effects of SpO2 and Temp are significant only when combined with HR or RR. In benchmarking relative to standard methods Systemic Inflammatory Response Syndrome (SIRS), National Early Warning Score (NEWS), and quick-Sequential Organ Failure Assessment (qSOFA), Vital-SEP outperformed all 3 of them.It can be concluded that using intensive care unit data even 2 vital signs are adequate to predict sepsis upto 6 h in advance with promising accuracy comparable to standard scoring methods and other sepsis predictive tools reported in literature. Vital-SEP can be used for fast-track prediction especially in limited resource hospital settings where laboratory based hematologic or biochemical assays may be unavailable, inaccurate, or entail clinically inordinate delays. A prospective study is essential to determine the clinical impact of the proposed sepsis prediction model and evaluate other outcomes such as mortality and duration of hospital stay.

    View details for DOI 10.1093/jamiaopen/ooac080

    View details for Web of Science ID 000868349400001

    View details for PubMedID 36267121

    View details for PubMedCentralID PMC9566305

  • Attentional Generative Multimodal Network for Neonatal Postoperative Pain Estimation. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Salekin, M. S., Zamzmi, G., Goldgof, D., Mouton, P. R., Anand, K. J., Ashmeade, T., Prescott, S., Huang, Y., Sun, Y. 2022; 13433: 749-759


    Artificial Intelligence (AI)-based methods allow for automatic assessment of pain intensity based on continuous monitoring and processing of subtle changes in sensory signals, including facial expression, body movements, and crying frequency. Currently, there is a large and growing need for expanding current AI-based approaches to the assessment of postoperative pain in the neonatal intensive care unit (NICU). In contrast to acute procedural pain in the clinic, the NICU has neonates emerging from postoperative sedation, usually intubated, and with variable energy reserves for manifesting forceful pain responses. Here, we present a novel multi-modal approach designed, developed, and validated for assessment of neonatal postoperative pain in the challenging NICU setting. Our approach includes a robust network capable of efficient reconstruction of missing modalities (e.g., obscured facial expression due to intubation) using an unsupervised spatio-temporal feature learning with a generative model for learning the joint features. Our approach generates the final pain score along with the intensity using an attentional cross-modal feature fusion. Using experimental dataset from postoperative neonates in the NICU, our pain assessment approach achieves superior performance (AUC 0.906, accuracy 0.820) as compared to the state-of-the-art approaches.

    View details for DOI 10.1007/978-3-031-16437-8_72

    View details for PubMedID 36939418

    View details for PubMedCentralID PMC10018439

  • Can Translational Social Neuroscience Research offer Insights to Mitigate Structural Racism in America? Biological psychiatry. Cognitive neuroscience and neuroimaging Singh, M. K., Nimarko, A., Bruno, J., Anand, K. J., Singh, S. P. 2022


    Social isolation and conflict due to structural racism may result in human suffering and loneliness across the lifespan. Given the rising prevalence of these problems in America, combined with disruptions experienced during the COVID-19 pandemic, the neurobiology of affiliative behaviors may offer practical solutions to the pressing challenges associated with structural racism. Controlled experiments across species demonstrate that social connections are critical to survival, although strengthening individual resilience is insufficient to address the magnitude and impact of structural racism. In contrast, the multi-level construct of social resilience, defined by the power of groups to cultivate, engage in, and sustain positive relationships that endure and recuperate from social adversities, offers unique insights that may have greater impact, reach, and durability than individual-level interventions. Here, we review the putative social resilience-enhancing interventions and, when available, their biological mediators, with the hope to stimulate discovery of novel approaches to mitigate structural racism. We will first explore the social neuroscience principles underlying psychotherapy and other psychiatric interventions. Then, we will explore translational efforts across species to tailor treatments that increase social resilience, with context and cultural sensitivity in mind. Finally, we will conclude with some practical future directions for understudied areas that may be essential for progress in biological psychiatry, including ethical ways to increase representation in research and developing social paradigms that inform dynamics toward or away from socially resilient outcomes.

    View details for DOI 10.1016/j.bpsc.2022.05.005

    View details for PubMedID 35609781

  • The social ecology of childhood and early life adversity. Pediatric research Lopez, M., Ruiz, M. O., Rovnaghi, C. R., Tam, G. K., Hiscox, J., Gotlib, I. H., Barr, D. A., Carrion, V. G., Anand, K. J. 2021


    An increasing prevalence of early childhood adversity has reached epidemic proportions, creating a public health crisis. Rather than focusing only on adverse childhood experiences (ACEs) as the main lens for understanding early childhood experiences, detailed assessments of a child's social ecology are required to assess "early life adversity." These should also include the role of positive experiences, social relationships, and resilience-promoting factors. Comprehensive assessments of a child's physical and social ecology not only require parent/caregiver surveys and clinical observations, but also include measurements of the child's physiology using biomarkers. We identify cortisol as a stress biomarker and posit that hair cortisol concentrations represent a summative and chronological record of children's exposure to adverse experiences and other contextual stressors. Future research should use a social-ecological approach to investigate the robust interactions among adverse conditions, protective factors, genetic and epigenetic influences, environmental exposures, and social policy, within the context of a child's developmental stages. These contribute to their physical health, psychiatric conditions, cognitive/executive, social, and psychological functions, lifestyle choices, and socioeconomic outcomes. Such studies must inform preventive measures, therapeutic interventions, advocacy efforts, social policy changes, and public awareness campaigns to address early life adversities and their enduring effects on human potential. IMPACT: Current research does not support the practice of using ACEs as the main lens for understanding early childhood experiences. The social ecology of early childhood provides a contextual framework for evaluating the long-term health consequences of early life adversity. Comprehensive assessments reinforced with physiological measures and/or selected biomarkers, such as hair cortisol concentrations to assess early life stress, may provide critical insights into the relationships between early adversity, stress axis regulation, and subsequent health outcomes.

    View details for DOI 10.1038/s41390-020-01264-x

    View details for PubMedID 33462396

  • Longitudinal Trajectories of Hair Cortisol: Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Early Childhood. Frontiers in pediatrics Rovnaghi, C. R., Rigdon, J., Roue, J., Ruiz, M. O., Carrion, V. G., Anand, K. J. 2021; 9: 740343


    The objective of this study was to examine if longitudinal trajectories of hair cortisol concentrations (HCC) measured at two or three yearly time points can identify 1-3 year old children at risk for altered hypothalamic-pituitary-adrenal (HPA)-axis function due to early life stress (ELS). HCC was measured (N = 575) in 265 children using a validated enzyme-linked immunosorbent assay. Hair was sampled in Clinic Visits (CV) centered at years 1, 2, and 3 (n = 45); 1 and 2 (n = 98); 1 and 3 (n = 27); 2 and 3 (n = 95). Log-transformed HCC values were partitioned using latent class mixed models (LCMM) to minimize the Bayesian Information Criterion. Multivariable linear mixed effects models for ln-HCC as a function of fixed effects for age in months and random effects for participants (to account for repeated measures) were generated to identify the factors associated with class membership. Children in Class 1 (n = 69; 9% Black) evidenced declining ln-HCC across early childhood, whereas Class 2 members (n = 196; 43% Black) showed mixed trajectories. LCMM with only Class 2 members revealed Class 2A (n = 17, 82% Black) with sustained high ln-HCC and Class 2B (n = 179, 40% Blacks) with mixed ln-HCC profiles. Another LCMM limited to only Class 2B members revealed Class 2B1 (n = 65, 57% Black) with declining ln-HCC values (at higher ranges than Class 1), and Class 2B2 (n = 113, 30% Black) with sustained high ln-HCC values. Class 1 may represent hair cortisol trajectories associated with adaptive HPA-axis profiles, whereas 2A, 2B1, and 2B2 may represent allostatic load with dysregulated profiles of HPA-axis function in response to varying exposures to ELS. Sequential longitudinal hair cortisol measurements revealed the allostatic load associated with ELS and the potential for developing maladaptive or dysregulated HPA-axis function in early childhood.

    View details for DOI 10.3389/fped.2021.740343

    View details for PubMedID 34708011

  • Neonatal opioids and preschool outcomes. Pediatric research Anand, K. J. 2020

    View details for DOI 10.1038/s41390-020-01208-5

    View details for PubMedID 33069161

  • The newborn infant parasympathetic evaluation index for acute procedural pain assessment in preterm infants. Pediatric research Gendras, J., Lavenant, P., Sicard-Cras, I., Consigny, M., Misery, L., Anand, K. J., Sizun, J., Roue, J. 2020


    BACKGROUND: Accurate assessments of pain in hospitalized preterm infants present a major challenge in improving the short- and long-term consequences associated with painful experiences. We evaluated the ability of the newborn infant parasympathetic evaluation (NIPE) index to detect acute procedural pain in preterm infants.METHODS: Different painful and stressful interventions were prospectively observed in preterm infants born at 25+0 to 35+6 weeks gestation. Pain responses were measured using the composite Premature Infant Pain Profile Revised (PIPP-R) scale, the NIPE index, and skin conductance responses (SCR). Outcome measures were correlations between the NIPE index, the PIPP-R score, and the SCR. Sensitivity/specificity analyses tested the accuracy of the NIPE index and SCR.RESULTS: Two hundred and fifty-four procedures were recorded in 90 preterm infants. No significant correlation was found between PIPP-R and the NIPE index. PIPP-R and SCR were positively correlated (r=0.27, P<0.001), with stronger correlations for painful procedures (r=0.68, P<0.001) and especially for skin-breaking procedures (r=0.82, P<0.001). The NIPE index and SCR had high sensitivity and high negative predictive values to predict PIPP-R>10, especially for skin-breaking painful procedures.CONCLUSIONS: We found no significant correlation between the NIPE index and PIPP-R during routine painful or stressful procedures in preterm infants.IMPACT: Exposure to repetitive pain can lead to neurodevelopmental sequelae. Behavior-based pain scales have limited clinical utility, especially for preterm infants.New devices for monitoring physiological responses to pain have not been validated sufficiently in preterm infants.This study found that the NIPE index was not significantly correlated to the validated PIPP-R scale during acute procedural pain.Secondary analysis of this study showed that NIPE index and SCRs may help to exclude severe pain in preterm infants.In clinical practice, measurements of physiological parameters should be combined with behavior-based scales for multidimensional pain assessments.

    View details for DOI 10.1038/s41390-020-01152-4

    View details for PubMedID 32961546

  • Demographic and psychosocial factors associated with hair cortisol concentrations in preschool children. Pediatric research Anand, K. J., Rovnaghi, C. R., Rigdon, J., Qin, F., Tembulkar, S., Murphy, L. E., Barr, D. A., Gotlib, I. H., Tylavsky, F. A. 2019


    BACKGROUND: Early life stress has enduring effects on physical and mental health. Hair cortisol concentrations (HCCs) reflect exposures to contextual stressors in early life, but are understudied in preschool children.METHODS: Hair samples from children (N=693) during clinic visits (CVs) scheduled at 1-4 years (CV1-CV4) were measured using validated assay methods for HCC.RESULTS: HCCs were highest at CV1 and decreased at CV2-CV4, with no sex differences. Black children had higher HCC than White/other children; these differences persisted even after adjusting for socioeconomic factors. Bivariable analyses showed significant effects on HCC for Black race, with specific demographic and psychosocial factors at different ages. Multivariable analyses showed that higher HCC at CV1 were associated with Black race and male sex; at CV2 with Black race, lower maternal self-esteem, socioeconomic adversity, and the child's risk for developmental delay; at CV3 with Black race; at CV4 with maternal depression and the child's prior HCC values.CONCLUSIONS: HCCs were higher in Black children than White/other races; differences were related to maternal factors, socioeconomic adversity, and the child's risk for developmental delay. Public health measures to reduce disparities between Blacks and other races must also consider the long-term effects of chronic stress in early life.

    View details for DOI 10.1038/s41390-019-0691-2

    View details for PubMedID 31791042

  • Measuring socioeconomic adversity in early life ACTA PAEDIATRICA Anand, K. S., Rigdon, J., Rovnaghi, C. R., Qin, F., Tembulkar, S., Bush, N., LeWinn, K., Tylavsky, F. A., Davis, R., Barr, D. A., Gotlib, I. H. 2019; 108 (7): 1267–77

    View details for DOI 10.1111/apa.14715

    View details for Web of Science ID 000471904300016

  • Measuring socioeconomic adversity in early life. Acta paediatrica (Oslo, Norway : 1992) Anand, K. J., Rigdon, J., Rovnaghi, C. R., Qin, F., Tembulkar, S., Bush, N., LeWinn, K., Tylavsky, F. A., Davis, R., Barr, D. A., Gotlib, I. H. 2019


    AIM: Early life adversity in leads to enduring effects on physical and mental health, school performance, and other outcomes. We sought to identify potentially modifiable factors leading to socioeconomic adversity in early life.METHODS: We enrolled 1,503 pregnant women aged 16-40 years, without pregnancy complications or pre-existing conditions from Shelby County, Tennessee. Social, familial, and economic variables were analyzed using principal components (PCs) analyses to generate the Socioeconomic Adversity Index (SAI). This was replicated using the National Survey of Children's Health (NSCH). Health and social outcomes were compared across the quintile groups defined by SAI values at the county, state, and national levels.RESULTS: Significant differences occurred across the SAI Quintile-1 to Quintile-5 groups in marital status, household structure, annual income, education, and health insurance. Significantly worse health and social outcomes occurred in the lower vs. higher SAI quintiles, including maternal depression, parental incarceration, child's birthweight, and potential for child abuse. Maternal age and race also differed significantly across the SAI quintiles.CONCLUSION: Modifiable factors contributing to socioeconomic adversity in early life included marital status, household structure, annual income, education, and health insurance. Those exposed to greater socioeconomic adversity as defined by SAI values had significantly worse maternal and child outcomes. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30614554

  • Discovering Pain in Newborn Infants. Anesthesiology Anand, K. J. 2019


    Randomised Trial of Fentanyl Anesthesia in Preterm Babies Undergoing Surgery: Effects on the Stress Response. By Anand KJ, Sippell WG, and Aynsley-Green A. Lancet 1987; 1:243-8. Reprinted with permission.In a randomised controlled trial, preterm babies undergoing ligation of a patent ductus arteriosus were given nitrous oxide and D-tubocurarine, with (n = 8) or without (n = 8) the addition of fentanyl (10 µg/kg intravenously) to the anesthetic regimen. Major hormonal responses to surgery, as indicated by changes in plasma adrenaline, noradrenaline, glucagon, aldosterone, corticosterone, 11-deoxycorticosterone, and 11-deoxycortisol levels, in the insulin/glucagon molar ratio, and in blood glucose, lactate, and pyruvate concentrations were significantly greater in the nonfentanyl than in the fentanyl group. The urinary 3-methylhistidine/creatinine ratios were significantly greater in the nonfentanyl group on the second and third postoperative days. Compared with the fentanyl group, the nonfentanyl group had circulatory and metabolic complications postoperatively. The findings indicate that preterm babies mount a substantial stress response to surgery under anesthesia with nitrous oxide and curare and that prevention of this response by fentanyl anesthesia may be associated with an improved postoperative outcome.

    View details for DOI 10.1097/ALN.0000000000002810

    View details for PubMedID 31233407

  • Toward the elimination of bias in Pediatric Research. Pediatric research Bearer, C. n., Agostoni, C. n., Anand, K. J., Ambalavanan, N. n., Bhandari, V. n., Bliss, J. M., Bloomfield, F. n., Bonifacio, S. L., Buhimschi, I. n., Cilio, M. R., Coppes, M. n., Czinn, S. J., El-Khuffash, A. n., Embleton, N. n., Felderhoff-Müser, U. n., Ferriero, D. M., Florin, T. n., Fuentes-Afflick, E. n., Gardner, W. n., Gospe, S. M., Gunn, A. n., Gressens, P. n., Guissani, D. n., Haiden, N. n., Hauptman, M. n., Kim, K. S., Klebanoff, M. n., Lachman, P. n., Lanphear, B. n., Ozen, S. n., Roehr, C. n., Roland, D. n., Rosenblum, N. n., Schwarz, M. n., Staiano, A. n., Stroustrup, A. n., Valente, E. M., Wilson-Costello, D. n., Wynn, J. n., Molloy, E. n. 2019

    View details for DOI 10.1038/s41390-019-0583-5

    View details for PubMedID 31533126

  • Maternal experiences of trauma and hair cortisol in early childhood in a prospective cohort PSYCHONEUROENDOCRINOLOGY Slopen, N., Roberts, A. L., LeWinn, K. Z., Bush, N. R., Rovnaghi, C. R., Tylaysky, F., Anand, K. S. 2018; 98: 168–76


    Maternal trauma can have intergenerational consequences but little is known about whether maternal traumas affect key biological domains associated with mental health in their offspring. The objective of this study was to examine maternal lifetime history of traumatic events through mid-gestation in relation to offspring cortisol production in early childhood.The sample was comprised of 660 children (49.9% Black, 44.4% White) from a longitudinal study of mother-offspring dyads in Shelby County, Tennessee, followed from mid-gestation to child age 4 years (enrolled 2006-2011). Maternal lifetime history of traumatic life events were assessed mid-gestation using the Traumatic Life Events Questionnaire. Total cortisol output among offspring was measured using hair cortisol concentrations at ages 1 to 4 years.Associations of maternal trauma history with child hair cortisol varied by child's age. No association was observed at age 1 or 2. In adjusted regression models, at ages 3 and 4, offspring of mothers in the third (β = 0.99, P < .01), fourth (β=0.72, P < .05), and fifth (β=0.83, P < .01) quintiles of trauma exposure history had elevated (natural log) hair cortisol concentrations, relative to mothers in the lowest quintile (P-trend = 0.003). The associations were not attenuated after adjustment for theorized pathways, including premature birth, maternal postpartum depression, and maternal parenting stress.Maternal lifetime trauma exposures are associated with offspring hair cortisol concentrations. Future research is needed to determine intermediary mechanisms and functional significance of elevated hair cortisol concentration in young children.

    View details for PubMedID 30170311

  • Pathways from adverse childhood experiences to nervous system dysregulation. ( Internal Medicine Review Rovnaghi, C. R., Anand, K. J. 2018; 4 (10): 1-20
  • Clinical Profile Associated with Adverse Childhood Experiences: The Advent of Nervous System Dysregulation. Children (Basel, Switzerland) Elbers, J., Rovnaghi, C. R., Golianu, B., Anand, K. J. 2017; 4 (11)


    BACKGROUND: We report the prevalence of children with multiple medical symptoms in a pediatric neurology clinic, describe their symptom profiles, and explore their association with adverse childhood experiences (ACEs).METHODS: We retrospectively reviewed 100 consecutive patients from an outpatient pediatric neurology clinic. Patients were included if they were ≥5 years old and reported ≥4 symptoms that were unexplained for ≥3-months. Symptom profiles across six functional domains were recorded: (1) executive dysfunction, (2) sleep disturbances, (3) autonomic dysregulation, (4) somatization, (5) digestive symptoms, and (6) emotional dysregulation. ACEs were scored for all patients.RESULTS: Seventeen patients reported ≥4 medical symptoms. Somatization, sleep disturbances, and emotional dysregulation occurred in 100% patients, with executive dysfunction (94%), autonomic dysregulation (76%), and digestive problems (71%) in the majority. Forty-two children reported ≥1 ACE, but children with ≥4 symptoms were more likely to report ACEs compared to other children (88% vs. 33%; p < 0.0001) and had a higher median total ACE score (3 vs. 1; p < 0.001).CONCLUSIONS: Children with multiple medical symptoms should be screened for potential exposure to ACEs. A clinical profile of symptoms across multiple functional domains suggests putative neurobiological mechanisms involving stress and nervous system dysregulation that require further study.

    View details for PubMedID 29140276

  • Clinical Profile Associated with Adverse Childhood Experiences: The Advent of Nervous System Dysregulation CHILDREN-BASEL Elbers, J., Rovnaghi, C. R., Golianu, B., Anand, K. S. 2017; 4 (11)
  • Defining pain in newborns: Need for a uniform taxonomy? Acta paediatrica (Oslo, Norway : 1992) Anand, K. J. 2017


    A scientific rationale for applying pain terms such as acute, persistent, prolonged, or chronic pain to newborns was derived from the scientific literature on neonatal pain assessments, previous attempts to define chronic pain, and the clinical and neurophysiological features of neonatal pain. This novel framework incorporates the temporal features, localizing characteristics, and secondary effects of the pain experienced, as well as the behavioral and physiological response patterns of newborns.Although not evidence-based, this framework provides an initial starting point for defining commonly used neonatal pain terms. It will require future revision/refinement based on the accumulating evidence for non-acute pain. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/apa.13936

    View details for PubMedID 28556311

  • Assessment of Continuous Pain in Newborns admitted to NICUs in 18 European Countries. Acta paediatrica Anand, K. J., Eriksson, M., Boyle, E. M., Avila-Alvarez, A., Andersen, R. D., Sarafidis, K., Polkki, T., Matos, C., Lago, P., Papadouri, T., Attard-Montalto, S., Ilmoja, M., Simons, S., Tameliene, R., Van Overmeire, B., Berger, A., Dobrzanska, A., Schroth, M., Bergqvist, L., Courtois, E., Rousseau, J., Carbajal, R. 2017


    Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown.A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission.Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001).Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.

    View details for DOI 10.1111/apa.13810

    View details for PubMedID 28257153

  • Does noninvasive electrical stimulation of acupuncture points reduce heelstick pain in neonates? Acta paediatrica Mitchell, A. J., Hall, R. W., Golianu, B., Yates, C., Williams, D. K., Chang, J., Anand, K. J. 2016


    Noninvasive electrical stimulation at acupuncture points (NESAP) for analgesia is used in children, but has not been widely studied in neonates. The purpose of this study was to determine whether NESAP alone or in combination with sucrose relieved heelstick pain in neonates.Term neonates (n = 162) receiving routine heelsticks for newborn screening were enrolled following parental consent. All infants received facilitated tucking and non-nutritive sucking. Neonates were randomised to standard care, sucrose, NESAP or sucrose plus NESAP. NESAP (3.5 mA, 10 Hz) or sham was administered over four acupuncture points. The Premature Infant Pain Profile (PIPP), heart rate variability (HRV) and salivary cortisol were used to measure heelstick pain.PIPP scores among all four treatment groups increased during heelstick, F (9,119) = 1.95, p = 0.05 and NESAP therapy had no significant effect on PIPP scores. However, PIPP scores from baseline to heelstick increased the most in the two groups not receiving sucrose (p < 0.01). Mean PIPP scores remained below five during the heelstick in all four groups, indicating minimal or no pain. Differences in HRV and salivary cortisol among groups were insignificant.NESAP at 3.5 mA, 10 Hz is not effective in relieving pain during heelsticks in neonates.

    View details for DOI 10.1111/apa.13581

    View details for PubMedID 27607517

    View details for PubMedCentralID PMC5118154

  • Epidemiology and neonatal pain management of heelsticks in intensive care units: EPIPPAIN 2, a prospective observational study. International journal of nursing studies Courtois, E., Droutman, S., Magny, J. F., Merchaoui, Z., Durrmeyer, X., Roussel, C., Biran, V., Eleni, S., Vottier, G., Renolleau, S., Desfrere, L., Castela, F., Boimond, N., Mellah, D., Bolot, P., Coursol, A., Brault, D., Chappuy, H., Cimerman, P., Anand, K. J., Carbajal, R. 2016; 59: 79-88


    Heelstick is the most frequently performed skin-breaking procedure in the neonatal intensive care units (NICUs). There are no large multicenter studies describing the frequency and analgesic approaches used for heelsticks performed in NICUs.To describe the frequency of heelsticks and their analgesic management in newborns in the NICU. To determine the factors associated with the lack of specific preprocedural analgesia for this procedure.EPIPPAIN 2 (Epidemiology of Procedural PAin In Neonates) is a descriptive prospective epidemiologic study.All 16 NICUs in the Paris region in France.All newborns in the NICU with a maximum corrected age of 44 weeks +6 days of gestation on admission who had at least one heelstick during the study period were eligible for the study. The study included 562 newborns.Data on all heelsticks and their corresponding analgesic therapies were prospectively collected. The inclusion period lasted six weeks, from June 2, 2011 to July 12, 2011. Newborns were followed from their admission to the 14th day of their NICU stay or discharge, whichever occurred first.The mean (SD) gestational age was 33.3 (4.4) weeks and duration of participation was 7.5 (4.4) days. The mean (SD; range) of heelsticks per neonate was 16.0 (14.4; 1-86) during the study period. Of the 8995 heelsticks studied, 2379 (26.4%) were performed with continuous analgesia, 5236 (58.2%) with specific preprocedural analgesia. Overall, 6764 (75.2%) heelsticks were performed with analgesia (continuous and/or specific). In a multivariate model, the increased lack of preprocedural analgesia was associated with female sex, term birth, high illness severity, tracheal or noninvasive ventilation, parental absence and use of continuous sedation/analgesia.Heelstick was very frequently performed in NICUs. Although, most heelsticks were performed with analgesia, this was not systematic. The high frequency of this procedure and the known adverse effects of repetitive pain in neonates should encourage the search of safe and effective strategies to reduce their number.

    View details for DOI 10.1016/j.ijnurstu.2016.03.014

    View details for PubMedID 27222453

  • Revisiting a dilemma: repetitive pain vs. opioid exposures? ACTA PAEDIATRICA Anand, K. J. 2016; 105 (7): 736-737

    View details for DOI 10.1111/apa.13442

    View details for Web of Science ID 000378565100012

    View details for PubMedID 27272629

  • The validity and reliability of the EValuation of INtervention Scale: preliminary report ACTA PAEDIATRICA Warren, I., Hicks, B., Kleberg, A., Eliahoo, J., Anand, K. J., Hickson, M. 2016; 105 (6): 618-622


    Pain management is a priority for infants receiving neonatal care as they undergo many necessary painful and stressful interventions, which are associated with negative short- or long-term consequences. This study aims to validate the content, and test the reliability, of the EValuation of INtervention Scale (EVIN), which is designed to evaluate the use of widely recommended nonpharmacological strategies to reduce neonatal pain and stress during procedures.The content of the EVIN was validated with multidisciplinary participation (N = 80), and consistency was established via observations on preterm infants (N = 12, at 31-34 weeks' gestation) during interventions in a neonatal unit. A revised scale was tested for inter-rater reliability with observations of invasive (blood sampling, N = 16) and noninvasive (nappy change, N = 18) interventions. The intraclass correlation coefficient (ICC) was used to determine inter-rater reliability. SPSS (PASW Statistics) version 18 was used for analysis.Very good intraclass correlation coefficients (>0.8) for both invasive (0.962) and noninvasive procedures (0.970) were achieved.These results indicate that the EVIN is suitable for the evaluation of nonpharmacological support during painful or stressful interventions.

    View details for DOI 10.1111/apa.13370

    View details for Web of Science ID 000376265400017

    View details for PubMedID 26896153

  • Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions ACTA ANAESTHESIOLOGICA SCANDINAVICA Dong, C., Rovnaghi, C. R., Anand, K. J. 2016; 60 (5): 579-587


    Developmental neurotoxicity of ketamine, an N-methyl-d-aspartate receptor antagonist, must be considered due to its widespread uses for sedation/analgesia/anesthesia in pediatric and obstetric settings. Dose-dependent effects of ketamine on cellular proliferation in the neurogenic regions of rat fetal cortex [ventricular zone (VZ) and subventricular zone (SVZ)] were investigated in this in vivo study.Timed-pregnant Sprague-Dawley rats at embryonic day 17 (E17) were given with different doses of ketamine intraperitoneally (0, 1, 2, 10, 20, 40, and 100 mg/kg). Proliferating cells in the rat fetal brains were labeled by injecting 100 mg/kg of 5-bromo-2'-deoxyuridine (BrdU) intraperitoneally. BrdU-labeled cells were detected by immunostaining methods. The numbers of BrdU-positive cells in VZ and SVZ of rat fetal cortex were employed to quantify proliferation in the developing rat cortex.Ketamine dose-dependently reduced the number of BrdU-positive cells in VZ (P < 0.001) and SVZ (P < 0.001) of the rat fetal cortex. SVZ showed greater susceptibility to ketamine-induced reduction of proliferation in rat fetal cortex, occurring even at clinically relevant doses (2 mg/kg).These data suggest that exposure to ketamine during embryogenesis can dose-dependently inhibit the cellular proliferation in neurogenic regions of the rat fetal cortex.

    View details for DOI 10.1111/aas.12689

    View details for Web of Science ID 000373773700004

    View details for PubMedID 26822861

  • Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial CYTOKINE Schwingshackl, A., Kimura, D., Rovnaghi, C. R., Saravia, J. S., Cormier, S. A., Teng, B., West, A. N., Meduri, U. G., Anand, K. J. 2016; 77: 63-71


    A double-blind, randomized controlled trial showed that low-dose glucocorticoid therapy in pediatric ARDS patients is feasible and may improve both ventilation and oxygenation indices in these patients. However, the molecular mechanisms underlying potential changes in outcomes remain unclear. Based on these clinical findings, this study was designed to examine the effects of intravenous methylprednisolone on circulating inflammatory biomarkers in pediatric ARDS patients.Double-blind, placebo-controlled randomized trial with blood collection on study entry and day 7.Tertiary care children's hospital.Children (0-18years) with ARDS undergoing mechanical ventilation.35 children were randomized within 72h of mechanical ventilation. The glucocorticoid group received methylprednisolone 2mg/kg loading dose followed by 1mg/kg/day continuous infusion from days 1 to 7. Both groups were ventilated following the ARDSnet recommendations. WBC and differential cell counts, plasma cytokines and CRP levels, and coagulation parameters were analyzed on days 0 and 7.At study entry, the placebo group had higher IL-15 and basophil levels. On day 7, in comparison to study entry, the placebo group had lower IL-1α, IFN-γ and IL-10 levels. The glucocorticoid group had lower INF-α, IL-6, IL-10, MCP-1, G-CSF and GM-CSF levels, and higher IL-17α levels on day 7 in comparison to study entry. Total and differential cell counts remained unchanged within the placebo group between days 0 and 7, whereas in the glucocorticoid group total WBC and platelets counts were increased on day 7. Pearson's correlation studies within the placebo and glucocorticoid groups revealed positive and negative correlations between cytokine levels, cell counts, coagulation parameters and relevant clinical parameters of disease severity identified in our previous study. Multiple regression models identified several cytokines as predictors for alterations in clinical parameters of disease severity.This pilot study shows the feasibility of simultaneously measuring multiple inflammatory cytokines, cell counts and coagulation parameters in pediatric ARDS patients. We report statistical models that may be useful for future, larger trials to predict ARDS severity and outcomes.

    View details for DOI 10.1016/j.cyto.2015.10.007

    View details for PubMedID 26545141

    View details for PubMedCentralID PMC4666843

  • Plasma Biomarker Analysis in Pediatric ARDS: Generating Future Framework from a Pilot Randomized Control Trial of Methylprednisolone: A Framework for Identifying Plasma Biomarkers Related to Clinical Outcomes in Pediatric ARDS. Frontiers in pediatrics Kimura, D., Saravia, J., Rovnaghi, C. R., Meduri, G. U., Schwingshackl, A., Cormier, S. A., Anand, K. J. 2016; 4: 31-?


    Lung injury activates multiple pro-inflammatory pathways, including neutrophils, epithelial, and endothelial injury, and coagulation factors leading to acute respiratory distress syndrome (ARDS). Low-dose methylprednisolone therapy (MPT) improved oxygenation and ventilation in early pediatric ARDS without altering duration of mechanical ventilation or mortality. We evaluated the effects of MPT on biomarkers of endothelial [Ang-2 and soluble intercellular adhesion molecule-1 (sICAM-1)] or epithelial [soluble receptor for activated glycation end products (sRAGE)] injury, neutrophil activation [matrix metalloproteinase-8 (MMP-8)], and coagulation (plasminogen activator inhibitor-1).Double-blind, placebo-controlled randomized trial.Tertiary-care pediatric intensive care unit (ICU).Mechanically ventilated children (0-18 years) with early ARDS.Blood samples were collected on days 0 (before MPT), 7, and 14 during low-dose MPT (n = 17) vs. placebo (n = 18) therapy. The MPT group received a 2-mg/kg loading dose followed by 1 mg/kg/day continuous infusions from days 1 to 7, tapered off over 7 days; placebo group received equivalent amounts of 0.9% saline. We analyzed plasma samples using a multiplex assay for five biomarkers of ARDS. Multiple regression models were constructed to predict associations between changes in biomarkers and the clinical outcomes reported earlier, including P/F ratio on days 8 and 9, plateau pressure on days 1 and 2, PaCO2 on days 2 and 3, racemic epinephrine following extubation, and supplemental oxygen at ICU discharge.No differences occurred in biomarker concentrations between the groups on day 0. On day 7, reduction in MMP-8 levels (p = 0.0016) occurred in the MPT group, whereas increases in sICAM-1 levels (p = 0.0005) occurred in the placebo group (no increases in sICAM-1 in the MPT group). sRAGE levels decreased in both MPT and placebo groups (p < 0.0001) from day 0 to day 7. On day 7, sRAGE levels were positively correlated with MPT group PaO2/FiO2 ratios on day 8 (r = 0.93, p = 0.024). O2 requirements at ICU transfer positively correlated with day 7 MMP-8 (r = 0.85, p = 0.016) and Ang-2 levels (r = 0.79, p = 0.036) in the placebo group and inversely correlated with day 7 sICAM-1 levels (r = -0.91, p = 0.005) in the MPT group.Biomarkers selected from endothelial, epithelial, or intravascular factors can be correlated with clinical endpoints in pediatric ARDS. For example, MPT could reduce neutrophil activation (⇓MMP-8), decrease endothelial injury (⇔sICAM-1), and allow epithelial recovery (⇓sRAGE). Large ARDS clinical trials should develop similar frameworks., NCT01274260.

    View details for DOI 10.3389/fped.2016.00031

    View details for PubMedID 27066464

    View details for PubMedCentralID PMC4815896

  • Research as a Standard of Care in the PICU PEDIATRIC CRITICAL CARE MEDICINE Zimmerman, J. J., Anand, K. J., Meert, K. L., Willson, D. F., Newth, C. J., Harrison, R., Carcillo, J. A., Berger, J., Jenkins, T. L., Nicholson, C., Dean, J. M. 2016; 17 (1): E13-E21


    Excellence in clinical care coupled with basic and applied research reflects the maturation of a medical subspecialty, advances that field, and provides objective data for identifying best practices. PICUs are uniquely suited for conducting translational and clinical research. In addition, multiple investigations have reported that a majority of parents are interested in their children's participation in clinical research, even when the research offers no direct benefit to their child. However, such activity may generate ethical conflict with bedside care providers trying to acutely identify the best approach for an individual critically ill child. Ultimately, this conflict may diminish enthusiasm for the generation of scientific evidence that supports the application of evidence-based medicine into PICU clinical standard work. Accordingly this review endeavors to provide an overview of current state PICU clinical research strengths, liabilities, opportunities, and barriers and contrast this with an established pediatric hematology-oncology iterative research model that constitutes a learning healthcare system.Narrative review of medical literature published in English.Currently, most PICU therapy is not evidence based. Developing a learning healthcare system in the PICU integrates clinical research into usual practice and fosters a culture of evidence-based learning and continual care improvement. As PICU mortality has significantly decreased, identification and validation of patient-centered, clinically relevant research outcome measures other than mortality is essential for future clinical trial design. Because most pediatric critical illness may be classified as rare diseases, participation in research networks will facilitate iterative, collaborative, multiinstitutional investigations that over time identify the best practices to improve PICU outcomes. Despite real ethical challenges, critically ill children and their families should have the opportunity to participate in translational/clinical research whenever feasible.

    View details for DOI 10.1097/PCC.0000000000000562

    View details for Web of Science ID 000367745900002

    View details for PubMedID 26513203

  • Methodological Considerations for Hair Cortisol Measurements in Children THERAPEUTIC DRUG MONITORING Slominski, R., Rovnaghi, C. R., Anand, K. J. 2015; 37 (6): 812-820


    Hair cortisol levels are used increasingly as a measure for chronic stress in young children. We propose modifications to the current methods used for hair cortisol analysis to more accurately determine reference ranges for hair cortisol across different populations and age groups.The authors compared standard (finely cutting hair) versus milled methods for hair processing (n = 16), developed a 4-step extraction process for hair protein and cortisol (n = 16), and compared liquid chromatography-mass spectrometry (LC-MS) versus enzyme-linked immunosorbent assays (ELISAs) for measuring hair cortisol (n = 28). The extraction process included sequential incubations in methanol and acetone, repeated twice. Hair protein was measured through spectrophotometric ratios at 260/280 nm to indicate the hair dissolution state using a BioTek plate reader and dedicated software. Hair cortisol was measured using an ELISA assay kit. Individual (n = 13), pooled hair samples (n = 12) with high, intermediate, and low cortisol values, and the ELISA assay internal standards (n = 3) were also evaluated by LC-MS.Milled and standard methods showed highly correlated hair cortisol (rs = 0.951, P < 0.0001) and protein values (rs = 0.902, P = 0.0002), although higher yields of cortisol and protein were obtained from the standard method in 13 of 16 and 14 of 16 samples, respectively (P < 0.05). Four sequential extractions yielded additional amounts of protein (36.5%, 27.5%, 30.5%, 3.1%) and cortisol (45.4%, 31.1%, 15.1%, 0.04%) from hair samples. Cortisol values measured by LC-MS and ELISA were correlated (rs = 0.737; P < 0.0001), although cortisol levels [median (interquartile range)] detected in the same samples by LC-MS [38.7 (14.4-136) ng/mL] were lower than that by ELISA [172.2 (67.9-1051) ng/mL]. LC-MS also detected cortisone, which comprised of 13.4% (3.7%-25.9%) of the steroids detected.Methodological studies suggest that finely cutting hair with sequential incubations in methanol and acetone, repeated twice, extracts greater yields of cortisol than does milled hair. Based on these findings, at least 3 incubations may be required to extract most of the cortisol in human hair samples. In addition, ELISA-based assays showed greater sensitivity for measuring hair cortisol levels than LC-MS-based assays.

    View details for DOI 10.1097/FTD.0000000000000209

    View details for Web of Science ID 000365594600017

    View details for PubMedID 25811341

  • Long-Acting Opioids for Treating Neonatal Abstinence Syndrome A High Price for a Short Stay? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Peltz, G., Anand, K. J. 2015; 314 (19): 2023-2024

    View details for DOI 10.1001/jama.2015.13537

    View details for PubMedID 26469386

  • Corticosteroids in pediatric ARDS: all cards on the table INTENSIVE CARE MEDICINE Schwingshackl, A., Meduri, G. U., Kimura, D., Cormier, S. A., Anand, K. J. 2015; 41 (11): 2036-2037

    View details for DOI 10.1007/s00134-015-4027-3

    View details for Web of Science ID 000361829900043

    View details for PubMedID 26359160

    View details for PubMedCentralID PMC4584398

  • Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study LANCET RESPIRATORY MEDICINE Carbajal, R., Eriksson, M., Courtois, E., Boyle, E., Avila-Alvarez, A., Andersen, R. D., Sarafidis, K., Polkki, T., Matos, C., Lago, P., Papadouri, T., Montalto, S. A., Ilmoja, M., Simons, S., Tameliene, R., Van Overmeire, B., Berger, A., Dobrzanska, A., Schroth, M., Bergqvist, L., Lagercrantz, H., Anand, K. J. 2015; 3 (10): 796-812


    Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries.EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with, number NCT01694745.From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35.0 weeks (SD 4.6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0.0001). In the participating NICUs, the median use of sedation or analgesia was 89.3% (70.0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0.0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136.2 h [SD 173.1] vs 39.8 h [94.7] h; p<0.0001). Multivariable and propensity score analyses confirmed this association (p<0.0001).Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia.European Community's Seventh Framework Programme.

    View details for DOI 10.1016/S2213-2600(15)00331-8

    View details for Web of Science ID 000362452900023

    View details for PubMedID 26420017

  • Pediatric Intensive Care Unit Mortality Among Latino Children Before and After a Multilevel Health Care Delivery Intervention JAMA PEDIATRICS Anand, K. J., Sepanski, R. J., Giles, K., Shah, S. H., Juarez, P. D. 2015; 169 (4): 383-390


    Research on health equity has focused on documenting health care disparities or understanding factors leading to disparities, but limited efforts have focused on reducing health care disparities in children. Latino children have increased prevalence of acute and chronic conditions; they have limited access and other barriers to high-quality health care, including intensive care.To determine whether pediatric intensive care unit mortality can be reduced by a multilevel health care delivery intervention.Observational study of factors associated with pediatric intensive care unit mortality at a tertiary care metropolitan children's hospital in Memphis, Tennessee. Participants were children younger than 18 years discharged from the pediatric intensive care unit during the 3-year preintervention period of 2007 to 2009 (n = 3891) and 3-year postintervention period of 2010 to 2012 (n = 4179).Multilevel health care intervention to address the increased odds of mortality among Latino children.The odds of mortality were analyzed over the 3-year preintervention period (2007-2009) using multivariable logistic regressions to control for age, sex, race/ethnicity, severity of illness, major diagnostic categories, diagnosed infections, and insurance status. Data from the postintervention period (2010-2012) were analyzed similarly to measure the effect of changes in health care delivery.Unadjusted mortality rates for white, African American, and Latino children in 2007 to 2009 were 3.3%, 3.3%, and 8.6%, respectively. After controlling for covariates, no differences in the odds of mortality were observed between white children and African American children (odds ratio [OR], 1.0; 95% CI, 0.6-1.7; P = .97), but Latino children had 3.7-fold (95% CI, 1.8-7.5; P < .001) higher odds of mortality. A multilevel and multidisciplinary intervention was launched to address these differences. In the postintervention period, unadjusted mortality rates for white, African American, and Latino children were 3.6%, 3.2%, and 4.0%, respectively, with no differences observed after adjustment for covariates (OR, 0.7; 95% CI, 0.2-2.1; P = .49). The odds of mortality decreased between the preintervention period and postintervention period for Latino children (OR, 0.24; 95% CI, 0.06-0.88; P = .03) but remained unchanged for white and African American children (OR, 1.02; 95% CI, 0.73-1.43; P = .90).Latino children had higher odds of mortality, even after controlling for age, sex, severity of illness, insurance status, and other covariates. These differences disappeared after culturally and linguistically sensitive interventions at multiple levels. Local multilevel interventions can reduce the effect of health care inequities on clinical outcomes, without requiring major changes in health care policy.

    View details for DOI 10.1001/jamapediatrics.2014.3789

    View details for Web of Science ID 000354995600022

    View details for PubMedID 25706478

  • Double-blind, placebo-controlled pilot randomized trial of methylprednisolone infusion in pediatric acute respiratory distress syndrome. Pediatric critical care medicine Drago, B. B., Kimura, D., Rovnaghi, C. R., Schwingshackl, A., Rayburn, M., Meduri, G. U., Anand, K. J. 2015; 16 (3): e74-81


    Low-dose methylprednisolone therapy in adults with early acute respiratory distress syndrome reduces systemic inflammation, duration of mechanical ventilation, and ICU length of stay. We report a pilot randomized trial of glucocorticoid treatment in early pediatric acute respiratory distress syndrome.Double-blind, placebo-controlled randomized clinical trial.Le Bonheur Children's Hospital, Memphis, TN.Children (0-18 yr) with acute respiratory distress syndrome undergoing mechanical ventilation.Patients were randomly assigned to steroid or placebo groups within 72 hours of intubation. IV methylprednisolone administered as loading dose (2 mg/kg) and continuous infusions (1 mg/kg/d) on days 1-7 and then tapered over days 8-14. Both groups were ventilated according to the Acute Respiratory Distress Syndrome Network protocol modified for children. Daily surveillance was performed for adverse effects.Thirty-five patients were randomized to the steroid (n = 17, no death) and placebo groups (n = 18, two deaths). No differences occurred in length of mechanical ventilation, ICU stay, hospital stay, or mortality between the two groups. At baseline, higher plateau pressures (p = 0.006) and lower Pediatric Logistic Organ Dysfunction scores (p = 0.04) occurred in the steroid group; other characteristics were similar. Despite higher plateau pressures on days 1 (p = 0.006) and 2 (p = 0.025) due to poorer lung compliance in the steroid group, they had lower PaCO2 values on days 2 (p = 0.009) and 3 (p = 0.014), higher pH values on day 2 (p = 0.018), and higher PaO2/FIO2 ratios on days 8 (p = 0.047) and 9 (p = 0.002) compared with the placebo group. Fewer patients in the steroid group required treatment for postextubation stridor (p = 0.04) or supplemental oxygen at ICU transfer (p = 0.012). Steroid therapy was not associated with detectable adverse effects.This study demonstrates the feasibility of administering low-dose glucocorticoid therapy and measuring clinically relevant outcomes in pediatric acute respiratory distress syndrome. Changes in oxygenation and/or ventilation are consistent with early acute respiratory distress syndrome pathophysiology and results of similar clinical trials in adults. We propose and design a larger randomized trial to define the role of glucocorticoid therapy in pediatric acute respiratory distress syndrome.

    View details for DOI 10.1097/PCC.0000000000000349

    View details for PubMedID 25634565

  • Clinical risk factors for central line-associated venous thrombosis in children. Frontiers in pediatrics Shah, S. H., West, A. N., Sepanski, R. J., Hannah, D., May, W. N., Anand, K. J. 2015; 3: 35-?


    Identifying risk factors related to central venous line (CVL) placement could potentially minimize central line-associated venous thrombosis (CLAVT). We sought to identify the clinical factors associated with CLAVT in children.Over a 3-year period, 3733 CVLs were placed at a tertiary-care children's hospital. Data were extracted from the electronic medical records of patients with clinical signs and symptoms of venous thromboembolism, diagnosed using Doppler ultrasonography and/or echocardiography. Statistical analyses examined differences in CLAVT occurrence between groups based on patient and CVL characteristics (type, brand, placement site, and hospital unit).Femoral CVL placement was associated with greater risk for developing CLAVT (OR 11.1, 95% CI 3.9-31.6, p < 0.0001). CVLs placed in the NICU were also associated with increased CLAVT occurrence (OR 5.3, 95% CI 2.1-13.2, p = 0.0003). CVL brand was also significantly associated with risk of CLAVT events.Retrospective analyses identified femoral CVL placement and catheter type as independent risk factors for CLAVT, suggesting increased risks due to mechanical reasons. Placement of CVLs in the NICU also led to an increased risk of CLAVT, suggesting that small infants are at increased risk of thrombotic events. Alternative strategies for CVL placement, thromboprophylaxis, and earlier diagnosis may be important for reducing CLAVT events.

    View details for DOI 10.3389/fped.2015.00035

    View details for PubMedID 26000265

  • Pain Management in Newborns CLINICS IN PERINATOLOGY Hall, R. W., Anand, K. J. 2014; 41 (4): 895-?


    As a standard of care for preterm/term newborns effective pain management may improve their clinical and neurodevelopmental outcomes. Neonatal pain is assessed using context-specific, validated, and objective pain methods, despite the limitations of currently available tools. Therapeutic approaches reducing invasive procedures and using pharmacologic, behavioral, or environmental measures are used to manage neonatal pain. Nonpharmacologic approaches like kangaroo care, facilitated tucking, non-nutritive sucking, sucrose, and others can be used for procedural pain or adjunctive therapy. Local/topical anesthetics, opioids, NSAIDs/acetaminophen and other sedative/anesthetic agents can be incorporated into NICU protocols for managing moderate/severe pain or distress in all newborns.

    View details for DOI 10.1016/j.clp.2014.08.010

    View details for Web of Science ID 000346216900011

    View details for PubMedID 25459780

    View details for PubMedCentralID PMC4254489

  • Chronic Pain in the Newborn Toward a Definition CLINICAL JOURNAL OF PAIN van Ganzewinkel, C., Anand, K. J., Kramer, B. W., Andriessen, P. 2014; 30 (11): 970-977


    Chronic pain is poorly addressed in neonatal pain research. We aimed at contributing to define the concept of chronic pain in the newborn.We designed a Web-based, 3-round Delphi survey. We invited an international panel of experts (health care providers and parents) in the fields of neonatology and neonatal pain to participate.In the first round, participants (n=189) answered 3 open-ended questions: (1) define chronic pain in your own words, (2) what are the possible causes, and (3) which signs and symptoms are used to diagnose chronic pain? The answers were categorized and summarized into 437 statements, which were valued by the participants (n=189) on a 5-point Likert scale. In the second round, the remaining participants (n=72) were asked to reflect on 65 selected statements with a mode or median ≥4 or mean ≥3.75. These threshold values provided the opportunity to reach consensus in the following round. In the third round, the remaining participants (n=33) were provided with the group and individual responses. This process resulted in 23 statements with mode, mean, and median of ≥4, on which the participants reached consensus.Although several etiologic factors were defined, no useful diagnostic criterion could be identified. The survey resulted in a description of chronic pain in the newborn. Identifying chronic pain is clinically relevant because it interferes with growth, prolongs hospitalization, leads to altered pain perception, and impairs cognitive and behavioral development.

    View details for DOI 10.1097/AJP.0000000000000056

    View details for Web of Science ID 000343247000006

    View details for PubMedID 24296909

  • Ketamine Affects the Neurogenesis of Rat Fetal Neural Stem Progenitor Cells via the PI3K/Akt-p27 Signaling Pathway BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY Dong, C., Rovnaghi, C. R., Anand, K. J. 2014; 101 (5): 355-363


    Ketamine is widely used as an anesthetic, analgesic, or sedative in pediatric patients. We reported that ketamine alters the normal neurogenesis of rat fetal neural stem progenitor cells (NSPCs) in the developing brain, but the underlying mechanisms remain unknown. The PI3K-PKB/Akt (phosphatidylinositide 3-kinase/protein kinase B) signaling pathway plays many important roles in cell survival, apoptosis, and proliferation. We hypothesized that PI3K-PKB/Akt signaling may be involved in ketamine-altered neurogenesis of cultured NSPCs in vitro. NSPCs were isolated from Sprague-Dawley rat fetuses on gestational day 17. 5-bromo-2'-deoxyuridine (BrdU) incorporation, Ki67 staining, and differentiation tests were utilized to identify primary cultured NSPCs. Immunofluorescent staining was used to detect Akt expression, whereas Western blots measured phosphorylated Akt and p27 expression in NSPCs exposed to different treatments. We report that cultured NSPCs had properties of neurogenesis: proliferation and neural differentiation. PKB/Akt was expressed in cultured rat fetal cortical NSPCs. Ketamine inhibited the phosphorylation of Akt and further enhanced p27 expression in cultured NSPCs. All ketamine-induced PI3K/Akt signaling changes could be recovered by N-methyl-d-aspartate (NMDA) receptor agonist, NMDA. These data suggest that the inhibition of PI3K/Akt-p27 signaling may be involved in ketamine-induced neurotoxicity in the developing brain, whereas excitatory NMDA receptor activation may reverse these effects.

    View details for DOI 10.1002/bdrb.21119

    View details for Web of Science ID 000344449800002

    View details for PubMedID 25231110

    View details for PubMedCentralID PMC4330101

  • A Single Nucleotide Polymorphism in the Corticotropin Receptor Gene Is Associated With a Blunted Cortisol Response During Pediatric Critical Illness PEDIATRIC CRITICAL CARE MEDICINE Jardine, D., Emond, M., Meert, K. L., Harrison, R., Carcillo, J. A., Anand, K. J., Berger, J., Newth, C. J., Willson, D. F., Nicholson, C., Dean, J. M., Zimmerman, J. J. 2014; 15 (8): 698-705


    The cortisol response during critical illness varies widely among patients. Our objective was to examine single nucleotide polymorphisms in candidate genes regulating cortisol synthesis, metabolism, and activity to determine if genetic differences were associated with variability in the cortisol response among critically ill children.This was a prospective observational study employing tag single nucleotide polymorphism methodology to examine genetic contributions to the variability of the cortisol response in critical illness. Thirty-one candidate genes and 31 ancestry markers were examined.Patients were enrolled from seven pediatric critical care units that constitute the Eunice Kennedy Shriver Collaborative Pediatric Critical Care Research Network.Critically ill children (n = 92), age 40 weeks gestation to 18 years old, were enrolled.Blood samples were obtained from all patients for serum cortisol measurements and DNA isolation. Demographic and illness severity data were collected.Single nucleotide polymorphisms were tested for association with serum free cortisol concentrations in context of higher illness severity as quantified by Pediatric Risk of Mortality III score greater than 7. A single nucleotide polymorphism (rs1941088) in the MC2R gene was strongly associated (p = 0.0005) with a low free cortisol response to critical illness. Patients with the AA genotype were over seven times more likely to have a low free cortisol response to critical illness than those with a GG genotype. Patients with the GA genotype exhibited an intermediate free cortisol response to critical illness.The A allele at rs1941088 in the MC2R gene, which encodes the adrenocorticotropic hormone (corticotropin, ACTH) receptor, is associated with a low cortisol response in critically ill children. These data provide evidence for a genetic basis for a portion of the variability in cortisol production during critical illness. Independent replication of these findings will be important and could facilitate development of personalized treatment for patients with a low cortisol response to severe illness.

    View details for DOI 10.1097/PCC.0000000000000193

    View details for Web of Science ID 000343049200006

    View details for PubMedID 25055195

    View details for PubMedCentralID PMC4712687

  • Pediatric critical care: grand challenges for a glowing future. Frontiers in pediatrics Anand, K. J. 2014; 2: 35-?

    View details for DOI 10.3389/fped.2014.00035

    View details for PubMedID 24818121

  • Eight Years Later, Are We Still Hurting Newborn Infants? NEONATOLOGY Roofthooft, D. W., Simons, S. H., Anand, K. J., Tibboel, D., van Dijk, M. 2014; 105 (3): 218-226


    To study whether new pharmacological and nonpharmacological guidelines lowered numbers of painful procedures in neonates and changed the amount and frequency of analgesic therapy as compared to the results of our previous study in 2001.A prospective observational study.Level III NICU of the Erasmus MC-Sophia Children's Hospital, Rotterdam.Neonates admitted at postnatal ages less than 3 days with length of stay at least 72 h.Number of all potentially painful procedures and analgesic therapy recorded at the bedside during the first 14 days of NICU stay.A total number of 21,076 procedures were performed in the 175 neonates studied during 1,730 patient-days (mean 12.2). The mean number of painful procedures per neonate per day was 11.4 (SD 5.7), significantly lower than the number of 14.3 (SD 4.0) in 2001 (p < 0.001). The use of analgesics was 36.6% compared to 60.3% in 2001. Sixty-three percent of all peripheral arterial line insertions failed versus 37.5% in 2001 and 9.1% venipunctures failed versus 21% in 2001.The mean number of painful procedures per NICU patient per day declined. Nonpharmacological pain- or stress-reducing strategies like NIDCAP and sucrose were fully embedded in our pain management. As further reduction of the number of painful procedures is unlikely, we should apply more nonpharmacological interventions and explore newer pharmacological agents.

    View details for DOI 10.1159/000357207

    View details for Web of Science ID 000333321100010

    View details for PubMedID 24503902

  • Early Adversity, Socioemotional Development, and Stress in Urban 1-Year-Old Children JOURNAL OF PEDIATRICS Palmer, F. B., Anand, K. J., Graff, J. C., Murphy, L. E., Qu, Y., Voelgyi, E., Rovnaghi, C. R., Moore, A., Tran, Q. T., Tylavsky, F. A. 2013; 163 (6): 1733-U291


    To determine demographic, maternal, and child factors associated with socioemotional (SE) problems and chronic stress in 1-year-old children.This was a prospective, longitudinal, community-based study, which followed mother-infant dyads (n = 1070; representative of race, education, and income status of Memphis/Shelby County, Tennessee) from midgestation into early childhood. Child SE development was measured using the Brief Infant-Toddler Social and Emotional Assessment in all 1097 1-year-olds. Chronic stress was assessed by hair cortisol in a subsample of 1-year-olds (n = 297). Multivariate regression models were developed to predict SE problems and hair cortisol levels.More black mothers than white mothers reported SE problems in their 1-year-olds (32.9% vs 10.2%; P < .001). In multivariate regression, SE problems in blacks were predicted by lower maternal education, greater parenting stress and maternal psychological distress, and higher cyclothymic personality score. In whites, predictors of SE problems were Medicaid insurance, higher maternal depression score at 1 year, greater parenting stress and maternal psychological distress, higher dysthymic personality score, and male sex. SE problem scores were associated with higher hair cortisol levels (P = .01). Blacks had higher hair cortisol levels than whites (P < .001). In the entire subsample, increased hair cortisol levels were associated with higher parenting stress (P = .001), lower maternal depression score (P = .01), lower birth length (P < .001), and greater length at 1 year of age (P = .003).Differences in maternal education, insurance, mental health, and early stress may disrupt SE development in children. Complex relationships between hair cortisol level in 1-year-olds and maternal parenting stress and depression symptoms suggest dysregulation of the child's hypothalamic-pituitary-adrenal axis.

    View details for DOI 10.1016/j.jpeds.2013.08.030

    View details for Web of Science ID 000327543200042

    View details for PubMedID 24070827

  • Pain Panacea for Opiophobia in Infants? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Anand, K. J. 2013; 309 (2): 183-184

    View details for DOI 10.1001/jama.2012.208359

    View details for Web of Science ID 000313517000028

    View details for PubMedID 23299611

  • A comparison of critical care research funding and the financial burden of critical illness in the United States CRITICAL CARE MEDICINE Coopersmith, C. M., Wunsch, H., Fink, M. P., Linde-Zwirble, W. T., Olsen, K. M., Sommers, M. S., Anand, K. J., Tchorz, K. M., Angus, D. C., Deutschman, C. S. 2012; 40 (4): 1072-1079


    To estimate federal dollars spent on critical care research, the cost of providing critical care, and to determine whether the percentage of federal research dollars spent on critical care research is commensurate with the financial burden of critical care.The National Institutes of Health Computer Retrieval of Information on Scientific Projects database was queried to identify funded grants whose title or abstract contained a key word potentially related to critical care. Each grant identified was analyzed by two reviewers (three if the analysis was discordant) to subjectively determine whether it was definitely, possibly, or definitely not related to critical care. Hospital and total costs of critical care were estimated from the Premier Database, state discharge data, and Medicare data. To estimate healthcare expenditures associated with caring for critically ill patients, total costs were calculated as the combination of hospitalization costs that included critical illness as well as additional costs in the year after hospital discharge.Of 19,257 grants funded by the National Institutes of Health, 332 (1.7%) were definitely related to critical care and a maximum of 1212 (6.3%) grants were possibly related to critical care. Between 17.4% and 39.0% of total hospital costs were spent on critical care, and a total of between $121 and $263 billion was estimated to be spent on patients who required intensive care. This represents 5.2% to 11.2%, respectively, of total U.S. healthcare spending.The proportion of research dollars spent on critical care is lower than the percentage of healthcare expenditures related to critical illness.

    View details for DOI 10.1097/CCM.0b013e31823c8d03

    View details for Web of Science ID 000301813700004

    View details for PubMedID 22202712

  • Pediatric Analgesic Clinical Trial Designs, Measures, and Extrapolation: Report of an FDA Scientific Workshop PEDIATRICS Berde, C. B., Walco, G. A., Krane, E. J., Anand, K. J., Aranda, J. V., Craig, K. D., Dampier, C. D., Finkel, J. C., Grabois, M., Johnston, C., Lantos, J., Lebel, A., Maxwell, L. G., McGrath, P., Oberlander, T. F., Schanberg, L. E., Stevens, B., Taddio, A., von Baeyer, C. L., Yaster, M., Zempsky, W. T. 2012; 129 (2): 354-364


    Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

    View details for DOI 10.1542/peds.2010-3591

    View details for Web of Science ID 000300395100058

    View details for PubMedID 22250028

  • Love, pain, and intensive care PEDIATRICS Anand, K. S., Hall, R. W. 2008; 121 (4): 825-827

    View details for DOI 10.1542/peds.2007-3828

    View details for Web of Science ID 000254576800019

    View details for PubMedID 18381545

  • Pain assessment in preterm neonates PEDIATRICS Anand, K. S. 2007; 119 (3): 605-607

    View details for DOI 10.1542/peds.2006-2723

    View details for Web of Science ID 000244579800019

    View details for PubMedID 17332212

  • Gastric suction at birth: Not an innocent bystander JOURNAL OF PEDIATRICS Anand, K. J., Jacobson, B., Hall, R. W. 2004; 145 (5): 714

    View details for DOI 10.1016/j.jpeds.2004.06.057

    View details for Web of Science ID 000225086800037

    View details for PubMedID 15520789

  • Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial LANCET Anand, K. J., Hall, R. W., Desai, N., Shephard, B., Bergqvist, L. L., Young, T. E., Boyle, E. M., Carbajal, R., Bhutani, V. K., Moore, M. B., Kronsberg, S. S., Barton, B. A. 2004; 363 (9422): 1673-1682


    Opioid analgesia is commonly used during neonatal intensive care. We undertook the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial to investigate whether pre-emptive morphine analgesia decreases the rate of a composite primary outcome of neonatal death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL) in preterm neonates.Ventilated preterm neonates (n=898) from 16 centres were randomly assigned masked placebo (n=449) or morphine (n=449) infusions. After a loading dose (100 microg/kg), morphine infusions (23-26 weeks of gestation 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); 30-32 weeks 30 microg kg(-1) h(-1)) were continued as long as clinically justified (maximum 14 days). Open-label morphine could be given on clinical judgment (placebo group 242/443 [54.6%], morphine group 202/446 [45.3%]). Analyses were by intention to treat.Baseline variables were similar in the randomised groups. The placebo and morphine groups had similar rates of the composite outcome (105/408 [26%] vs 115/419 [27%]), neonatal death (47/449 [11%] vs 58/449 [13%]), severe IVH (46/429 [11%] vs 55/411 [13%]), and PVL (34/367 [9%] vs 27/367 [7%]). For neonates who were not given open-label morphine, rates of the composite outcome (53/225 [24%] vs 27/179 [15%], p=0.0338) and severe IVH (19/219 [9%] vs 6/189 [3%], p=0.0209) were higher in the morphine group than the placebo group. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine (78/228 [34%] vs 27/179 [15%], p<0.0001). Morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (36/190 [19%] vs 19/219 [9%], p=0.0024).Pre-emptive morphine infusions did not reduce the frequency of severe IVH, PVL, or death in ventilated preterm neonates, but intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome. The morphine doses used in this study decrease clinical signs of pain but can cause significant adverse effects in ventilated preterm neonates.

    View details for Web of Science ID 000221546300007

    View details for PubMedID 15158628

  • Opiold receptor desensitization contributes to thennal hyperalgesia in infant rats EUROPEAN JOURNAL OF PHARMACOLOGY Liu, J. G., Rovnaghi, C. R., Garg, S., Anand, K. J. 2004; 491 (2-3): 127-136


    Central nociceptive processing includes spinal and supraspinal neurons, but the supraspinal mechanisms mediating changes in pain threshold remain unclear. We investigated the role of forebrain neurons in capsaicin-induced hyperalgesia. Long-Evans rat pups at 21 days were randomized to undisturbed control group, or to receive tactile stimulation, saline injection (0.9% w/v) or capsaicin injection (0.01% w/v) applied to each paw at hourly intervals. Thermal paw withdrawal latency was measured 1 h later, forebrains were removed and purified forebrain neuronal membranes were assayed for adenylyl cyclase activity and opioid receptor function. Capsaicin-injected rats had decreased thermal latency (P < 0.0001) compared to the other groups. Neuronal membranes showed increased basal (P = 0.0003) and forskolin-stimulated (P=0.0002) adenylyl cyclase activity in the capsaicin group compared to other groups. The selective mu-opioid receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) was less effective in inhibiting adenylyl cyclase activity in the capsaicin group (P < 0.001) compared to other groups. These effects were naloxone-reversible and pertussis toxin-sensitive (P < 0.01) in the control, tactile stimulation and saline injection groups but not in the capsaicin group. Binding capacity and affinity for micro-opioid receptors were similar in all four groups, suggesting that receptor downregulation was not involved. Exposure to DAMGO increased [35S]GTPgammaS binding to neuronal membranes from the control, tactile and saline groups (P<0.001) in a naloxone-reversible and pertussis toxin-sensitive manner (P < 0.01) but not in the capsaicin group, suggesting mu-opioid receptor desensitization. Dose responses to systemic morphine were also reduced in the capsaicin group compared to the tactile group (P < 0.05). Capsaicin-induced hyperalgesia in 21-day-old rats was associated with an uncoupling of micro-opioid receptors in the forebrain. Opioid receptor desensitization in the forebrain may reduce opioidergic inputs to the descending inhibitory controls, associated with behavioral hyperalgesia and reduced responsiveness to morphine analgesia in capsaicin-injected young rats.

    View details for DOI 10.1016/j.ejphar.2004.03.042

    View details for Web of Science ID 000221590400006

    View details for PubMedID 15140629

  • Gastric suction at birth associated with long-term risk for functional intestinal disorders in later life JOURNAL OF PEDIATRICS Anand, K. J., Runeson, B., Jacobson, B. 2004; 144 (4): 449-454


    To test the hypothesis that noxious stimulation at birth may increase the long-term risk for developing psychosomatic or functional disorders during later life.Matched case-control study using sibling controls. The birth records were retrieved for the offspring of 494 mothers who, after uncomplicated pregnancies, had delivered two or more children with birth weights at least 2500 g, if at least one child was exposed to a perinatal complication or birth asphyxia. Among their offspring (N=1110), the 108 cases hospitalized for functional intestinal symptoms were identified from nationwide hospital discharge records. Of these, 96 cases were compared with 116 unaffected sibling controls.Functional intestinal symptoms occurred more commonly among the 1110 subjects (9.5%) than in the general population (3.4%, chi(2)=124, P<10(-6)). Gastric suction at birth occurred more frequently among the cases compared with their siblings (22.9% vs 11.2%). There were no differences in the number of cases and controls exposed to perinatal trauma or birth asphyxia. Multivariate logistic regression analyses showed that gastric suction at birth was associated with functional intestinal disorders during later life (odds ratio, 2.99; 95% confidence interval, 1.32-6.79; P=.009), whereas maternal, perinatal, or other confounding variables were not significant.Noxious stimulation caused by gastric suction at birth may promote the development of long-term visceral hypersensitivity and cognitive hypervigilance, leading to an increased prevalence of functional intestinal disorders in later life.

    View details for DOI 10.1016/j.jpeds.2003.12.035

    View details for Web of Science ID 000220760600021

    View details for PubMedID 15069391

  • Cognitive and behavioral outcomes of school-aged children who were born preterm - A meta-analysis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bhutta, A. T., Cleves, M. A., Casey, P. H., Cradock, M. M., Anand, K. J. 2002; 288 (6): 728-737


    The cognitive and behavioral outcomes of school-aged children who were born preterm have been reported extensively. Many of these studies have methodological flaws that preclude an accurate estimate of the long-term outcomes of prematurity.To estimate the effect of preterm birth on cognition and behavior in school-aged children.MEDLINE search (1980 to November 2001) for English-language articles, supplemented by a manual search of personal files maintained by 2 of the authors.We included case-control studies reporting cognitive and/or behavioral data of children who were born preterm and who were evaluated after their fifth birthday if the attrition rate was less than 30%. From the 227 reviewed studies, cognitive data from 15 studies and behavioral data from 16 studies were selected.Data on population demographics, study characteristics, and cognitive and behavioral outcomes were extracted from each study, entered in a customized database, and reviewed twice to minimize error. Differences between the mean cognitive scores of cases and controls were pooled. Homogeneity across studies was formally tested using a general variance-based method and graphically using Galbraith plots. Linear meta-analysis regression models were fitted to explore the impact of birth weight and gestational age on cognitive outcomes. Study-specific relative risks (RRs) were calculated for the incidence of attention-deficit/hyperactivity disorder (ADHD) and pooled. Quality assessment of the studies was performed based on a 10-point scale. Publication bias was examined using Begg modified funnel plots and formally tested using the Egger weighted-linear regression method.Among 1556 cases and 1720 controls, controls had significantly higher cognitive scores compared with children who were born preterm (weighted mean difference, 10.9; 95% confidence interval [CI], 9.2-12.5). The mean cognitive scores of preterm-born cases and term-born controls were directly proportional to their birth weight (R(2) = 0.51; P<.001) and gestational age (R(2) = 0.49; P<.001). Age at evaluation had no significant correlation with mean difference in cognitive scores (R(2) = 0.12; P =.20). Preterm-born children showed increases in externalizing and internalizing behaviors in 81% of studies and had more than twice the RR for developing ADHD (pooled RR, 2.64; 95% CI, 1.85-3.78). No differences were noted in cognition and behaviors based on the quality of the study.Children who were born preterm are at risk for reduced cognitive test scores and their immaturity at birth is directly proportional to the mean cognitive scores at school age. Preterm-born children also show an increased incidence of ADHD and other behaviors.

    View details for DOI 10.1001/jama.288.6.728

    View details for Web of Science ID 000177408100034

    View details for PubMedID 12169077

  • Consensus statement for the prevention and management of pain in the newborn ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Anand, K. J., Int Evidence-based Grp Neonatal Pa 2001; 155 (2): 173-180


    To develop evidence-based guidelines for preventing or treating neonatal pain and its adverse consequences. Compared with older children and adults, neonates are more sensitive to pain and vulnerable to its long-term effects. Despite the clinical importance of neonatal pain, current medical practices continue to expose infants to repetitive, acute, or prolonged pain.Experts representing several different countries, professional disciplines, and practice settings used systematic reviews, data synthesis, and open discussion to develop a consensus on clinical practices that were supported by published evidence or were commonly used, the latter based on extrapolation of evidence from older age groups. A practical format was used to describe the analgesic management for specific invasive procedures and for ongoing pain in neonates.Recognition of the sources of pain and routine assessments of neonatal pain should dictate the avoidance of recurrent painful stimuli and the use of specific environmental, behavioral, and pharmacological interventions. Individualized care plans and analgesic protocols for specific clinical situations, patients, and health care settings can be developed from these guidelines. By clearly outlining areas where evidence is not available, these guidelines may also stimulate further research. To use the recommended therapeutic approaches, clinicians must be familiar with their adverse effects and the potential for drug interactions.Management of pain must be considered an important component of the health care provided to all neonates, regardless of their gestational age or severity of illness.

    View details for DOI 10.1001/archpedi.155.2.173

    View details for Web of Science ID 000166822000013

    View details for PubMedID 11177093

  • Pain, plasticity, and premature birth: a prescription for permanent suffering? NATURE MEDICINE Anand, K. J. 2000; 6 (9): 971-973

    View details for DOI 10.1038/79658

    View details for Web of Science ID 000089190500022

    View details for PubMedID 10973310

  • Can adverse neonatal experiences alter brain development and subsequent behavior? BIOLOGY OF THE NEONATE Anand, K. J., Scalzo, F. M. 2000; 77 (2): 69-82


    Self-destructive behavior in current society promotes a search for psychobiological factors underlying this epidemic. Perinatal brain plasticity increases the vulnerability to early adverse experiences, thus leading to abnormal development and behavior. Although several epidemiological investigations have correlated perinatal and neonatal complications with abnormal adult behavior, our understanding of the underlying mechanisms remains rudimentary. Models of early experience, such as repetitive pain, sepsis, or maternal separation in rodents and other species have noted multiple alterations in the adult brain, correlated with specific behavioral phenotypes depending on the timing and nature of the insult. The mechanisms mediating such changes in the neonatal brain have remained largely unexplored. We propose that lack of N-methyl-D-aspartate (NMDA) receptor activity from maternal separation and sensory isolation leads to increased apoptosis in multiple areas of the immature brain. On the other hand, exposure to repetitive pain may cause excessive NMDA/excitatory amino acid activation resulting in excitotoxic damage to developing neurons. These changes promote two distinct behavioral phenotypes characterized by increased anxiety, altered pain sensitivity, stress disorders, hyperactivity/attention deficit disorder, leading to impaired social skills and patterns of self-destructive behavior. The clinical important of these mechanisms lies in the prevention of early insults, effective treatment of neonatal pain and stress, and perhaps the discovery of novel therapeutic approaches that limit neuronal excitotoxicity or apoptosis.

    View details for DOI 10.1159/000014197

    View details for Web of Science ID 000085350400001

    View details for PubMedID 10657682

  • New perspectives on the definition of pain PAIN Anand, K. J., Craig, K. D. 1996; 67 (1): 3-6

    View details for Web of Science ID A1996VL90100002

    View details for PubMedID 8895225

  • Hyperoxemia among Pediatric Intensive Care Unit Patients Receiving Oxygen Therapy. Journal of pediatric intensive care Fayazi, A. R., Sesia, M., Anand, K. J. 2024; 13 (2): 184-191


    Supratherapeutic oxygen levels consistently cause oxygen toxicity in the lungs and other organs. The prevalence and severity of hyperoxemia among pediatric intensive care unit (PICU) patients remain unknown. This was the first study to examine the prevalence and duration of hyperoxemia in PICU patients receiving oxygen therapy. This is a retrospective chart review. This was performed in a setting of 36-bed PICU in a quaternary-care children's hospital. All the patients were children aged <18 years, admitted to the PICU for ≥24 hours, receiving oxygen therapy for ≥12 hours who had at least one arterial blood gas during this time. There was no intervention. Of 5,251 patients admitted to the PICU, 614 were included in the study. On average, these patients received oxygen therapy for 91% of their time in the PICU and remained hyperoxemic, as measured by pulse oximetry, for 65% of their time on oxygen therapy. Patients on oxygen therapy remained hyperoxemic for a median of 38 hours per patient and only 1.1% of patients did not experience any hyperoxemia. Most of the time (87.5%) patients received oxygen therapy through a fraction of inspired oxygen (FiO 2 )-adjustable device. Mean FiO 2 on noninvasive support was 0.56 and on invasive support was 0.37. Mean partial pressure of oxygen (PaO 2 ) on oxygen therapy was 108.7 torr and 3,037 (42.1%) of PaO 2 measurements were >100 torr. Despite relatively low FiO 2 , PICU patients receiving oxygen therapy are commonly exposed to prolonged hyperoxemia, which may contribute to ongoing organ injury.

    View details for DOI 10.1055/s-0041-1740586

    View details for PubMedID 38919694

    View details for PubMedCentralID PMC11196156

  • An Evidence-Based Discussion of Fetal Pain and Stress. Neonatology Mohamed, S. H., Reissland, N., Anand, K. J. 2024: 1-7


    The concept of fetal pain results from procedures conducted without anesthesia in preterm newborns and fetuses, which indicate that it is possible to examine fetal pain based on stress hormone, metabolic, and behavioral changes. Anatomical and physiological data suggest that fetuses become capable of processing nociceptive stimuli around midgestation, although the associated changes in fetal brain development remain unclear. What constitutes fetal pain remains controversial in the light of the definition of pain adopted by the International Association for the Study of Pain (IASP), which posits pain as an "unpleasant sensory and emotional experience."Here, we examine the notion that human fetuses cannot "experience" pain and potential implications of this claim. We highlight the key scientific evidence related to fetal pain, including clinical studies on pain in fetuses and preterm newborns. We argue that consistent patterns of stress hormones, metabolic changes, body movements, hemodynamic changes, and pain-related facial expressions in fetuses exposed to invasive procedures overcome the need for subjective proof of pain as articulated in the IASP definition. No study to date has conclusively proven the absence of fetal pain beyond the age of viability.Based on the current evidence, we propose that all fetuses receive anesthesia regardless of the invasive procedures being performed to guarantee the least possible pain and physiological, behavioral, or hormonal responses without exposing the mother or her baby to unnecessary complications.

    View details for DOI 10.1159/000538848

    View details for PubMedID 38781940

  • Incidence of mental health conditions following pediatric hospital admissions: analysis of a national database. Frontiers in pediatrics Daughtrey, H. R., Ruiz, M. O., Felix, N., Saynina, O., Sanders, L. M., Anand, K. J. 2024; 12: 1344870


    Introduction: Despite increasing survival of children following hospitalization, hospitalization may increase iatrogenic risk for mental health (MH) disorders, including acute stress, post-traumatic stress, anxiety, or depression. Using a population-based retrospective cohort study, we assessed the rates of new MH diagnoses during the 12 months after hospitalization, including the moderating effects of ICU exposure.Study design/methods: This was a retrospective case control study using the Truven Health Analytics insurance database. Inclusion criteria included children aged 3-21 years, insurance enrollment for >12 months before and after hospital admission. We excluded children with hospitalization 2 years prior to index hospitalization and those with prior MH diagnoses. We extracted admission type, ICD-10 codes, demographic, clinical, and service coordination variables from the database. We established age- and sex-matched cohorts of non-hospitalized children. The primary outcome was a new MH diagnosis. Multivariable regression methods examined the risk of incident MH disorder(s) between hospitalized and non-hospitalized children. Among hospitalized children, we further assessed effect modification from ICU (vs. non-ICU) stay, admission year, length of stay, medical complexity, and geographic region.Results: New MH diagnoses occurred among 19,418 (7%) hospitalized children, 3,336 (8%) ICU-hospitalized children and 28,209 (5%) matched healthy controls. The most common MH diagnoses were anxiety (2.5%), depression (1.9%), and stress/trauma (2.2%) disorders. Hospitalization increased the odds of new MH diagnoses by 12.3% (OR: 1.123, 95% CI: 1.079-1.17) and ICU-hospitalization increased these odds by 63% (OR: 1.63, 95% CI: 1.483-1.79) as compared to matched, non-hospitalized children. Children with non-complex chronic diseases (OR: 2.91, 95% CI: 2.84-2.977) and complex chronic diseases (OR: 5.16, 95% CI: 5.032-5.289) had a substantially higher risk for new MH diagnoses after hospitalization compared to patients with acute illnesses.Conclusion: Pediatric hospitalization is associated with higher, long-term risk of new mental health diagnoses, and ICU hospitalization further increases that risk within 12 months of the acute episode. Acute care hospitalization confers iatrogenic risks that warrant long-term mental and behavioral health follow-up.

    View details for DOI 10.3389/fped.2024.1344870

    View details for PubMedID 38450296

  • Informative Artifacts in AI-Assisted Care. The New England journal of medicine Azizi, Z., Vedelli, J. K., Anand, K. J. 2023; 389 (22)

    View details for DOI 10.1056/NEJMc2311525

    View details for PubMedID 38048204

  • Bibliometric analysis with reference publication year spectroscopy showed how key programmes drove developmental care in newborn infants. Acta paediatrica (Oslo, Norway : 1992) Smith, M., Marx, W., Anand, K. S., Haunschild, R., Bornmann, L., Sizun, J., Roue, J. M. 2023


    We investigated the historical origins of developmental care for newborn infants using Reference Publication Year Spectroscopy (RPYS), an innovative method of bibliometric analysis.A Web of Science search query that combined infant and intervention-related synonyms was performed on 2 February 2022. RPYS analysis was performed on this dataset to identify the most referenced historical publications for developmental care in newborn infants. Median deviation analysis identified the peak publication years, including the most cited historical references. Landmark publications were defined as those belonging to the top 10% of the most frequently referenced publications for at least 20 years.The RPYS peaks showed an early phase (1936-1986), during which infant development was studied and analysed, leading to a conceptualisation of developmental care for newborn infants. The following years (1987-2020), showed an explosion of interest in developmental care and highlighted two main programmes. The Neonatal Individualized Developmental Care Assessment Program (NIDCAP) and the Infant Health and Development Program (IHDP) inspired numerous publications during those years, which strove to demonstrate evidence of their clinical benefits.Developmental care has become increasingly important, thanks to the implementation of NIDCAP and IHDP.

    View details for DOI 10.1111/apa.16996

    View details for PubMedID 37849411

  • Linear hair growth rates in preschool children PEDIATRIC RESEARCH Ruiz, M. O., Rovnaghi, C. R., Tembulkar, S., Qin, F., Truong, L., Shen, S., Anand, K. S. 2023
  • Missing Race and Ethnicity Data in Pediatric Studies JAMA Pediatr Vedelli, J. K., Azizi, Z., Anand, K. J. 2023
  • What is the definition of acute episodic and chronic pain in critically ill neonates and infants? A global, four-stage consensus and validation study. BMJ open Ilhan, E., Pacey, V., Brown, L., Spence, K., van Ganzewinkel, C., Pillai Riddell, R., Campbell-Yeo, M., Stevens, B. J., Eriksson, M., Shah, V., Anand, K. J., Bellieni, C., Daly, M., Johnston, C., Hush, J. 2022; 12 (3): e055255


    OBJECTIVES: To define and validate types of pain in critically ill neonates and infants by researchers and clinicians working in the neonatal intensive care unit (NICU) and high dependency unit (HDU).DESIGN: A qualitative descriptive mixed-methods design.PROCEDURE/S: Each stage of the study was built on and confirmed the previous stages. Stage 1 was an expert panel to develop definitions; stage 2 was a different expert panel made up of neonatal clinicians to propose clinical characteristics associated with the definitions from stage 1; stage 3 was a focus group of neonatal clinicians to provide clinical case scenarios associated with each definition and clinical characteristics; and stage 4 was a survey administered to neonatal clinicians internationally to test the validity of the definitions using the clinical case scenarios.RESULTS: In stage 1, the panel (n=10) developed consensus definitions for acute episodic pain and chronic pain in neonates and infants. In stage 2, a panel (n=8) established clinical characteristics that may be associated with each definition. In stage 3, a focus group (n=11) created clinical case scenarios of neonates and infants with acute episodic pain, chronic pain and no pain using the definitions and clinical characteristics. In stage 4, the survey (n=182) revealed that the definitions allowed an excellent level of discrimination between case scenarios that described neonates and infants with acute episodic pain and chronic pain (area under the receiver operating characteristic=0.87and 0.89, respectively).CONCLUSIONS: This four-stage study enabled the development of consensus-based and clinically valid definitions of acute episodic pain and chronic pain. There is a need to define and validate other pain types to inform a taxonomy of pain experienced by neonates and infants in the NICU and HDU.

    View details for DOI 10.1136/bmjopen-2021-055255

    View details for PubMedID 35264356

  • Hyperoxemia among Pediatric Intensive Care Unit Patients Receiving Oxygen Therapy JOURNAL OF PEDIATRIC INTENSIVE CARE Fayazi, A. R., Sesia, M., Anand, K. S. 2021
  • Using sensor-fusion and machine-learning algorithms to assess acute pain in non-verbal infants: a study protocol. BMJ open Roue, J., Morag, I., Haddad, W. M., Gholami, B., Anand, K. J. 2021; 11 (1): e039292


    INTRODUCTION: Objective pain assessment in non-verbal populations is clinically challenging due to their inability to express their pain via self-report. Repetitive exposures to acute or prolonged pain lead to clinical instability, with long-term behavioural and cognitive sequelae in newborn infants. Strong analgesics are also associated with medical complications, potential neurotoxicity and altered brain development. Pain scores performed by bedside nurses provide subjective, observer-dependent assessments rather than objective data for infant pain management; the required observations are labour intensive, difficult to perform by a nurse who is concurrently performing the procedure and increase the nursing workload. Multimodal pain assessment, using sensor-fusion and machine-learning algorithms, can provide a patient-centred, context-dependent, observer-independent and objective pain measure.METHODS AND ANALYSIS: In newborns undergoing painful procedures, we use facial electromyography to record facial muscle activity-related infant pain, ECG to examine heart rate (HR) changes and HR variability, electrodermal activity (skin conductance) to measure catecholamine-induced palmar sweating, changes in oxygen saturations and skin perfusion, and electroencephalography using active electrodes to assess brain activity in real time. This multimodal approach has the potential to improve the accuracy of pain assessment in non-verbal infants and may even allow continuous pain monitoring at the bedside. The feasibility of this approach will be evaluated in an observational prospective study of clinically required painful procedures in 60 preterm and term newborns, and infants aged 6 months or less.ETHICS AND DISSEMINATION: The Institutional Review Board of the Stanford University approved the protocol. Study findings will be published in peer-reviewed journals, presented at scientific meetings, taught via webinars, podcasts and video tutorials, and listed on academic/scientific websites. Future studies will validate and refine this approach using the minimum number of sensors required to assess neonatal/infant pain.TRIAL REGISTRATION NUMBER: Registry (NCT03330496).

    View details for DOI 10.1136/bmjopen-2020-039292

    View details for PubMedID 33408199

  • Association of Continuous Opioids and/or Midazolam during Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort. The Journal of pediatrics Tristan, M. d., Martin-Marchand, L. n., Roué, J. M., Anand, K. J., Pierrat, V. n., Tourneux, P. n., Kuhn, P. n., Milesi, C. n., Benhammou, V. n., Ancel, P. Y., Carbajal, R. n., Durrmeyer, X. n. 2021


    To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2 years in ventilated very premature infants.This national observational study included premature infants born before 32 weeks of gestation intubated within 1 hour after birth and still intubated at 24 hours from the French EPIPAGE 2 cohort. Bolus only-treated infants were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7 days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n=450) vs naive (n=472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age 2.Survival at age 2 was significantly higher in the treated group (92.5% vs 87.9%, risk difference [RD] 4.7%; 95%CI, 0.3 to 9.1; P=.037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%, RD 5.3%; 95%CI -0.3 to 11.0; P=.063). These results were confirmed by sensitivity analyses using 5 alternative models.Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24 hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2 years.

    View details for DOI 10.1016/j.jpeds.2020.12.069

    View details for PubMedID 33395567

  • Historical roots of pain management in infants: A bibliometric analysis using reference publication year spectroscopy. Paediatric & neonatal pain Anand, K. J., Roue, J. M., Rovnaghi, C. R., Marx, W., Bornmann, L. 2020; 2 (2): 22-32


    Retrospective evaluations of the historical role of previously published research are often fraught with subjective bias and misrepresentation, which leads to contested scientific claims. This paper investigates the historical roots of infant pain management using novel quantitative methods to identify the published literature and evaluate its relative importance. A bibliometric analysis named "reference publication year spectroscopy" (RPYS), was performed using the program CitedReferencesExplorer (CRExplorer) to avoid the subjectivity associated with comparative evaluations of individual research studies. Web of Science (WoS) search queries on infant-related synonyms, pain-related synonyms, and analgesia or anesthesia-related synonyms were combined using the Boolean operator "AND," to identify all publications related to pain management in infants. The RPYS analyses were based on 8697 papers in our publication set containing the citations for 86268 references. Selected cited publications were associated with peak citation years in 1951, 1954, 1957, 1965, 1987, 1990, 1997, 1999, and 2000. Subsequent analyses suggested that research on infant pain management made rapid progress during 1982-1992. Landmark publications were defined as those belonging to the top 10% of the most frequently referenced publications for longer than 25 years. Through this analysis, we identified and ranked 24 landmark publications to illustrate the historical background and early research on infant pain management. From the first-ever application of RPYS (an objective, reproducible approach to study the early history of any scholarly activity) to pain research, infant pain management appears rooted in the scientific rationale for neonatal pain perception, randomized trials of opioid anesthesia/analgesia, and studies describing the facial expressions and crying activity following heel-lance procedures in newborns.

    View details for DOI 10.1002/pne2.12035

    View details for PubMedID 35548591

    View details for PubMedCentralID PMC8975229

  • COVID-19 PICU guidelines: for high- and limited-resource settings. Pediatric research Kache, S. n., Chisti, M. J., Gumbo, F. n., Mupere, E. n., Zhi, X. n., Nallasamy, K. n., Nakagawa, S. n., Lee, J. H., Di Nardo, M. n., de la Oliva, P. n., Katyal, C. n., Anand, K. J., de Souza, D. C., Lanziotti, V. S., Carcillo, J. n. 2020


    Fewer children than adults have been affected by the COVID-19 pandemic, and the clinical manifestations are distinct from those of adults. Some children particularly those with acute or chronic comorbidities are likely to develop critical illness. Recently, a Multisystem Inflammatory Syndrome (MIS-C) has been described in children with these patients often requiring care in the Pediatric ICU. An international collaboration was formed to review the available evidence and develop evidence-based guidelines for the care of critically ill children with SARS-CoV-2 infection. Where the evidence was lacking, those gaps were replaced with consensus-based guidelines. This process has generated 44 recommendations related to pediatric COVID-19 patients presenting with respiratory distress or failure, sepsis or septic shock, cardiopulmonary arrest, MIS-C, or those requiring adjuvant therapies, or ECMO. Evidence to explain the milder disease patterns in children and the potential to use repurposed antiviral drugs, anti-inflammatory or antithrombotic therapies are also described. Brief summaries of pediatric SARS-CoV-2 infection in different regions of the world are included since few registries are capturing these data globally. These guidelines seek to harmonize the standards and strategies for intensive care that critically ill children with COVID-19 receive across the world. IMPACT: At the time of publication, this is the latest evidence for managing critically ill children infected with SARS-CoV-2.Referring to these guidelines can decrease the morbidity and potentially the mortality of children effected by COVID-19 and its sequalae.These guidelines can be adapted to both high- and limited-resource settings.

    View details for DOI 10.1038/s41390-020-1053-9

    View details for PubMedID 32634818

  • Civil discourse in scholarly communications: an editorial responsibility? Pain reports Craig, K. D., Williams, A. m., Anand, K. J. 2020; 5 (2): e811

    View details for DOI 10.1097/PR9.0000000000000811

    View details for PubMedID 32441703

    View details for PubMedCentralID PMC7209819

  • Response to letter to the Editor ACTA PAEDIATRICA Rovnaghi, C. R., Tembulkar, S., Rigdon, J., Anand, K. S. 2019; 108 (7): 1362

    View details for DOI 10.1111/apa.14768

    View details for Web of Science ID 000471904300030

  • Response to letter to the Editor. Acta paediatrica (Oslo, Norway : 1992) Rovnaghi, C. R., Tembulkar, S., Rigdon, J., Anand, K. J. 2019


    We agree with Dr. Meyer (1) that socioeconomic disparities are far from being solved and, in fact, US disparities have increased in the past decade. Most studies on socioeconomic status attempt to disentangle specific factors mediating the inequities linked with poor health outcomes. Because of complex interactions between individual factors, we proposed a socioeconomic adversity index (SAI) combining such factors in the US(2). This article is protected by copyright. All rights reserved.

    View details for PubMedID 30825246

  • Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations PAIN Walco, G. A., Kopecky, E. A., Weisman, S. J., Stinson, J., Stevens, B., Desjardins, P. J., Berde, C. B., Krane, E. J., Anand, K. S., Yaster, M., Dampier, C. D., Dworkin, R. H., Gilron, I., Lynn, A. M., Maxwell, L. G., Raja, S., Schachtel, B., Turk, D. C. 2018; 159 (2): 193–205


    Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts - neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts. (216 words).

    View details for PubMedID 29140927

  • Editorial: Work-Life Balance: Essential or Ephemeral? FRONTIERS IN PEDIATRICS Schwingshackl, A., Anand, K. J. 2017; 5

    View details for DOI 10.3389/fped.2017.00108

    View details for Web of Science ID 000401578500005

    View details for PubMedID 28540286

    View details for PubMedCentralID PMC5423898

  • Editorial: ARDS: Reaching for the Horizon FRONTIERS IN PEDIATRICS McGuire, J. K., Schwingshackl, A., Anand, K. J. 2017; 5

    View details for DOI 10.3389/fped.2017.00100

    View details for Web of Science ID 000401576900001

    View details for PubMedID 28555176

    View details for PubMedCentralID PMC5430045

  • Sedation and analgesia practices at Italian neonatal intensive care units: results from the EUROPAIN study. Italian journal of pediatrics Lago, P., Frigo, A. C., Baraldi, E., Pozzato, R., Courtois, E., Rambaud, J., Anand, K. J., Carbajal, R. 2017; 43 (1): 26-?


    We aimed to examine current bedside analgesia/sedation (A/S) and pain assessment (PA) practices in Italian neonatal intensive care units (NICUs) in relation to the findings of an epidemiological European study and recently-introduced national guidelines.We analyzed the Italian data from the EUROPAIN (EUROpean-Pain-Audit-In-Neonates) prospective observational study on A/S practices that involved 6680 newborns admitted to tertiary-level NICUs in 18 European countries. Demographics, type of assisted ventilation, type and mode of A/S administration and PA were analyzed. Multivariate linear regression models were used to identify factors predicting A/S and PA practices.From October 1(st), 2012 to June 30(th), 2013, thirty Italian NICUs gathered data on 422 newborn: 131 on invasive ventilation (IV); 150 on noninvasive ventilation (NIV); and 141 on spontaneous ventilation (SV). A/S was documented for 35.3% of all infants admitted (86.3% IV; 17.3% NIV; 7.1% SV [p = 0.0001]), and varied considerably between NICUs (as reported in other European countries). Strong analgesics were used in 32.5% of cases, sedatives in 10.2%, mild analgesics in 3.8%. Fentanyl was used in 78.6% of cases, morphine in 8.4%, neuromuscular blockers in 5.3%, midazolam in 22.1%. The performance of PA was documented in 67.5% of all newborn (85.5% IV; 67.3% NIV; 51.1% SV [p = 0.001]). Illness severity, type of ventilation, bedside PA, and number of NICU beds were all factors associated with A/S use on multivariate analysis, while gestational age ≤ 32 weeks, and type of ventilation and presence of a pain team were associated with PA.We documented a generally widespread, but still highly variable use of A/S and PA at Italian NICUs, despite the diffusion of national guidelines. There is an urgent need to improve routine PA to enable customized pain and stress control (and prevention) in all infants.Clinical # NCT01694745 .

    View details for DOI 10.1186/s13052-017-0343-2

    View details for PubMedID 28270167

    View details for PubMedCentralID PMC5341165

  • [Clinical assessment of pain in Spanish Neonatal Intensive Care Units]. Anales de pediatria (Barcelona, Spain : 2003) Avila-Alvarez, A., Carbajal, R., Courtois, E., Pertega-Diaz, S., Anand, K. J., Muñiz-Garcia, J. 2015


    Clinical scales are currently the best method to assess pain in the neonate, given the impossibility of self-report in this age group. A study is designed with the aim of determining the current practices as regards the clinical assessment of pain in Spanish Neonatal Units and the factors associated with the use of clinical scales.A prospective longitudinal observational study was conducted. A total of 30 Units participated and 468 neonates were included.Only 13 Units (43.3%) had pain assessment protocols. Pain was evaluated with a scale in 78 neonates (16.7%, 95% CI; 13.1-20.1) and the mean number of pain assessments per patient and per day was 2.3 (Standard Deviation; 4.8), with a median of 0.75. Of the total number of 7,189 patient-days studied, there was at least one pain assessment in 654 (9.1%). No pain assessment was performed with a clinical scale on any patient in 20 (66.7%) Units. Among those that did, a wide variation was observed in the percentage of patients in whom pain was assessed, as well as in the scales used. The CRIES (C-Crying; R-Requires increased oxygen administration; I-Increased vital signs; E-Expression; S-Sleeplessness) scale was that used in most Units. In the multivariate analysis, only invasive mechanical ventilation was associated with receiving a pain assessment with a scale (OR 1.46, P=.042).The majority of neonates admitted into Intensive Care in Spain do not receive a pain assessment. Many units still do not routinely use clinical scales, and there is a wide variation between those that do use them. These results could serve as a basis for preparing national guidelines as regards pain in the neonate.

    View details for DOI 10.1016/j.anpedi.2015.09.019

    View details for PubMedID 26553356

  • Consequences of prenatal opioid use for newborns ACTA PAEDIATRICA Anand, K. J., Campbell-Yeo, M. 2015; 104 (11): 1066-1069


    One-third of childbearing women take prescription opioids, previously occurring only in 6-7% of pregnant women. Prenatal opioid exposures may cause birth defects, altered brain development and neonatal abstinence syndrome (NAS). NAS incidence increased fourfold and length of stay increased from 13 to 19 days over 10 years (2004-2013), leading to sevenfold increases in NICU days due to NAS. Initial data suggest that recent NAS increases have resulted from increased use of prescription opioids rather than illicit drugs.Paediatricians will have to manage the consequences of prenatal opioid exposures, as the offspring often have complex medical and social issues associated with these families.

    View details for DOI 10.1111/apa.13121

    View details for Web of Science ID 000363866200017

    View details for PubMedID 26174725

  • Sedation and analgesia practices among Spanish neonatal intensive care units ANALES DE PEDIATRIA Avila-Alvarez, A., Carbajal, R., Courtois, E., Pertega-Diaz, S., Muniz-Garcia, J., Anand, K. J. 2015; 83 (2): 75-84


    Pain management and sedation is a priority in neonatal intensive care units. A study was designed with the aim of determining current clinical practice as regards sedation and analgesia in neonatal intensive care units in Spain, as well as to identify factors associated with the use of sedative and analgesic drugs.A multicenter, observational, longitudinal and prospective study.Thirty neonatal units participated and included 468 neonates. Of these, 198 (42,3%) received sedatives or analgesics. A total of 19 different drugs were used during the study period, and the most used was fentanyl. Only fentanyl, midazolam, morphine and paracetamol were used in at least 20% of the neonates who received sedatives and/or analgesics. In infusions, 14 different drug prescriptions were used, with the most frequent being fentanyl and the combination of fentanyl and midazolam. The variables associated with receiving sedation and/or analgesia were, to have required invasive ventilation (P<.001; OR=23.79), a CRIB score >3 (P=.023; OR=2.26), the existence of pain evaluation guides in the unit (P<.001; OR=3.82), and a pain leader (P=.034; OR=2.35).Almost half of the neonates admitted to intensive care units receive sedatives or analgesics. There is significant variation between Spanish neonatal units as regards sedation and analgesia prescribing. Our results provide evidence on the "state of the art", and could serve as the basis of preparing clinical practice guidelines at a national level.

    View details for DOI 10.1016/j.anpedi.2015.03.017

    View details for Web of Science ID 000361502100002

    View details for PubMedID 25979386

  • Inverse Relationship between Cardio-Ankle Vascular Index and Body Mass Index in Healthy Children JOURNAL OF PEDIATRICS Philip, R., Alpert, B. S., Schwingshackl, A., Huang, X., Blakely, D., Rovnaghi, C. R., Tran, Q. T., Velasquez, A., Arevalo, A., Anand, K. J. 2015; 167 (2): 361-?


    To establish reference scores for cardio-ankle vascular index (CAVI), a noninvasive measure of vascular function, which reflects the stiffness of arteries, in healthy children, to test for racial and ethnic differences, and to compare CAVI scores between overweight and normal weight children.Subjects included 292 children aged 10-18 years: 100 non-Hispanic whites, 89 non-Hispanic blacks, and 103 Hispanics. Subjects were grouped as normal weight (body mass index [BMI] <85th percentile for age) and overweight (BMI >85th percentile for age). Blood pressure (BP) and CAVI scores were measured in all subjects.After controlling for age, sex, and BMI, normal weight black males had a higher CAVI score (indicating stiffer arteries) in comparison with Hispanic males and white males (5.53 ± 0.15 vs 5.13 ± 0.15 vs 5.02 ± 0.15, P = .04). BMI had an inverse association on the CAVI score (r = -0.335, P < .0001). In multivariable analysis, BMI and average CAVI scores were significant predictors of each other (R(2) = 0.37, P < .0001, R(2) = 0.21, P < .0001). There was no significant correlation between CAVI scores and resting BP values, confirming that CAVI scores were independent of concurrent BP values.Significant differences in vascular function exist among ethnic groups of children. Overweight children had lower CAVI scores, suggestive of vascular adaptation to obesity in early life. CAVI, by providing a noninvasive measure of vascular health, may help identify children at increased risk for cardiovascular disease.

    View details for DOI 10.1016/j.jpeds.2015.04.042

    View details for Web of Science ID 000362455300031

    View details for PubMedID 26003881

  • [Sedation and analgesia for neonates in NICUs across Europe]. Archives de pe´diatrie : organe officiel de la Socie´te franc¸aise de pe´diatrie Carbajal, R., Eriksson, M., Courtois, E., Anand, K. J. 2015; 22 (5): 95-96

    View details for DOI 10.1016/S0929-693X(15)30048-8

    View details for PubMedID 26112539

  • Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants ACTA PAEDIATRICA van Ganzewinkel, C., Derijks, L., Anand, K. J., Van Lingen, R. A., Neef, C., Kramer, B. W., Andriessen, P. 2014; 103 (6): 612-617


    The therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of <32 weeks' gestation.Fifteen very preterm infants received five, six-hourly doses of intravenous paracetamol (7.5 mg/kg). Blood samples were taken to measure paracetamol, glutathione and hepatic function, together with urine samples for paracetamol metabolites.A two-compartment pharmacokinetic model gave the best fit for all individual patients and resulted in a predictable pharmacokinetic profile. The estimated pharmacokinetic population parameters were volume of distribution 0.764 ± 0.225 L/kg, elimination rate constant (ke ) 0.117 ± 0.091/h and intercompartment rate constants k12 0.607 ± 0.734/h and k21 1.105 ± 0.762/h.Our study found that multiple doses of intravenous paracetamol resulted in a predictable pharmacokinetic profile in very preterm infants. Increases in postmenstrual age and weight were associated with increased clearance. No evidence of hepatotoxicity was found.

    View details for DOI 10.1111/apa.12638

    View details for Web of Science ID 000335754700017

    View details for PubMedID 24654967

  • Interpretation of Cortisol Concentrations and Reference Intervals from the CALIPER Database CLINICAL CHEMISTRY Rovnaghi, C. R., Kala, A. F., Allen, S. L., Anand, K. J. 2014; 60 (2): 418-419

    View details for DOI 10.1373/clinchem.2013.212944

    View details for Web of Science ID 000335146300021

    View details for PubMedID 24363368

  • Does neonatal pain management in intensive care units differ between night and day? An observational study BMJ OPEN Guedj, R., Danan, C., Daoud, P., Zupan, V., Renolleau, S., Zana, E., Aizenfisz, S., Lapillonne, A., de Saint Blanquat, L., Granier, M., Durand, P., Castela, F., Coursol, A., Hubert, P., Cimerman, P., Anand, K. J., Khoshnood, B., Carbajal, R. 2014; 4 (2)


    To determine whether analgesic use for painful procedures performed in neonates in the neonatal intensive care unit (NICU) differs during nights and days and during each of the 6 h period of the day.Conducted as part of the prospective observational Epidemiology of Painful Procedures in Neonates study which was designed to collect in real time and around-the-clock bedside data on all painful or stressful procedures.13 NICUs and paediatric intensive care units in the Paris Region, France.All 430 neonates admitted to the participating units during a 6-week period between September 2005 and January 2006.During the first 14 days of admission, data were collected on all painful procedures and analgesic therapy. The five most frequent procedures representing 38 012 of all 42 413 (90%) painful procedures were analysed.Observational study.We compared the use of specific analgesic for procedures performed during each of the 6 h period of a day: morning (7:00 to 12:59), afternoon, early night and late night and during daytime (morning+afternoon) and night-time (early night+late night).7724 of 38 012 (20.3%) painful procedures were carried out with a specific analgesic treatment. For morning, afternoon, early night and late night, respectively, the use of analgesic was 25.8%, 18.9%, 18.3% and 18%. The relative reduction of analgesia was 18.3%, p<0.01, between daytime and night-time and 28.8%, p<0.001, between morning and the rest of the day. Parental presence, nurses on 8 h shifts and written protocols for analgesia were associated with a decrease in this difference.The substantial differences in the use of analgesics around-the-clock may be questioned on quality of care grounds.

    View details for DOI 10.1136/bmjopen-2013-004086

    View details for Web of Science ID 000334459100006

    View details for PubMedID 24556241

    View details for PubMedCentralID PMC3931991

  • Repetitive neonatal pain and neurocognitive abilities in ex-preterm children PAIN Anand, K. J., Palmer, F. B., Papanicolaou, A. C. 2013; 154 (10): 1899-1901

    View details for DOI 10.1016/j.pain.2013.06.027

    View details for Web of Science ID 000324475500001

    View details for PubMedID 23792285

  • Physicians' Conceptualization of "Closure" as a Benefit of Physician-Parent Follow-up Meetings after a Child's Death in the Pediatric Intensive Care Unit JOURNAL OF PALLIATIVE CARE Eggly, S., Meert, K. L., Berger, J., Zimmerman, J., Anand, K. J., Newth, C. J., Harrison, R., Carcillo, J., Dean, J. M., Willson, D. F., Nicholson, C. 2013; 29 (2): 69-75


    We examined physicians' conceptualization of closure as a benefit of follow-up meetings with bereaved parents. The frequency of use and the meaning of the word "closure" were analyzed in transcripts of interviews with 67 critical care physicians affiliated with the Collaborative Pediatric Critical Care Research Network. In all, 38 physicians (57 percent) used the word "closure" at least once (median: 2; range: 1 to 7), for a total of 86 times. Physicians indicated that closure is a process or trajectory rather than an achievable goal. They also indicated that parents and physicians can move toward closure by gaining a better understanding of the causes and circumstances of the death and by reconnecting with, or resolving relationships between, parents and health professionals. Physicians suggested that a primary reason to conduct follow-up meetings is that such meetings offer parents and physicians an opportunity to move toward closure. Future research should attempt to determine whether followup meetings reduce the negative effects of bereavement for parents and physicians.

    View details for Web of Science ID 000321412100002

    View details for PubMedID 23923469

    View details for PubMedCentralID PMC3817557

  • Developmental neurotoxicity of ketamine in pediatric clinical use TOXICOLOGY LETTERS Dong, C., Anand, K. J. 2013; 220 (1): 53-60


    Ketamine is widely used as an anesthetic, analgesic, and sedative in pediatric clinical practice and it is also listed as an illicit drug by most countries. Recent in vivo and in vitro animal studies have confirmed that ketamine can induce neuronal cell death in the immature brain, resulting from widespread neuronal apoptosis. These effects can disturb normal development further altering the structure and functions of the brain. Our recent studies further indicate that ketamine can alter neurogenesis from neural stem progenitor cells in the developing brain. Taken together, these findings identify a novel complication associated with ketamine use in premature infants, term newborns, and pregnant women. Recent data on the developmental neurotoxicity of ketamine are reviewed with proposed future directions for evaluating the safety of ketamine in these patient populations.

    View details for DOI 10.1016/j.toxlet.2013.03.030

    View details for Web of Science ID 000319449300007

    View details for PubMedID 23566897

  • The Role of the Data and Safety Monitoring Board in a Clinical Trial: The CRISIS Study PEDIATRIC CRITICAL CARE MEDICINE Holubkov, R., Casper, T. C., Dean, J. M., Anand, K. J., Zimmerman, J., Meert, K. L., Newth, C. J., Berger, J., Harrison, R., Willson, D. F., Nicholson, C. 2013; 14 (4): 374-383


    Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials.Case study, narrative review.The Data and Safety Monitoring Board's role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described.The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility.The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The Data and Safety Monitoring Board must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.

    View details for DOI 10.1097/PCC.0b013e318274568c

    View details for Web of Science ID 000318680000011

    View details for PubMedID 23392377

    View details for PubMedCentralID PMC3648617

  • Baseline Serum Concentrations of Zinc, Selenium, and Prolactin in Critically III Children PEDIATRIC CRITICAL CARE MEDICINE Heidemann, S. M., Holubkov, R., Meert, K. L., Dean, J. M., Berger, J., Bell, M., Anand, K. J., Zimmerman, J., Newth, C. J., Harrison, R., Willson, D. F., Nicholson, C., Carcillo, J. 2013; 14 (4): E202-E206


    To describe serum concentrations of zinc, selenium, and prolactin in critically ill children within 72 hours of PICU admission, and to investigate relationships between these immunomodulators and lymphopenia.An analysis of baseline data collected as part of the multicenter Critical Illness Stress Induced Immune Suppression (CRISIS) Prevention Trial.PICUs affiliated with the Collaborative Pediatric Critical Care Research Network.All children enrolled in the CRISIS Prevention Trial that had baseline serum samples available for analysis.None.Of 293 critically ill children enrolled in the CRISIS Prevention Trial, 284 had baseline serum samples analyzed for prolactin concentration, 280 for zinc concentration, and 278 for selenium concentration within 72 hours of PICU admission. Lymphocyte counts were available for 235 children. Zinc levels ranged from nondetectable (< 0.1 μg/mL) to 2.87 μg/mL (mean 0.46 μg/mL and median 0.44 μg/mL) and were below the normal reference range for 235 (83.9%) children. Selenium levels ranged from 26 to 145 ng/mL (mean 75.4 ng/mL and median 74.5 ng/mL) and were below the normal range for 156 (56.1%) children. Prolactin levels ranged from nondetectable (< 1 ng/mL) to 88 ng/mL (mean 12.2 ng/mL and median 10 ng/mL). Hypoprolactinemia was present in 68 (23.9%) children. Lymphopenia was more likely in children with zinc levels below normal than those with zinc levels within or above the normal range (82 of 193 [42.5%] vs. 10 of 39 [25.6%], p = 0.0498). Neither selenium nor prolactin concentrations were associated with lymphopenia (p = 1.0 and p = 0.72, respectively).Serum concentrations of zinc, selenium, and prolactin are often low in critically ill children early after PICU admission. Low serum zinc levels are associated with lymphopenia, whereas low selenium and prolactin levels are not. The implications of these findings and the mechanisms by which they occur merit further study.

    View details for DOI 10.1097/PCC.0b013e31827200f5

    View details for Web of Science ID 000318680000006

    View details for PubMedID 23392368

    View details for PubMedCentralID PMC3913275

  • Severe acute asthma exacerbation in children: a stepwise approach for escalating therapy in a pediatric intensive care unit. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG Nievas, I. F., Anand, K. J. 2013; 18 (2): 88-104


    An increasing prevalence of pediatric asthma has led to increasing burdens of critical illness in children with severe acute asthma exacerbations, often leading to respiratory distress, progressive hypoxia, and respiratory failure. We review the definitions, epidemiology, pathophysiology, and clinical manifestations of severe acute asthma, with a view to developing an evidence-based, stepwise approach for escalating therapy in these patients.Subject headings related to asthma, status asthmaticus, critical asthma, and drug therapy were used in a MEDLINE search (1980-2012), supplemented by a manual search of personal files, references cited in the reviewed articles, and treatment algorithms developed within Le Bonheur Children's Hospital.Patients with asthma require continuous monitoring of their cardiorespiratory status via noninvasive or invasive devices, with serial clinical examinations, objective scoring of asthma severity (using an objective pediatric asthma score), and appropriate diagnostic tests. All patients are treated with β-agonists, ipratropium, and steroids (intravenous preferable over oral preparations). Patients with worsening clinical status should be progressively treated with continuous β-agonists, intravenous magnesium, helium-oxygen mixtures, intravenous terbutaline and/or aminophylline, coupled with high-flow oxygen and non-invasive ventilation to limit the work of breathing, hypoxemia, and possibly hypercarbia. Sedation with low-dose ketamine (with or without benzodiazepines) infusions may allow better toleration of non-invasive ventilation and may also prepare the patient for tracheal intubation and mechanical ventilation, if indicated by a worsening clinical status.Severe asthma can be a devastating illness in children, but most patients can be managed by using serial objective assessments and the stepwise clinical approach outlined herein. Following multidisciplinary education and training, this approach was successfully implemented in a tertiary-care, metropolitan children's hospital.

    View details for DOI 10.5863/1551-6776-18.2.88

    View details for PubMedID 23798903

  • Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain de Graaf, J., van Lingen, R. A., Valkenburg, A. J., Weisglas-Kuperus, N., Groot Jebbink, L., Wijnberg-Williams, B., Anand, K. J., Tibboel, D., van Dijk, M. 2013; 154 (3): 449-458


    Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.

    View details for DOI 10.1016/j.pain.2012.12.006

    View details for PubMedID 23352760

  • Opioid Analgesia in Mechanically Ventilated Children: Results From the Multicenter Measuring Opioid Tolerance Induced by Fentanyl Study PEDIATRIC CRITICAL CARE MEDICINE Anand, K. J., Clark, A. E., Willson, D. F., Berger, J., Meert, K. L., Zimmerman, J. J., Harrison, R., Carcillo, J. A., Newth, C. J., Bisping, S., Holubkov, R., Dean, J. M., Nicholson, C. E. 2013; 14 (1): 27-36


    To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit.Prospective, observational study with 100% accrual of eligible patients.Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network.Four hundred nineteen children treated with morphine or fentanyl infusions.None.Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03).Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

    View details for DOI 10.1097/PCC.0b013e318253c80e

    View details for Web of Science ID 000313352200010

    View details for PubMedID 23132396

    View details for PubMedCentralID PMC3581608

  • Ketamine alters the neurogenesis of rat cortical neural stem progenitor cells CRITICAL CARE MEDICINE Dong, C., Rovnaghi, C. R., Anand, K. J. 2012; 40 (8): 2407-2416


    High doses or prolonged exposure to ketamine increase neuronal apoptosis in the developing brain, although effects on neural stem progenitor cells remain unexplored. This study investigated dose- and time-dependent responses to ketamine on cell death and neurogenesis in cultured rat fetal cortical neural stem progenitor cells.Laboratory-based study.University research laboratory.Sprague-Dawley rats.Neural stem progenitor cells were isolated from the cortex of Sprague-Dawley rat fetuses on embryonic day 17. In dose-response experiments, cultured neural stem progenitor cells were exposed to different concentrations of ketamine (0-100 µM) for 24 hrs. In time-course experiments, neural stem progenitor cells cultures were exposed to 10 µM ketamine for different durations (0-48 hrs).Apoptosis and necrosis in neural stem progenitor cells were assessed using activated caspase-3 immunostaining and lactate dehydrogenase assays, respectively. Proliferative changes in neural stem progenitor cells were detected using bromo-deoxyuridine incorporation and Ki67 immunostaining. Neuronal differentiation was assessed using Tuj-1 immunostaining. Cultured neural stem progenitor cells were resistant to apoptosis and necrosis following all concentrations and durations of ketamine exposure tested. Ketamine inhibited proliferation with decreased numbers of bromo-deoxyuridine-positive cells following ketamine exposure to 100 µM for 24 hrs (p<.005) or 10 µM for 48 hrs (p< .01), and reduced numbers of Ki67-positive cells following exposure to ketamine concentration>10 µM for 24 hrs (p<.001) or at 10 µM for 48 hrs (p<.01). Ketamine enhanced neuronal differentiation, with all ketamine concentrations increasing Tuj-1-positive neurons (p<.001) after 24-hrs of exposure. This also occurred with all exposures to 10 µM ketamine for >8 hrs (p<.001).Clinically relevant concentrations of ketamine do not induce cell death in neural stem progenitor cells via apoptosis or necrosis. Ketamine alters the proliferation and increases the neuronal differentiation of neural stem progenitor cells isolated from the rat neocortex. These studies imply that ketamine exposure during fetal or neonatal life may alter neurogenesis and subsequent brain development.

    View details for DOI 10.1097/CCM.0b013e318253563c

    View details for Web of Science ID 000306604900019

    View details for PubMedID 22635046

    View details for PubMedCentralID PMC3507468

  • Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: A pilot randomized, double-blind, placebo-controlled trial PEDIATRIC CRITICAL CARE MEDICINE Bhutta, A. T., Schmitz, M. L., Swearingen, C., James, L. P., Wardbegnoche, W. L., Lindquist, D. M., Glasier, C. M., Tuzcu, V., Prodhan, P., Dyamenahalli, U., Imamura, M., Jaquiss, R. D., Anand, K. J. 2012; 13 (3): 328-337


    Infants are potentially more susceptible to cell death mediated via glutamate excitotoxicity attributed to cardiopulmonary bypass. We hypothesized that ketamine, via N-methyl D-aspartate receptor blockade and anti-inflammatory effects, would reduce central nervous system injury during cardiopulmonary bypass.We randomized 24 infants, without chromosomal abnormalities, to receive ketamine (2 mg/kg, n = 13) or placebo (saline, n = 11) before cardiopulmonary bypass for repair of ventricular septal defects. Plasma markers of inflammation and central nervous system injury were compared at the end of surgery, and 6, 24, and 48 hrs after surgery. Magnetic resonance imaging and spectroscopy before cardiopulmonary bypass and at the time of hospital discharge were performed in a subset of cases and controls (n = 5 in each group). Cerebral hemodynamics were monitored postoperatively using near-infrared spectroscopy, and neurodevelopmental outcomes were assessed using Bayley Scales of Infant Development-II before and 2-3 wks after surgery.Statistically significant differences were noted in preoperative inspired oxygen levels, intraoperative cooling and postoperative temperature, respiratory rate, platelet count, and bicarbonate levels. The peak concentration of C-reactive protein was lower in cases compared to controls at 24 hrs (p = .048) and 48 hrs (p = .001). No significant differences were noted in the expression of various cytokines, chemokines, S100, and neuron-specific enolase between the cases and controls. Magnetic resonance imaging with spectroscopy studies showed that ketamine administration led to a significant decrease in choline and glutamate plus glutamine/creatine in frontal white matter. No statistically significant differences occurred between pre- and postoperative Bayley Scales of Infant Development-II scores.We did not find any evidence for neuroprotection or neurotoxicity in our pilot study. A large, adequately powered randomized control trial is needed to discern the central nervous system effect of ketamine on the developing brain. brain.The trial is registered at, NCT00556361.

    View details for DOI 10.1097/PCC.0b013e31822f18f9

    View details for Web of Science ID 000303984800024

    View details for PubMedID 21926656

  • The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial PEDIATRIC CRITICAL CARE MEDICINE Carcillo, J. A., Dean, J. M., Holubkov, R., Berger, J., Meert, K. L., Anand, K. J., Zimmerman, J., Newth, C. J., Harrison, R., Burr, J., Willson, D. F., Nicholson, C. 2012; 13 (2): 165-173


    Nosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population.Randomized, double-blinded, comparative effectiveness trial.Eight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.Two hundred ninety-three long-term intensive care patients (age 1-17 yrs) expected to require >72 hrs of invasive care.Patients were stratified according to immunocompromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n = 149), or daily enteral whey protein (n = 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat.There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p = .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .011).Compared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient.

    View details for DOI 10.1097/PCC.0b013e31823896ae

    View details for Web of Science ID 000301230100019

    View details for PubMedID 22079954

    View details for PubMedCentralID PMC3302948

  • Oral Sucrose and "Facilitated Tucking" for Repeated Pain Relief in Preterms: A Randomized Controlled Trial PEDIATRICS Cignacco, E. L., Sellam, G., Stoffel, L., Gerull, R., Nelle, M., Anand, K. J., Engberg, S. 2012; 129 (2): 299-308


    To test the comparative effectiveness of 2 nonpharmacologic pain-relieving interventions administered alone or in combination across time for repeated heel sticks in preterm infants.A multicenter randomized controlled trial in 3 NICUs in Switzerland compared the effectiveness of oral sucrose, facilitated tucking (FT), and a combination of both interventions in preterm infants between 24 and 32 weeks of gestation. Data were collected during the first 14 days of their NICU stay. Three phases (baseline, heel stick, recovery) of 5 heel stick procedures were videotaped for each infant. Four independent experienced nurses blinded to the heel stick phase rated 1055 video sequences presented in random order by using the Bernese Pain Scale for Neonates, a validated pain tool.Seventy-one infants were included in the study. Interrater reliability was high for the total Bernese Pain Scale for Neonates score (Cronbach's α: 0.90-0.95). FT alone was significantly less effective in relieving repeated procedural pain (P < .002) than sucrose (0.2 mL/kg). FT in combination with sucrose seemed to have added value in the recovery phase with lower pain scores (P = .003) compared with both the single-treatment groups. There were no significant differences in pain responses across gestational ages.Sucrose with and without FT had pain-relieving effects even in preterm infants of <32 weeks of gestation having repeated pain exposures. These interventions remained effective during repeated heel sticks across time. FT was not as effective and cannot be recommended as a nonpharmacologic pain relief intervention for repeated pain exposure.

    View details for DOI 10.1542/peds.2011-1879

    View details for Web of Science ID 000300395100052

    View details for PubMedID 22232305

  • A pilot study of preemptive morphine analgesia in preterm neonates: Effects on head circumference, social behavior, and response latencies in early childhood NEUROTOXICOLOGY AND TERATOLOGY Ferguson, S. A., Ward, W. L., Paule, M. G., Hall, R. W., Anand, K. J. 2012; 34 (1): 47-55


    Use of preemptive analgesia in Neonatal Intensive Care Units is recommended for severe and/or invasive procedures. However, the potential long-term consequences of such analgesia, which may be prolonged, are only beginning to be studied. In this pilot study, a subset of subjects previously enrolled in the Neurological Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial was assessed at early childhood. These ex-preterm infants (born at 23-32 weeks of gestational age) required intubation within 72 h postpartum and were randomized to receive either preemptive morphine analgesia (maximum of 14 days) or placebo within 8h post-intubation. At 5-7 years of age, neuropsychological outcomes, morphometrics, adaptive behavior, parent-rated behavior, motivation, and short-term memory were measured. Although overall IQ and academic achievement did not differ between the morphine treated (n=14) and placebo (n=5) groups, preemptive morphine analgesia was associated with distinct differences in other outcome variables. Head circumference of morphine treated children was approximately 7% smaller (Cohen'sd: 2.83, effect size large) and body weight was approximately 4% less (Cohen'sd: 0.81, effect size large); however, height did not differ. In the short-term memory task (delayed matching to sample), morphine treated children exhibited significantly longer choice response latencies than placebo children (3.86±0.33 and 2.71±0.24 s, respectively) (p<0.03) and completed approximately 27% less of the task than placebo children (Cohen'sd: 0.96, effect size large). Parents described morphine treated children as having more social problems, an effect specific to creating and maintaining friendships (Cohen'sd: -0.83, effect size large). Despite the small sample size and the preliminary nature of this study, these results are strongly suggestive of long-lasting effects of preemptive morphine analgesia. A larger investigation with more comprehensive assessments of some of these key features will enable a more complete understanding of the relationship between preemptive morphine treatment and long-term neurocognitive, behavioral, and adaptive outcomes.

    View details for DOI 10.1016/

    View details for Web of Science ID 000301037100006

    View details for PubMedID 22094261

  • Real-time free cortisol quantification among critically ill children PEDIATRIC CRITICAL CARE MEDICINE Zimmerman, J. J., Donaldson, A., Barker, R. M., Meert, K. L., Harrison, R., Carcillo, J. A., Anand, K. S., Newth, C. L., Berger, J., Willson, D. F., Jack, R., Nicholson, C., Dean, J., Eunice Kennedy Shriver Natl Inst C, Human Dev Collaborative Pediat Cri 2011; 12 (5): 525-531


    Ascertainment of adrenal function assessing free rather that total cortisol may be beneficial for the diagnosis of critical illness-related cortisol insufficiency. We hypothesized that centrifugal ultrafiltration would provide timely free cortisol data that highly correlated with the gold standard, but logistically cumbersome, equilibrium dialysis technique when the free cortisol fractions were identically quantified by chemiluminescence immunoassay. We also hypothesized that free cortisol would correlate with illness severity in a large cohort of critically ill children.Prospective, multi-institutional, observational cohort investigation.Seven pediatric intensive care units within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.One hundred sixty-five critically ill children across the spectrum of illness severity.Blood sampling.Time to derive plasma free cortisol concentrations after centrifugal ultrafiltration or equilibrium dialysis fractionation with chemiluminescence immunoassay was approximately 2 vs. approximately 24 hrs, respectively. Using centrifugal ultrafiltration, mean plasma free cortisol was 4.1 ± 6.7 μg/dL (median, 1.6 μg/dL; range, 0.2-43.6 μg/L), representing an average of 15.2 ± 9.4% of total cortisol. Nearly 60% of subjects exhibited free cortisol <2 and 30% <0.8 μg/dL, previously suggested threshold concentrations for defining critical illness-related cortisol insufficiency. Plasma-free cortisol concentrations comparing centrifugal ultrafiltration vs. equilibrium dialysis fractionation demonstrated a strong correlation (R2 = 0.97). For free cortisol <2 μg/dL, Bland-Altman analysis revealed minimal negative bias for the centrifugal ultrafiltration technique. Illness severity assessed by Pediatric Risk of Mortality III correlated moderately with free cortisol and percent total cortisol as free cortisol.Determination of centrifugal ultrafiltration fractionated free cortisol was fast and results correlated highly with equilibrium dialysis fractionated free cortisol. Many children exhibited free cortisol <2 and <0.8 μg/dL but did not demonstrate clinical evidence of critical illness-related cortisol insufficiency. This study ascertains that real-time free cortisol quantification is feasible to potentially help guide clinical decision-making for cortisol replacement therapy in the pediatric intensive care unit.

    View details for DOI 10.1097/PCC.0b013e3181fe4474

    View details for Web of Science ID 000294598400013

    View details for PubMedID 21057361

    View details for PubMedCentralID PMC3566572

  • The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study: Collaborative research in pediatric critical care medicine PEDIATRIC CRITICAL CARE MEDICINE Burr, J. S., Jenkins, T. L., Harrison, R., Meert, K., Anand, K. S., Berger, J. T., Zimmerman, J., Carcillo, J., Dean, J., Newth, C. L., Willson, D. F., Sanders, R. C., Pollack, M. M., Harvill, E., Nicholson, C. E. 2011; 12 (4): 387-392


    To provide an updated overview of critical pertussis to the pediatric critical care community and describe a study of critical pertussis recently undertaken.The six sites, seven hospitals of the Collaborative Pediatric Critical Care Research Network, and 17 outside sites at academic medical centers with pediatric intensive care units.Despite high coverage for childhood vaccination, pertussis causes substantial morbidity and mortality in US children, especially among infants. In pediatric intensive care units, Bordetella pertussis is a community-acquired pathogen associated with critical illness and death. The incidence of medical and developmental sequelae in critical pertussis survivors remains unknown, and the appropriate strategies for treatment and support remain unclear. The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study has begun to evaluate critical pertussis in a prospective cohort.Research is urgently needed to provide an evidence base that might optimize management for critical pertussis, a serious, disabling, and too often fatal illness for U.S. children and those in the developing world.

    View details for DOI 10.1097/PCC.0b013e3181fe4058

    View details for Web of Science ID 000292448200007

    View details for PubMedID 21057366

    View details for PubMedCentralID PMC3439849

  • Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: Five-year follow-up of a randomized controlled trial PAIN de Graaf, J., van Lingen, R. A., Simons, S. P., Anand, K. S., Duivenvoorden, H. J., Weisglas-Kuperus, N., Roofthooft, D. E., Jebbink, L., Veenstra, R. R., Tibboel, D., van Dijk, M. 2011; 152 (6): 1391-1397


    Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long-term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child's functioning. We conducted a follow-up study among 5-year-olds who, as mechanically ventilated neonates, had participated in a placebo-controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health-related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between-group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open-label morphine consumption over the first 28 days, and a propensity score for clinically relevant co-variables in multiple regression analyses. However, scores on one IQ subtest, "visual analysis," were significantly negatively related to having received morphine and to open-label morphine consumption the first 28 days. The finding of a significant effect of morphine on the "visual analysis" IQ subtest calls for follow-up at a later age focusing on the higher-order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child's cognitive functioning at the age of 5 years which warrants follow-up at a later age.

    View details for DOI 10.1016/j.pain.2011.02.017

    View details for Web of Science ID 000290710100027

    View details for PubMedID 21402444

  • Physicians' experiences and perspectives regarding follow-up meetings with parents after a child's death in the pediatric intensive care unit PEDIATRIC CRITICAL CARE MEDICINE Meert, K. L., Eggly, S., Berger, J., Zimmerman, J., Anand, K. S., Newth, C. L., Harrison, R., Carcillo, J., Dean, J., Willson, D. F., Nicholson, C., Eunice Kennedy Shriver Natl Inst 2011; 12 (2): E64-E68


    To investigate critical care physicians' experiences and perspectives regarding follow-up meetings with parents after a child's death in the pediatric intensive care unit. Parents of children who die in the pediatric intensive care unit often desire a follow-up meeting with the physicians who cared for their child.Semistructured, audio-recorded telephone interviews.Six clinical centers affiliated with the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.Seventy critical care physicians (i.e., attendings and fellows) practicing or training at a Child Health and Human Development Collaborative Pediatric Critical Care Research Network clinical center between February 1, 2008 and June 30, 2008.Twenty-three (33%) physicians reported never participating in a follow-up meeting with bereaved parents; 22 (31%) participated in one to five meetings; and 25 (36%) participated in more than five meetings. Of those with prior experience, 44 (94%) met with parents at the hospital and 40 (85%) met within 3 months of the death. Meeting content included discussing autopsy, parent questions, hospital course, cause of death, genetic risk, bereavement services, and legal or administrative issues; providing emotional support; and receiving parent feedback. Forty (85%) physicians perceived the meetings to be beneficial to families, and 35 (74%) to physicians. Barriers included time and scheduling, family and physician unwillingness, distance and transportation, language and cultural issues, parent anger, and lack of a system for meeting initiation and planning.Critical care physicians have a wide range of experience conducting follow-up meetings with bereaved parents. Although physicians perceive benefits to follow-up meetings, barriers exist that interfere with their implementation in clinical practice.

    View details for DOI 10.1097/PCC.0b013e3181e89c3a

    View details for Web of Science ID 000288006100037

    View details for PubMedID 20581729

    View details for PubMedCentralID PMC3327296

  • A framework for conducting follow-up meetings with parents after a child's death in the pediatric intensive care unit PEDIATRIC CRITICAL CARE MEDICINE Eggly, S., Meert, K. L., Berger, J., Zimmerman, J., Anand, K. S., Newth, C. L., Harrison, R., Carcillo, J., Dean, J., Willson, D. F., Nicholson, C., Eunice Kennedy Shriver Natl Inst C 2011; 12 (2): 147-152


    To describe a framework to assist pediatric intensive care unit physicians in conducting follow-up meetings with parents after their child's death. Many childhood deaths occur in pediatric intensive care units. Parents of children who die in pediatric intensive care units often desire a follow-up meeting with the physician(s) who cared for their child.Prior research conducted by the Collaborative Pediatric Critical Care Research Network on the experiences and perspectives of bereaved parents and pediatric intensive care unit physicians regarding the desirability, content, and conditions of follow-up meetings.The framework includes suggestions for inviting families to follow-up meetings (i.e., developing an institutional system, invitation timing, and format); preparing for the meeting (i.e., assessing family preferences; determining location, attendees, and discussion topics; reviewing medical and psychosocial history); structure of the meeting (i.e., opening, closing, and developing a meeting agenda); communicating effectively during the meeting; and follow-up for both parents and physicians.This framework is based on the experience and perspectives of bereaved parents and pediatric intensive care unit physicians. Future research should be conducted to determine the extent to which physician-parent follow-up meetings provide a benefit to parents, families, physicians, and other healthcare providers participating in these encounters.

    View details for DOI 10.1097/PCC.0b013e3181e8b40c

    View details for Web of Science ID 000288006100004

    View details for PubMedID 20625339

    View details for PubMedCentralID PMC3285236

  • Neonatal pain assessment in Sweden - a fifteen-year follow up ACTA PAEDIATRICA Gradin, M., Eriksson, M. 2011; 100 (2): 204-208


    It has been proposed that a systematic pain assessment increases the awareness of the need to treat and prevent pain, and most international and national neonatal pain guidelines state that pain assessment should be performed in a systematic way. National surveys show a wide variation in compliance to these guidelines.A survey to all Swedish neonatal units was performed in 1993, 1998, 2003 and 2008, concerning the use of, and need for, pain assessment tools.The number of units that tried to assess pain increased from 64% in 1993 to 83% in 2008. Forty-four per cent of these used a structured method in 2003, compared to three per cent in 1998. The most common pain indicator was facial actions.The proportion of neonatal units that reported the use of a structured pain assessment tool has increased significantly from 1993 to 2008. There is a need for better evidence for the relation between the implementation of pain guidelines and the actual performance of pain assessment.

    View details for DOI 10.1111/j.1651-2227.2010.01996.x

    View details for Web of Science ID 000285971100011

    View details for PubMedID 20804461

  • Follow-Up Study of Complicated Grief among Parents Eighteen Months after a Child's Death in the Pediatric Intensive Care Unit JOURNAL OF PALLIATIVE MEDICINE Meert, K. L., Shear, K., Newth, C. L., Harrison, R., Berger, J., Zimmerman, J., Anand, K. S., Carcillo, J., Donaldson, A. E., Dean, J., Willson, D. F., Nicholson, C., Eunice Kennedy Shriver Natl Inst C 2011; 14 (2): 207-214


    We previously demonstrated that parents whose children die in a pediatric intensive care unit (PICU) have a high level of complicated grief symptoms 6 months after the death. In this study, we investigate the change in the extent of complicated grief symptoms among these parents between 6 and 18 months postdeath and identify factors predicting improvement.One hundred thirty-eight parents of 106 children completed surveys at 6 and 18 months. Surveys included the Inventory of Complicated Grief (ICG), measures of grief avoidance, attachment, caregiving and social support, and demographics. Multivariable analysis was performed using generalized estimating equations to identify characteristics independently associated with improvement in ICG score.ICG scores were 33.4 ± 13.6 at 6 months and 28.0 ± 13.5 at 18 months, representing an improvement in ICG score of 5.4 + 8.0 (95% confidence interval [CI] 4.1-6.8, p < 0.001). Variables independently associated with greater improvement in ICG score included traumatic death and greater grief avoidance. Variables independently associated with less improvement included being the biological parent and having more responsive caregiving. Parents with one or two surviving children had more improvement in ICG score than those with no surviving children whereas parents with three or more surviving children had less improvement.Complicated grief symptoms decrease among parents between 6 and 18 months after their child's death in the PICU; however, high symptom levels persists for some. Better understanding of the trajectory of complicated grief will allow parents at risk for persistent distress to receive professional support.

    View details for DOI 10.1089/jpm.2010.0291

    View details for Web of Science ID 000287236200017

    View details for PubMedID 21281122

    View details for PubMedCentralID PMC3037801

  • Enhanced Monitoring Improves Pediatric Transport Outcomes: A Randomized Controlled Trial PEDIATRICS Stroud, M. H., Prodhan, P., Moss, M., Fiser, R., Schexnayder, S., Anand, K. 2011; 127 (1): 42-48


    The "golden-hour" concept has led to emphasis on speed of patient delivery during pediatric interfacility transport. Timely intervention, in addition to enhanced monitoring during transport, is the key to improved outcomes in critically ill patients. Taking the ICU to the patient may be more beneficial than rapid delivery to a tertiary care center.The Improved Monitoring During Pediatric Interfacility Transport trial was the first randomized controlled trial in the out-of-hospital pediatric transport environment. It was designed to determine the impact of improved blood pressure monitoring during pediatric interfacility transport and the effect on clinical outcomes in patients with systemic inflammatory response syndrome and moderate-to-severe head trauma. Patients in the control group had their blood pressure monitored intermittently with an oscillometric device; those in the intervention group had their blood pressure monitored every 12 to 15 cardiac contractions with a near-continuous, noninvasive device.Between May 2006 and June 2007, 1995, consecutive transport patients were screened, and 94 were enrolled (48 control, 46 intervention). Patients in the intervention group received more intravenous fluid (19.8 ± 22.2 vs 9.9 ± 9.9 mL/kg; P = .01), had a shorter hospital stay (6.8 ± 7.8 vs 10.9 ± 13.4 days; P = .04), and had less organ dysfunction (18 of 206 vs 32 of 202 PICU days; P = .03).Improved monitoring during pediatric transport has the potential to improve outcomes of critically ill children. Clinical trials, including randomized controlled trials, can be accomplished during pediatric transport. Future studies should evaluate optimal equipment, protocols, procedures, and interventions during pediatric transport, aimed at improving the clinical and functional outcomes of critically ill patients.

    View details for DOI 10.1542/peds.2010-1336

    View details for Web of Science ID 000285782200043

    View details for PubMedID 21173006

  • Pediatric Patients Seen in Port-au-Prince, Haiti CLINICAL PEDIATRICS Anand, K. S., Eubanks, J. W., Kelly, D. M., Meier, J. W., Saltzman, J. A., Crisler, S., Kraus, G. J., Spentzas, T., Chesney, R. W. 2010; 49 (12): 1147-1152

    View details for DOI 10.1177/0009922810378737

    View details for Web of Science ID 000284587200009

    View details for PubMedID 20724324

  • Facilitated tucking as a non-pharmacological intervention for neonatal pain relief: is it clinically feasible? ACTA PAEDIATRICA Cignacco, E., Axelin, A., Stoffel, L., Sellam, G., Anand, K. S., Engberg, S. 2010; 99 (12): 1763-1765


    There is an impressive body of knowledge on pain management in infants hospitalized in neonatal intensive care units. However, deficits in the clinical management of pain in these infants remain. One reason is the gap between research evidence and translation of this knowledge into the clinical setting. This is particularly true for non-pharmacological pain-relieving methods. Effective performance of some of these methods requires additional staffing and time. This viewpoint articles describes the clinical challenges associated with implementing 'facilitated tucking'. Although 'facilitated tucking' is described as an efficient method for acute pain relief, the clinical facilitators required to successfully implement such a resource consuming-intervention remain unclear.  Translational research on the feasibility of using 'facilitated tucking' in the management of neonatal pain is warranted, including the economic impact of this intervention. Increased manpower costs need to be weighed against the possible long-term economical consequences of pain exposure in infants.

    View details for DOI 10.1111/j.1651-2227.2010.01941.x

    View details for Web of Science ID 000283690300006

    View details for PubMedID 20618166

  • Complicated Grief and Associated Risk Factors Among Parents Following a Child's Death in the Pediatric Intensive Care Unit ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Meert, K. L., Donaldson, A. E., Newth, C. L., Harrison, R., Berger, J., Zimmerman, J., Anand, K. S., Carcillo, J., Dean, J., Willson, D. F., Nicholson, C., Shear, K., Eunice Kennedy Shriver Natl Inst 2010; 164 (11): 1045-1051


    To investigate the extent of complicated grief symptoms and associated risk factors among parents whose child died in a pediatric intensive care unit.Cross-sectional survey conducted by mail and telephone.Seven children's hospitals affiliated with the Collaborative Pediatric Critical Care Research Network from January 1, 2006, to June 30, 2008.Two hundred sixty-one parents from 872 families whose child died in a pediatric intensive care unit 6 months earlier.Assessment of potential risk factors, including demographic and clinical variables, and parent psychosocial characteristics, such as attachment style, caregiving style, grief avoidance, and social support.Parent report of complicated grief symptoms using the Inventory of Complicated Grief. Total scale range is from 0 to 76; scores of 30 or higher suggest complicated grief.Mean (SD) Inventory of Complicated Grief scores among parents were 33.7 (14.1). Fifty-nine percent of parents (95% confidence interval, 53%-65%) had scores of 30 or higher. Variables independently associated with higher symptom scores in multivariable analysis included being the biological mother or female guardian, trauma as the cause of death, greater attachment-related anxiety and attachment-related avoidance, and greater grief avoidance.Parents who responded to our survey experienced a high level of complicated grief symptoms 6 months after their child's death in the pediatric intensive care unit. However, our estimate of the extent of complicated grief symptoms may be biased because of a high number of nonresponders. Better understanding of complicated grief and its risk factors among parents will allow those most vulnerable to receive professional bereavement support.

    View details for DOI 10.1001/archpediatrics.2010.187

    View details for Web of Science ID 000283735700012

    View details for PubMedID 21041597

    View details for PubMedCentralID PMC3279721

  • Pain Assessment in Cognitively Impaired, Functionally Impaired Children: Pilot Study Results JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES McJunkins, A., Green, A., Anand, K. S. 2010; 25 (4): 307-309

    View details for DOI 10.1016/j.pedn.2008.09.006

    View details for Web of Science ID 000208547800013

    View details for PubMedID 20620814

  • Tolerance and Withdrawal From Prolonged Opioid Use in Critically III Children PEDIATRICS Anand, K. S., Willson, D. F., Berger, J., Harrison, R., Meert, K. L., Zimmerman, J., Carcillo, J., Newth, C. L., Prodhan, P., Dean, J., Nicholson, C., Eunice Kennedy Shriver Natl Inst H 2010; 125 (5): E1208-E1225


    After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal.Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid," "opiate," "sedation," "analgesia," "child," "infant-newborn," "tolerance," "dependency," "withdrawal," "analgesic," "receptor," and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis.Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia.Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

    View details for DOI 10.1542/peds.2009-0489

    View details for Web of Science ID 000277232800057

    View details for PubMedID 20403936

    View details for PubMedCentralID PMC3275643

  • Use of Analgesic and Sedative Drugs in the NICU: Integrating Clinical Trials and Laboratory Data PEDIATRIC RESEARCH Durrmeyer, X., Vutskits, L., Anand, K. S., Rimensberger, P. C. 2010; 67 (2): 117-127


    Recent advances in neonatal intensive care include and are partly attributable to growing attention for comfort and pain control in the term and preterm infant requiring intensive care.Limitation of painful procedures is certainly possible, but most critically ill infants require unavoidable painful or stressful procedures such as intubation, mechanical ventilation, or catheterization.Many analgesics (opioids and nonsteroidal anti-inflammatory drugs)and sedatives (benzodiazepines and other anesthetic agents) are available but their use varies considerably among units. This review summarizes current experimental knowledge on the effects of sedative and analgesic drugs on brain development and reviews clinical evidence that speaks for or against the use of common analgesic and sedative drugs in the NICU but avoids any discussion of anesthesia during surgery. Risk/benefit ratios of intermittent boluses or continuous infusions for the commonly used sedative and analgesic agents are discussed in the light of clinical and experimental studies. The limitations of extrapolating experimental results from animals to humans must be considered while making practical recommendations based on the currently available evidence.

    View details for DOI 10.1203/PDR.0b013e3181c8eef3

    View details for Web of Science ID 000273790800001

    View details for PubMedID 20091937

  • Collaborative Pediatric Critical Care Research Network: Looking back and moving forward PEDIATRIC CRITICAL CARE MEDICINE Willson, D. F., Dean, J., Meert, K. L., Newth, C. L., Anand, K. S., Berger, J., Harrison, R., Zimmerman, J., Carcillo, J., Pollack, M., Holubkov, R., Jenkins, T. L., Nicholson, C., Eunice Kennedy Shriver Natl Inst C, Human Dev Collaborative Pediat Cri 2010; 11 (1): 1-6


    To update the pediatric critical care community on the progress of the Collaborative Pediatric Critical Care Research Network and plans for the future.The six sites, seven hospitals of the Collaborative Pediatric Critical Care Research Network.From the time of its inception in August 2005, the Network has engaged in a number of observational and interventional trials, several of which are ongoing. Additional studies are in the planning stages. To date, these studies have resulted in the publication of six manuscripts and five abstracts, with five additional manuscripts accepted and in press.The Network remains committed to its stated goal "to initiate a multicentered program designed to investigate the safety and efficacy of treatment and management strategies to care for critically ill children, as well as the pathophysiologic basis of critical illness and injury in childhood."

    View details for DOI 10.1097/PCC.0b013e3181c01302

    View details for Web of Science ID 000273401800001

    View details for PubMedID 19794321

    View details for PubMedCentralID PMC3293213

  • Taking Up the Challenge of Measuring Prolonged Pain in (Premature) Neonates The COMFORTneo Scale Seems Promising CLINICAL JOURNAL OF PAIN van Dijk, M., Roofthooft, D. E., Anand, K. S., Guldemond, F., de Graaf, J., Simons, S., de Jager, Y., van Goudoever, J. B., Tibboel, D. 2009; 25 (7): 607-616


    Pain assessment is essential to tailor intensive care of neonates. The present focus is on acute procedural pain; assessment of pain of longer duration remains a challenge. We therefore tested a modified version of the COMFORT-behavior scale-named COMFORTneo-for its psychometric qualities in the Neonatal Intensive Care Unit setting.In a clinical observational study, nurses assessed patients with COMFORTneo and Numeric Rating Scales (NRS) for pain and distress, respectively. Interrater reliability, concurrent validity, and sensitivity to change were calculated as well as sensitivity and specificity for different cut-off scores for subsets of patients.Interrater reliability was good: median linearly weighted Cohen kappa 0.79. Almost 3600 triple ratings were obtained for 286 neonates. Internal consistency was good (Cronbach alpha 0.84 and 0.88). Concurrent validity was demonstrated by adequate and good correlations, respectively, with NRS-pain and NRS-distress: r=0.52 (95% confidence interval 0.44-0.59) and r=0.70 (95% confidence interval 0.64-0.75). COMFORTneo cut-off scores of 14 or higher (score range is 6 to 30) had good sensitivity and specificity (0.81 and 0.90, respectively) using NRS-pain or NRS-distress scores of 4 or higher as criterion.The COMFORTneo showed preliminary reliability. No major differences were found in cut-off values for low birth weight, small for gestational age, neurologic impairment risk levels, or sex. Multicenter studies should focus on establishing concurrent validity with other instruments in a patient group with a high probability of ongoing pain.

    View details for DOI 10.1097/AJP.0b013e3181a5b52a

    View details for Web of Science ID 000269331400009

    View details for PubMedID 19692803

  • Is "rescue" therapy ethical in randomized controlled trials? PEDIATRIC CRITICAL CARE MEDICINE Holubkov, R., Dean, J., Berger, J., Anand, K. S., Carcillo, J., Meert, K., Zimmerman, J., Newth, C., Harrison, R., Willson, D. F., Nicholson, C., Eunice Kennedy Shriver Natl 2009; 10 (4): 431-438


    There is a commonly held belief that randomized, placebo-controlled trials in pediatric critical care should incorporate "rescue" therapy (open-label administration of active drug) when a child's condition is deteriorating. The ethical, conceptual, and analytic challenges related to rescue therapy in randomized trials can be misrepresented.Narrative review.The ethical basis of rescue therapy, the equipoise concept, and intention-to-treat analysis are examined in the setting of a hypothetical randomized trial comparing corticosteroids vs. placebo in pediatric septic shock.The perceived need for rescue therapy may be partly motivated by the moral imperative to save a child's life. However, allowing rescue therapy in a trial is misconceived and inconsistent with equipoise regarding the efficacy of the study drug. If rescue therapy is permitted, intention-to-treat analysis can only compare immediate vs. delayed use of the study drug. When rescue therapy is beneficial, the observed treatment effect is substantially diminished from true effect of the study drug, leading to increased sample size and thereby placing more children at risk (18 "excess" placebo-arm deaths occur in our hypothetical example). Analysis of a trial incorporating rescue therapy cannot definitively assess overall efficacy of the agent, or distinguish beneficial or harmful treatment effects related to timing of drug use.Although a rescue therapy component in a randomized trial may be perceived as ethically desirable, inconsistency of rescue therapy with full equipoise may itself raise significant ethical concerns. Increased sample sizes expose more children to the risks of study participation, including death. Researchers should be aware that clinical trials designed with rescue therapy cannot definitively determine the beneficial or harmful effects of a treatment per se, and can only assess the effects of delayed vs. immediate provision of the treatment.

    View details for DOI 10.1097/PCC.0b013e318198bd13

    View details for Web of Science ID 000267840500001

    View details for PubMedID 19307815

    View details for PubMedCentralID PMC3259684

  • Rationale and Design of the Pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Carcillo, J., Holubkov, R., Dean, J., Berger, J., Meert, K. L., Anand, K. S., Zimmerman, J., Newth, C. L., Harrison, R., Wilson, D. F., Nicholson, C., Child Hlth Human Dev Collaborative 2009; 33 (4): 368-374


    Despite implementation of CDC recommendations and bundled interventions for preventing catheter-associated blood stream infection, ventilator-associated pneumonia, or urinary catheter-associated infections, nosocomial infections and sepsis remain a significant cause of morbidity and mortality in critically ill children. Recent studies suggest that acquired critical illness stress-induced immune suppression (CRISIS) plays a role in the development of nosocomial infection and sepsis. This condition can be related to inadequate zinc, selenium, and glutamine levels, as well as hypoprolactinemia, leading to stress-induced lymphopenia, a predominant T(H)2 monocyte/macrophage state, and subsequent immune suppression. Prolonged immune dysfunction increases the likelihood of nosocomial infections associated with invasive devices. Although strategies to prevent common complications of critical illness are routinely employed (eg, prophylaxis for gastrointestinal bleeding, thrombophlebitis), no prophylactic strategy is used to prevent stress-induced immune suppression. This is the authors' rationale for the pediatric CRISIS prevention trial (NCT00395161), designed as a randomized, double-blind, controlled clinical investigation to determine if daily enteral supplementation with zinc, selenium, and glutamine as well as parenteral metoclopramide (a dopamine 2 receptor antagonist that reverses hypoprolactinemia) prolongs the time until onset of nosocomial infection or sepsis in critically ill children compared to enteral supplementation with whey protein. If effective, this combined nutritional and pharmacologic approach may lessen the excess morbidity and mortality as well as resource utilization associated with nosocomial infections and sepsis in this population. The authors present the design and analytic plan for the CRISIS prevention trial.

    View details for DOI 10.1177/0148607108327392

    View details for Web of Science ID 000267184800003

    View details for PubMedID 19380753

    View details for PubMedCentralID PMC2918276

  • Functional Status Scale: New Pediatric Outcome Measure PEDIATRICS Pollack, M. M., Holubkov, R., Glass, P., Dean, J., Meert, K. L., Zimmerman, J., Anand, K. S., Carcillo, J., Newth, C. L., Harrison, R., Willson, D. F., Nicholson, C., Eunice Kennedy Shriver Natl Inst 2009; 124 (1): E18-E28


    The goal was to create a functional status outcome measure for large outcome studies that is well defined, quantitative, rapid, reliable, minimally dependent on subjective assessments, and applicable to hospitalized pediatric patients across a wide range of ages and inpatient environments.Functional Status Scale (FSS) domains of functioning included mental status, sensory functioning, communication, motor functioning, feeding, and respiratory status, categorized from normal (score = 1) to very severe dysfunction (score = 5). The Adaptive Behavior Assessment System II (ABAS II) established construct validity and calibration within domains. Seven institutions provided PICU patients within 24 hours before or after PICU discharge, high-risk non-PICU patients within 24 hours after admission, and technology-dependent children. Primary care nurses completed the ABAS II. Statistical analyses were performed.A total of 836 children, with a mean FSS score of 10.3 (SD: 4.4), were studied. Eighteen percent had the minimal possible FSS score of 6, 44% had FSS scores of >or=10, 14% had FSS scores of >or=15, and 6% had FSS scores of >or=20. Each FSS domain was associated with mean ABAS II scores (P < .0001). Cells in each domain were collapsed and reweighted, which improved correlations with ABAS II scores (P < .001 for improvements). Discrimination was very good for moderate and severe dysfunction (ABAS II categories) and improved with FSS weighting. Intraclass correlations of original and weighted total FSS scores were 0.95 and 0.94, respectively.The FSS met our objectives and is well suited for large outcome studies.

    View details for DOI 10.1542/peds.2008-1987

    View details for Web of Science ID 000267448100059

    View details for PubMedID 19564265

    View details for PubMedCentralID PMC3191069

  • More Information, Less Understanding: A Randomized Study on Consent Issues in Neonatal Research PEDIATRICS Freer, Y., McIntosh, N., Teunisse, S., Anand, K. S., Boyle, E. M. 2009; 123 (5): 1301-1305


    Valid consent for research requires comprehensive and understandable information to be disclosed to participants. The way that information is shared varies, but regulatory bodies usually determine style. Some reports have suggested that although information may be all-inclusive, it does little to support understanding.To explore the impact of various information-sharing approaches on parents' understanding of a research study and the validity of their consent.This was a randomized, controlled trial. Parents of immature but well infants admitted to a large tertiary NICU in Edinburgh, Scotland, were randomly assigned within 72 hours of their infant's admission to receive 1 of 2 information leaflets, with or without a standardized verbal explanation, for a hypothetical intensive care research study. The leaflets differed in length and in the amount of detail in which the study process, risks, benefits, and patient rights were described. A questionnaire was used to elicit understanding about the purpose of the research, design of the study, procedures involved, and the consent process.Forty-one parents participated in the study. Those who received the longer leaflet without verbal explanation gained only limited understanding of the purpose of the research. The procedures involved in the study were understood better by those who received the shorter leaflet. Issues relating to consent and study design were readily understood in all groups. Irrespective of documentation style, verbal explanation significantly improved understanding. Differences in understanding had little effect on whether a parent would enroll his or her infant into the study.Verbal explanation significantly enhances understanding of the research process for participants regardless of the style of written documentation. However, shorter written information may lead to better understanding than lengthy, more complex documentation.

    View details for DOI 10.1542/peds.2007-3860

    View details for Web of Science ID 000265528900008

    View details for PubMedID 19403495

  • The Effect of Tai Chi on Knee Osteoarthritis Pain in Cognitively Impaired Elders: Pilot Study GERIATRIC NURSING Tsai, P., Beck, C., Chang, J. Y., Hagen, J., Kuo, Y., Roberson, P. K., Rosengren, K., Beuscher, L., Doan, C. L., Anand, K. S. 2009; 30 (2): 132-139


    This article reports a pilot study of the effect of tai chi (TC), a pharmacological adjunct and mild aerobic exercise, on osteoarthritic knee pain in elders with cognitive impairment (CI). The TC program included a warm-up, 12-form Sun-style TC, and a cool-down period, for a total of 20-40 minutes per session, twice a week for 15 weeks. The results showed no significant differences in knee pain after the TC intervention in 7 elders with CI. However, more minutes of TC attendance were related to improved pain scores (Spearman's rho=.78, P < .05). Greater accuracy in TC performance was also correlated with improvements in pain scores (Spearman's rho = .70, P=.08). Of 4 elders who participated in TC practice regularly (more than 20 sessions), 3 showed clinically important improvements, but 3 elders who participated in no sessions or only a few sessions showed no improvement.

    View details for DOI 10.1016/j.gerinurse.2007.11.002

    View details for Web of Science ID 000265573000010

    View details for PubMedID 19345855

    View details for PubMedCentralID PMC2748759

  • Accounting for medical communication: parents' perceptions of communicative roles and responsibilities in the pediatric intensive care unit. Communication & medicine Gordon, C., Barton, E., Meert, K. L., Eggly, S., Pollacks, M., Zimmerman, J., Anand, K. J., Carcillo, J., Newth, C. J., Dean, J. M., Willson, D. F., Nicholson, C., Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network 2009; 6 (2): 177-88


    Through discourse analysis of transcribed interviews conducted over the phone with parents whose child died in the Pediatric Intensive Care Unit (PICU) (n = 51), this study uncovers parents' perceptions of clinicians' and their own communicative roles and responsibilities in the context of team-based care. We examine parents' descriptions and narratives of communicative experiences they had with PICU clinicians, focusing on how parents use accounts to evaluate the communicative behaviors they report (n = 47). Findings indicate that parental perceptions of communicative responsibilities are more nuanced than assumed in previous research: Parents identified their own responsibilities as participating as part of the team of care, gathering information, interacting with appropriate affect, and working to understand complex and uncertain medical information. Complementarily, parents identified clinician responsibilities as communicating professionally, providing medical information clearly, managing parents' hope responsibly, and communicating with appropriate affect. Through the accounts they provide, parents evaluate both parental and clinician role-responsibilities as fulfilled and unfulfilled. Clinicians' management of prognostic uncertainty and parents' struggles to understand that uncertainty emerged as key, complementary themes with practical implications for incorporating parents into the PICU care team. The study also highlights insights retrospective interview data bring to the examination of medical communication.

    View details for PubMedID 20635554

  • Mode of delivery modulates physiological and behavioral responses to neonatal pain JOURNAL OF PERINATOLOGY Bergqvist, L. L., Katz-Salamon, M., Hertegard, S., Anand, K. S., Lagercrantz, H. 2009; 29 (1): 44-50


    To study whether the mode of delivery alters pain expression.Full-term infants born by vaginal delivery or elective caesarean section were observed following high- and low-intensity pain stimuli, with recording of electrocardiogram, facial expression and vocalization.Graded physiological and behavioral responses occurred, with greater responses to higher than lower intensity pain stimuli. Elevation in heart rate following both stimuli increased with time after vaginal delivery. Infants delivered by elective caesarean section showed stronger facial expressions and briefer time in vocalizations response to both interventions.Diminished responses following vaginal delivery suggest that physiological events associated with a normal delivery reduce the physiologic and sympathoadrenal activation by nociceptive mechanisms. Pain and stress reactivity appear to be inhibited during fetal life and sensory inputs during vaginal delivery may reverse this inhibition. To minimize neonatal pain, we recommend that postnatal invasive procedures to be performed shortly after vaginal birth.

    View details for DOI 10.1038/jp.2008.129

    View details for Web of Science ID 000262043200008

    View details for PubMedID 18769380

  • Weaning and extubation readiness in pediatric patients PEDIATRIC CRITICAL CARE MEDICINE Newth, C. L., Venkataraman, S., Willson, D. F., Meert, K. L., Harrison, R., Dean, J., Dean, M., Pollack, M., Zimmerman, J., Anand, K. S., Carcillo, J. A., Nicholson, C. E., Eunice Shriver Kennedy Natl Inst C 2009; 10 (1): 1-11


    A systematic review of weaning and extubation for pediatric patients on mechanical ventilation.Pediatric and adult literature, English language.Invited review.Literature review using National Library of Medicine PubMed from January 1972 until April 2008, earlier cross-referenced article citations, the Cochrane Database of Systematic Reviews, and the Internet.Despite the importance of minimizing time on mechanical ventilation, only limited guidance on weaning and extubation is available from the pediatric literature. A significant proportion of patients being evaluated for weaning are actually ready for extubation, suggesting that weaning is often not considered early enough in the course of ventilation. Indications for extubation are even less clear, although a trial of spontaneous breathing would seem a prerequisite. Several indices have been developed in an attempt to predict weaning and extubation success but the available literature would suggest they offer no improvement over clinical judgment. Extubation failure rates range from 2% to 20% and bear little relationship to the duration of mechanical ventilation. Upper airway obstruction is the single most common cause of extubation failure. A reliable method of assessing readiness for weaning and predicting extubation success is not evident from the pediatric literature.

    View details for DOI 10.1097/PCC.0b013e318193724d

    View details for Web of Science ID 000262574800001

    View details for PubMedID 19057432

    View details for PubMedCentralID PMC2849975

  • Prevention of Pain in Neonates Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Carbajal, R., Anand, K. S. 2008; 300 (19): 2248-2249
  • Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial BRITISH JOURNAL OF ANAESTHESIA Anand, K. S., Anderson, B. J., Holford, N. G., Hall, R. W., Young, T., Shephard, B., Desai, N. S., Barton, B. A., NEOPAIN Trial Invest Grp 2008; 101 (5): 680-689


    Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates.Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 microg kg(-1)), morphine infusions [23-26 weeks postmenstrual age (PMA) 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); and 30-32 weeks 30 microg kg(-1) h(-1)] were established for a maximum of 14 days. Open-label morphine (20-100 microg kg(-1)) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20-28 and 70-76 h after starting the drug infusion and at 10-14 h after discontinuation of the study drug. The concentration-effect response was investigated using non-linear mixed effects models.A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat(50)) and increased from 2.05 litre h(-1) 70 kg(-1) at 24 weeks PMA to 6.04 litre h(-1) 70 kg(-1) at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg(-1) (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0-440 microg litre(-1)) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile.A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.

    View details for DOI 10.1093/bja/aen248

    View details for Web of Science ID 000260131900013

    View details for PubMedID 18723857

    View details for PubMedCentralID PMC2733178

  • Morphine analgesia and gastrointestinal morbidity in preterm infants: secondary results from the NEOPAIN trial ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Menon, G., Boyle, E. M., Bergqvist, L. L., McIntosh, N., Barton, B. A., Anand, K. S. 2008; 93 (5): F362-F367


    To investigate the influence of morphine therapy and other factors on the attainment of full enteral feeds and on acquired gastrointestinal pathology in preterm infants.Secondary data analysis from a randomised, placebo controlled trial.16 neonatal intensive care units in USA, Sweden, France and UK.898 infants (treatment group 449, control 449). Gestation (median (range)): 27 (23-32) weeks; birth weight (median (range)): 985 (420-2440) g.Morphine (M) or placebo (Pl) given pre-emptively by intravenous loading dose (100 microg/kg of morphine) and infusion (10-30 microg/kg/h depending on gestation) while infants were ventilated, for up to 14 days. "Open-label" morphine (A) could be given if clinically indicated.Age at full enteral feeds and major acquired gastrointestinal pathology.The group randomised to morphine was later in attaining full feeds (median days (quartiles): M 20 (13-29), Pl 17 (12-26); p = 0.003), and in starting feeds (median days (quartiles): M 5 (3-8), Pl 4 (2-7)). In a linear regression model, age at full feeds was independently associated with birth weight, a score of neonatal morbidities, neonatal dexamethasone use and cumulative morphine dose. There was no relationship between morphine use and acquired gastrointestinal pathology (M 9/449, Pl 8/449; chi2 p = 0.81).Morphine delays the attainment of full enteral feeds, partly by delaying the start of feeding, but does not discernibly increase gastrointestinal complications. The attainment of full feeds is influenced by morphine dose, but other factors seem to be important, including birth weight and neonatal morbidity.

    View details for DOI 10.1136/adc.2007.119297

    View details for Web of Science ID 000258867700008

    View details for PubMedID 18089630

  • Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects BEHAVIORAL AND BRAIN FUNCTIONS Rovnaghi, C. R., Garg, S., Hall, R. W., Bhutta, A. T., Anand, K. S. 2008; 4: 35


    Neonatal rats exposed to repetitive inflammatory pain have altered behaviors in young adulthood, partly ameliorated by Ketamine analgesia. We examined the relationships between protein expression, neuronal survival and plasticity in the neonatal rat brain, and correlated these changes with adult cognitive behavior.Using Western immunoblot techniques, homogenates of cortical tissue were analyzed from neonatal rats 18-20 hours following repeated exposure to 4% formalin injections (F, N = 9), Ketamine (K, 2.5 mg/kg x 2, N = 9), Ketamine prior to formalin (KF, N = 9), or undisturbed controls (C, N = 9). Brain tissues from another cohort of rat pups (F = 11, K = 12, KF = 10, C = 15) were used for cellular staining with Fos immunohistochemistry or FluoroJade-B (FJB), followed by cell counting in eleven cortical and three hippocampal areas. Long-term cognitive testing using a delayed non-match to sample (DNMS) paradigm in the 8-arm radial maze was performed in adult rats receiving the same treatments (F = 20, K = 24, KF = 21, C = 27) in the neonatal period.Greater cell death occurred in F vs. C, K, KF in parietal and retrosplenial areas, vs. K, KF in piriform, temporal, and occipital areas, vs. C, K in frontal and hindlimb areas. In retrosplenial cortex, less Fos expression occurred in F vs. C, KF. Cell death correlated inversely with Fos expression in piriform, retrosplenial, and occipital areas, but only in F. Cortical expression of glial fibrillary acidic protein (GFAP) was elevated in F, K and KF vs. C. No significant differences occurred in Caspase-3, Bax, and Bcl-2 expression between groups, but cellular changes in cortical areas were significantly correlated with protein expression patterns. Cluster analysis of the frequencies and durations of behaviors grouped them as exploratory, learning, preparatory, consumptive, and foraging behaviors. Neonatal inflammatory pain exposure reduced exploratory behaviors in adult males, learning and preparatory behaviors in females, whereas Ketamine ameliorated these long-term effects.Neuroprotective effects of Ketamine attenuate the impaired cognitive behaviors resulting from pain-induced cell death in the cortical and hippocampal fields of neonatal rats. This cell death was not dependent on the apoptosis associated proteins, but was correlated with glial activation.

    View details for DOI 10.1186/1744-9081-4-35

    View details for Web of Science ID 000259014500001

    View details for PubMedID 18687139

    View details for PubMedCentralID PMC2527299

  • Epidemiology and treatment of painful procedures in neonates in intensive care units JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Carbajal, R., Rousset, A., Danan, C., Coquery, S., Nolent, P., Ducrocq, S., Saizou, C., Lapillonne, A., Granier, M., Durand, P., Lenclen, R., Coursol, A., Hubert, P., de Saint Blanquat, L., Boelle, P., Annequin, D., Cimerman, P., Anand, K. S., Breart, G. 2008; 300 (1): 60-70


    Effective strategies to improve pain management in neonates require a clear understanding of the epidemiology and management of procedural pain.To report epidemiological data on neonatal pain collected from a geographically defined region, based on direct bedside observation of neonates.Between September 2005 and January 2006, data on all painful and stressful procedures and corresponding analgesic therapy from the first 14 days of admission were prospectively collected within a 6-week period from 430 neonates admitted to tertiary care centers in the Paris region of France (11.3 millions inhabitants) for the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study.Number of procedures considered painful or stressful by health personnel and corresponding analgesic therapy.The mean (SD) gestational age and intensive care unit stay were 33.0 (4.6) weeks and 8.4 (4.6) calendar days, respectively. Neonates experienced 60,969 first-attempt procedures, with 42,413 (69.6%) painful and 18,556 (30.4%) stressful procedures; 11,546 supplemental attempts were performed during procedures including 10,366 (89.8%) for painful and 1180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4-613) procedures during the study period and 16 (range, 0-62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3-364) painful procedures during the study period and 10 (range, 0-51) painful procedures per day of hospitalization. Of the 42,413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia.During neonatal intensive care in the Paris region, large numbers of painful and stressful procedures were performed, the majority of which were not accompanied by analgesia.

    View details for DOI 10.1001/jama.300.1.60

    View details for Web of Science ID 000257242800025

    View details for PubMedID 18594041

  • Comparison at 32-37 weeks postconception of infants born 1983-1989 and 1995-2004 on the neurobehavioral assessment of the preterm infant INFANCY Brown, J. V., Bakeman, R., Sampers, J. S., Korner, A. F., Constantinou, J. C., Anand, K. J. 2008; 13 (4): 393-409
  • Redefining the golden hour in pediatric transport PEDIATRIC CRITICAL CARE MEDICINE Stroud, M. H., Prodhan, P., Moss, M. M., Anand, K. S. 2008; 9 (4): 435-437


    To emphasize the urgent need for research efforts and application of goal-directed therapy in the pediatric transport environment.Review of existing literature and commentary on current pediatric transport practices.Pediatric transport has evolved significantly since its inception >2 decades ago. Advancements in technology and therapeutic interventions now afford an opportunity to extend intensive care into the transport environment. However, misapplication of the concept of the golden hour has led to a focus on speed of transfer to tertiary care facilities, often delaying early, goal-directed therapeutic interventions. If we are to further improve outcomes for critically ill children, we must extend early institution of goal-directed therapy into the pretertiary hospital setting and bring expertise to the child.

    View details for DOI 10.1097/PCC.0b013e318172da62

    View details for Web of Science ID 000257627600014

    View details for PubMedID 18496407

  • Analgesia for skin-breaking procedures in newborns and children: What works best? CANADIAN MEDICAL ASSOCIATION JOURNAL Anand, K. S. 2008; 179 (1): 11-12

    View details for DOI 10.1503/cmaj.080834

    View details for Web of Science ID 000256897900002

    View details for PubMedID 18591514

    View details for PubMedCentralID PMC2464482

  • Long-term deficits of preterm birth: Evidence for arousal and attentional disturbances CLINICAL NEUROPHYSIOLOGY Hall, R., Huitt, T., Thapa, R., Williams, D., Anand, K. S., Garcia-Rill, E. 2008; 119 (6): 1281-1291


    Quantitative measures of pre-attentional, attentional and frontal lobe processes were compared to evaluate quantitative measures of these deficits in Ex-Preterm vs. Ex-Term adolescents.We compared 43 Ex-Preterm with 26 Ex-Term adolescents using the P50 auditory potential, the Psychomotor Vigilance Task (PVT), a reaction time (RT) test, and Near Infrared Spectroscopy (NIRS).The mean amplitude (+/-SE) of the P50 amplitude was similar in the Ex-Preterm (1.8+/-1.4 microV) vs. Ex-Term adolescents (1.8+/-0.6 microV, df = 68, F = 0.05, p = 0.8), but the Ex-Preterm group showed a trimodal distribution in amplitude (High, 3.3+/-0.4 microV, df=42.25, F=19.2, p < 0.01; Medium, 1.7+/-0.1 microV, df = 39, F = 0.41, p = 0.53; Low, 0.7+/-0.1 microV, df = 40, F = 49.5, p < 0.01) suggested by statistically significant variance between populations (Kolmogorov-Kuiper test, df = 42.25, F = 5.4, p < 0.01). Mean RT was longer in Ex-Preterm (250+/-8 ms) vs. Ex-Term subjects (200+/-5 ms, df = 68, F = 18.8, p < 0.001). PVT lapses were increased in Ex-Preterm subjects, and varied inversely with P50 amplitude (Overall Mean 17+/-5 lapses, df = 67, F = 5.34, p < 0.05; Low P50 amplitude, 25+/-10, df = 40, F = 8.8, p < 0.01; Medium, 21+/-11, df = 38, F = 5.37, p < 0.05; High, 6+/-2, df = 39, F = 6.78, p < 0.01) vs. Ex-Term subjects (2+/-0.4 lapses, p < 0.01). NIRS levels did not differ statistically, but tended to correlate with P50 amplitude in the Ex-Preterm group.These findings suggest differential pre-attentional, attentional and frontal lobe dysfunction in Ex-Preterm adolescents.These measures could provide a means to objectively assess differential dysregulation of arousal and attention in Ex-Preterm adolescents, allowing optimization of therapeutic designs.

    View details for DOI 10.1016/j.clinph.2007.12.021

    View details for Web of Science ID 000256499000009

    View details for PubMedID 18372212

    View details for PubMedCentralID PMC2670248

  • Ethical and logistical considerations of multicenter parental bereavement research JOURNAL OF PALLIATIVE MEDICINE Meert, K., Eggly, S., Dean, J., Pollack, M., Zimmerman, J., Anand, K. S., Newth, C. L., Willson, D. F., Nicholson, C. 2008; 11 (3): 444-450


    Multicenter research has the potential to recruit participants with diverse racial, ethnic, and geographic backgrounds and is essential for understanding heterogeneity in bereavement. The National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) is a multicenter network charged with conducting research on the pathophysiology and management of critical illness in childhood. Among its research activities, the CPCCRN has undertaken research in parental bereavement because most childhood deaths in the United States occur in hospitals, primarily in critical care units.The purpose of this paper is to discuss ethical and logistical issues found by the CPCCRN to be problematic to multicenter research with bereaved parents and to explore research strategies that may be practicably implemented.Ethical and logistical challenges encountered by the CPCCRN included issues of privacy; confidentiality; voluntariness; minimizing risks; working with multiple institutional review boards; researcher qualifications, training and support; and methods of data collection. Strategies to address these challenges included local recruitment of participants; flexibility in consent methods across sites; participant options for methods of data collection; involvement of local bereavement support services; central training of researchers with systematic monitoring and opportunities for support; and use of a secure Web-based collaborative workspace.Multicenter parental bereavement research has distinct ethical issues that must be addressed by the logistics of the research plan. Greater attention to the issues identified may facilitate research to reduce adverse mental and physical health outcomes in a diverse population of bereaved individuals.

    View details for DOI 10.1089/jpm.2007.0120

    View details for Web of Science ID 000254651800012

    View details for PubMedID 18363487

    View details for PubMedCentralID PMC3279723

  • Parents' perspectives on physician-parent communication near the time of a child's death in the pediatric intensive care unit PEDIATRIC CRITICAL CARE MEDICINE Meert, K. L., Eggly, S., Pollack, M., Anand, K. S., Zimmerman, J., Carcillo, J., Newth, C. L., Dean, J., Willson, D. F., Nicholson, C., Natl Inst Child Hlth 2008; 9 (1): 2-7


    Communicating bad news about a child's illness is a difficult task commonly faced by intensive care physicians. Greater understanding of parents' scope of experiences with bad news during their child's hospitalization will help physicians communicate more effectively. Our objective is to describe parents' perceptions of their conversations with physicians regarding their child's terminal illness and death in the pediatric intensive care unit (PICU).A secondary analysis of a qualitative interview study.Six children's hospitals in the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.Fifty-six parents of 48 children who died in the PICU 3-12 months before the study.Parents participated in audio recorded semistructured telephone interviews. Interviews were analyzed using established qualitative methods.Of the 56 parents interviewed, 40 (71%) wanted to provide feedback on the way information about their child's terminal illness and death was communicated by PICU physicians. The most common communication issue identified by parents was the physicians' availability and attentiveness to their informational needs. Other communication issues included honesty and comprehensiveness of information, affect with which information was provided, withholding of information, provision of false hope, complexity of vocabulary, pace of providing information, contradictory information, and physicians' body language.The way bad news is discussed by physicians is extremely important to most parents. Parents want physicians to be accessible and to provide honest and complete information with a caring affect, using lay language, and at a pace in accordance with their ability to comprehend. Withholding prognostic information from parents often leads to false hopes and feelings of anger, betrayal, and distrust. Future research is needed to investigate whether the way bad news is discussed influences psychological adjustment and family functioning among bereaved parents.

    View details for DOI 10.1097/01.PCC.0000298644.13882.88

    View details for Web of Science ID 000252462200002

    View details for PubMedID 18477906

    View details for PubMedCentralID PMC3198033

  • Anaesthetic neurotoxicity in rodents: is the ketamine controversy real ? ACTA PAEDIATRICA Bhutta, A. T., Venkatesan, A. K., Rovnaghi, C. R., Anand, K. S. 2007; 96 (11): 1554-1556
  • Non-pharmacological techniques for pain management in neonates SEMINARS IN PERINATOLOGY Golianu, B., Krane, E., Seybold, J., Almgren, C., Anand, K. J. 2007; 31 (5): 318-322


    Significant progress in understanding the physiology, clinical correlates, and consequences of neonatal pain have resulted in greater attention to pain management during neonatal intensive care. A number of nonpharmacological therapies have been investigated, including nonnutritive sucking, with and without sucrose use, swaddling or facilitated tucking, kangaroo care, music therapy, and multi-sensorial stimulation. Although the efficacy of these approaches is clearly evident, they cannot provide analgesia for moderate or severe pain in the neonate. Further, some of these therapies cannot be effectively applied to all populations of critically ill neonates. Acupuncture, an ancient practice in Chinese medicine, has gained increasing popularity for symptom control among adults and older children. Acupuncture may provide an effective nonpharmacological approach for the treatment of pain in neonates, even moderate or severe pain, and should be considered for inclusion in a graduated multidisciplinary algorithm for neonatal pain management.

    View details for DOI 10.1053/j.semperi.2007.07.007

    View details for PubMedID 17905187

  • Controversies in neonatal pain: An introduction SEMINARS IN PERINATOLOGY Anand, K. S. 2007; 31 (5): 273-274
  • Neurodevelopmental changes of fetal pain SEMINARS IN PERINATOLOGY Lowery, C. L., Hardman, M. P., Manning, N., Hall, R., Anand, K. S. 2007; 31 (5): 275-282


    Pain in the developing fetus is controversial because of the difficulty in measuring and interpreting pain during gestation. It has received increased attention lately because of recently introduced legislation that would require consideration of fetal pain during intentional termination of pregnancy. During development, sensory fibers are abundant by 20 weeks; a functional spinal reflex is present by 19 weeks; connections to the thalamus are present by 20 weeks; and connections to subplate neurons are present by 17 weeks with intensive differentiation by 25 weeks. These cells are important developmentally, but decline as a result of natural apoptosis. Mature thalamocortical projections are not present until 29 to 30 weeks, which has led many to believe the fetus does not experience emotional "pain" until then. Pain requires both nociception and emotional reaction or interpretation. Nociception causes physiologic stress, which in turn causes increases in catecholamines, cortisol, and other stress hormones. Physiological stress is different from the emotional pain felt by the more mature fetus or infant, and this stress is mitigated by pain medication such as opiates. The plasticity of the developing brain makes it vulnerable to the stressors that cause long-term developmental changes, ultimately leading to adverse neurological outcomes. Whereas evidence for conscious pain perception is indirect, evidence for the subconscious incorporation of pain into neurological development and plasticity is incontrovertible. Scientific data, not religious or political conviction, should guide the desperately needed research in this field. In the meantime, it seems prudent to avoid pain during gestation.

    View details for DOI 10.1053/j.semperi.2007.07.004

    View details for Web of Science ID 000250093900002

    View details for PubMedID 17905181

  • Premedication for tracheal intubation in neonates: Confusion or controversy? SEMINARS IN PERINATOLOGY Carbajal, R., Eble, B., Anand, K. S. 2007; 31 (5): 309-317


    Tracheal intubation is performed frequently in the NICU and delivery room. This procedure is extremely distressing, painful, and has the potential for airway injury. Premedication with sedatives, analgesics, and muscle relaxants is standard practice for pediatric and adult intubation, yet the use of these drugs is not common for intubation in neonates. The risks and benefits of using premedications for intubating unstable newborns are hotly debated, although recent evidence shows that premedication for non-urgent or semi-urgent intubations is safer and more effective than awake intubations. This article reviews clinical practices reported in surveys on premedication for neonatal intubation, the physiological effects of laryngoscopy and intubation on awake neonates, as well as the clinical and physiological effects of different drug combinations used for intubation. A wide variety of drugs, either alone or in combination, have been used as premedication for elective intubation in neonates. Schematically, these studies have been of three main types: (a) studies comparing awake intubation versus those with sedation or analgesia, (b) studies comparing different premedication regimens comprising sedatives, analgesics, and anesthetics, and (c) case series of neonates in which some authors have reported their experience with a specific premedication regimen. The clinical benefits described in these studies and the need for pain control in neonates make the case for using appropriate premedication routinely for elective or semi-urgent intubations. Tracheal intubation without the use of analgesia or sedation should be performed only for urgent resuscitations in the delivery room or other life-threatening situations when intravenous access is unavailable.

    View details for DOI 10.1053/j.semperi.2007.07.006

    View details for Web of Science ID 000250093900007

    View details for PubMedID 17905186

  • Neurobehavior of preterm infants at 36 weeks Postconception as a function of morphine analgesia AMERICAN JOURNAL OF PERINATOLOGY Rao, R., Sampers, J. S., Kronsberg, S. S., Brown, J. V., Desai, N. S., Anand, K. S. 2007; 24 (9): 511-517


    This study evaluated early neurobehavioral outcomes in ventilated preterm infants randomized to receive morphine analgesia or placebo in the Neurological Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial. Eight hundred and ninety-eight infants between 23 and 32 weeks of gestation were randomized to receive preemptive morphine analgesia (morphine) or placebo. Infants also received additional analgesia (AA) with open-label morphine. The Neurobehavioral Assessment of the Preterm Infant (NAPI) was used to evaluate 572 of 793 survivors (72.1%) at 36 weeks of postconceptual age. The Neonatal Medical Index (NMI) was used to evaluate the severity of medical complications. Regression analyses were used to determine the effect of covariates. Infants were equally distributed in morphine and placebo groups with similar neonatal and demographic characteristics. Infants assessed with the NAPI were more likely to have sepsis ( P = 0.03), bronchopulmonary dysplasia ( P = 0.02), and longer length of stay ( P = 0.008). Infants randomized to the morphine group had higher NMI scores (odds ratio [OR]; 95% confidence interval [CI]: 1.75; 1.23 to 2.50; P = 0.002). Use of AA was associated with higher NMI scores (OR; 95% CI: 4.5; 2.9 to 5.9; P < 0.001). Of the NAPI subscales, the (mean +/- standard deviation [SD]) popliteal angle cluster scores were significantly higher in the morphine group compared with placebo (51.2 +/- 33.2 versus 45.0 +/- 33.5; P = 0.03). AA use was associated with lower (mean +/- SD) MOTOR scores in the morphine group (48.2 +/- 16.1 versus 52.7 +/- 19.1; P = 0.03) and with lower POPLITEAL ANGLE cluster scores in both the morphine group (41.5 +/- 34.0 versus 59.5 +/- 30.1; P < 0.0001) and the placebo group (40.8 +/- 36.8 versus 49.4 +/- 28.0; P = 0.004). No differences were noted in the other NAPI subscales cluster scores in either subgroup. We conclude that morphine analgesia may result in subtle neurobehavioral differences in premature infants.

    View details for DOI 10.1055/s-2007-986675

    View details for Web of Science ID 000250400500002

    View details for PubMedID 17907073

  • Current controversies regarding pain assessment in neonates SEMINARS IN PERINATOLOGY Ranger, M., Johnston, C., Anand, K. S. 2007; 31 (5): 283-288


    Although over 40 methods of pain assessment in infants are available for use in clinical practice, unrecognized and under-treated pain remains one of the most commonly reported problems within the Neonatal Intensive Care Units. A number of factors have been found to account for differences in the robustness of the pain response in neonates of varying gestational ages. Discrepancies between behavioral and physiological pain indicators have also been reported. With newer technologies, there is an opportunity not only to verify infant pain perception, but these tools may allow an identification of which of the observed indicators are most sensitive in particular clinical situations. The current controversies regarding pain assessment in preterm and term infants are reviewed to define the most important issues and to develop a dialogue for future directions.

    View details for DOI 10.1053/j.semperi.2007.07.003

    View details for Web of Science ID 000250093900003

    View details for PubMedID 17905182

  • Extrapolating brain development from experimental species to humans Clancy, B., Finlay, B. L., Darlington, R. B., Arland, K. S. ELSEVIER SCIENCE BV. 2007: 931-937


    To better understand the neurotoxic effects of diverse hazards on the developing human nervous system, researchers and clinicians rely on data collected from a number of model species that develop and mature at varying rates. We review the methods commonly used to extrapolate the timing of brain development from experimental mammalian species to humans, including morphological comparisons, "rules of thumb" and "event-based" analyses. Most are unavoidably limited in range or detail, many are necessarily restricted to rat/human comparisons, and few can identify brain regions that develop at different rates. We suggest this issue is best addressed using "neuroinformatics", an analysis that combines neuroscience, evolutionary science, statistical modeling and computer science. A current use of this approach relates numeric values assigned to 10 mammalian species and hundreds of empirically derived developing neural events, including specific evolutionary advances in primates. The result is an accessible, online resource ( that can be used to equate dates in the neurodevelopmental literature across laboratory species to humans, predict neurodevelopmental events for which data are lacking in humans, and help to develop clinically relevant experimental models.

    View details for DOI 10.1016/j.neuro.2007.01.014

    View details for Web of Science ID 000250905100005

    View details for PubMedID 17368774

    View details for PubMedCentralID PMC2077812

  • Ketamine reduces the cell death following inflammatory pain in newborn rat brain PEDIATRIC RESEARCH Anand, K. S., Garg, S., Rovnaghi, C. R., Narsinghani, U., Bhutta, A. T., Hall, R. W. 2007; 62 (3): 283-290


    Premature infants experience untreated repetitive pain that may alter their brain development. Effects of ketamine and repetitive pain on cellular death and subsequent behavior were studied in neonatal rats. Rat pups were randomized to undisturbed controls (C), 4% formalin injection (F), ketamine alone (K, 5 mg/kg) or formalin plus ketamine (KF) and were assessed for neuroactivation with Fos protein, cellular death with FluoroJade-B, cognition with the radial arm maze, and pain thresholds with the hot-plate. Greater Fos expression and cell death occurred in F vs. C groups in defined brain areas at 1 and 4 h in F compared with other groups. Cell death was accentuated 3.3-fold in cortical areas and 1.6-fold in subcortical areas in the F compared with the C group following repetitive pain and sacrifice 18-20 h later. These effects were ameliorated by ketamine. Compared with the F group, all other groups demonstrated greater exploratory and rearing behaviors and decreased time for bait consumption at 1-h and 3-h intervals. Significantly greater thermal pain latencies occurred in the KF and F groups. Repetitive neonatal pain accentuates neuronal excitation and cell death in developmentally regulated cortical and subcortical areas, which decreases the acquisition of visual-spatial clues, short-term and long-term memory, and increases pain latencies. Ketamine analgesia mitigates most of these effects.

    View details for DOI 10.1203/PDR.0b013e3180986d2f

    View details for Web of Science ID 000248973200010

    View details for PubMedID 17551412

  • Parents' perspectives regarding a physician-parent conference after their child's death in the pediatric intensive care unit JOURNAL OF PEDIATRICS Meert, K. L., Eggly, S., Pollack, M., Anand, K. S., Zimmerman, J., Carcillo, J., Newth, C. L., Dean, J., Willson, D. F., Nicholson, C., Natl Inst Child Hlth Human Dev Col 2007; 151 (1): 50-55


    To investigate parents' perspectives on the desirability, content, and conditions of a physician-parent conference after their child's death in the pediatric intensive care unit (PICU).Audio-recorded telephone interviews were conducted with 56 parents of 48 children. All children died in the PICU of one of six children's hospitals in the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) 3 to 12 months before the study.Only seven (13%) parents had a scheduled meeting with any physician to discuss their child's death; 33 (59%) wanted to meet with their child's intensive care physician. Of these, 27 (82%) were willing to return to the hospital to meet. Topics that parents wanted to discuss included the chronology of events leading to PICU admission and death, cause of death, treatment, autopsy, genetic risk, medical documents, withdrawal of life support, ways to help others, bereavement support, and what to tell family. Parents sought reassurance and the opportunity to voice complaints and express gratitude.Many bereaved parents want to meet with the intensive care physician after their child's death. Parents seek to gain information and emotional support, and to give feedback about their PICU experience.

    View details for DOI 10.1016/j.jpeds.2007.01.050

    View details for Web of Science ID 000247851900013

    View details for PubMedID 17586190

    View details for PubMedCentralID PMC1993355

  • Anesthetic neurotoxicity in newborns - Should we change clinical practice? ANESTHESIOLOGY Anand, K. S. 2007; 107 (1): 2-4
  • Seeing through the blind! Ability of hospital staff to differentiate morphine from placebo, in neonates at a placebo controlled trial ACTA PAEDIATRICA Bergqvist, L. L., Eriksson, M., Kronsberg, S. S., Schollin, J., Barton, B., Anand, K. S. 2007; 96 (7): 1004-1007


    To investigate whether professional training and/or clinical experience affect the ability of caregiver to assess clinical signs of pre-emptive morphine analgesia.In the Neurological Outcomes & Pre-emptive Analgesia In Neonates trial preterm infants undergoing mechanical ventilation were randomized to receive continuous infusion, either of morphine or placebo blinded. Staff from centres in Sweden (Stockholm and Orebro) completed an assessment form.A total of 360 assessment forms were collected from 52 neonates. In 59% of the cases, caregivers correctly identified patients group. Comparable proportion of answers were correct between physicians, nurses and assistant nurses (63, 60 and 54%, respectively, p = 0.60). Staff with Neonatal intensive care unit experience <1 year identified 63%, as compared to 65% for working 1-5 year, and 55% that has been working >5 years (p = 0.28). Staff's ability to correctly identify group assignment was reduced by amount of additional morphine (p < 0.01) and severity of illness (p = 0.01).Clinical medical staffs, including neonatologists, have great difficulties in assessing the presence and severity of pain. Further studies should focus on the methods for assessment of prolonged pain in preterm neonates, define the effects of adequate analgesia, and investigate the clinical factors that may alter neonatal responses to acute and prolonged pain.

    View details for DOI 10.1111/j.1651-2227.2007.00270.x

    View details for Web of Science ID 000247681600015

    View details for PubMedID 17498195

  • Pharmacological approaches to the management of pain in the neonatal intensive care unit Anand, K. S. NATURE PUBLISHING GROUP. 2007: S4-S11


    Effective and consistent management of neonatal pain remains a controversial issue. Premature infants are repeatedly subjected to painful tests and procedures or suffer painful conditions when they are most vulnerable. With different mechanisms transducing various types of pain the practice of 'one-drug fits all' becomes questionable. Clinicians must use the latest non-pharmacologic and pharmacologic therapies for effective management of neonatal pain, distress, or agitation. Pharmacologic strategies for dealing with neonatal pain in the neonatal intensive care unit are described. Opioid therapy, once considered the mainstay for neonatal analgesia, may not be as effective as previously thought. Morphine infusions do not alter the neurological outcomes of preterm neonates and may not be effective against acute pain. Alternative approaches with methadone, ketamine, or local anesthetics should be considered. Clinicians must understand the contextual circumstances underlying pain in individual neonates and tailor therapy accordingly, using the most current evidence related to neonatal pain assessment and management.

    View details for DOI 10.1038/

    View details for Web of Science ID 000246136300003

    View details for PubMedID 17453028

  • Parent bed spaces in the PICU: effect on parental stress. Pediatric nursing Smith, A. B., Hefley, G. C., Anand, K. J. 2007; 33 (3): 215-21


    The purpose of this comparative descriptive study was to identify the impact of providing a parent bed space in the PICU, allowing for continual parental presence, on stress of the parents of critically ill children. Data were collected from parents (n = 86) at two children's hospitals 3 months prior to the opening of new PICUs with parent bed spaces. Following a transition period, data were collected from a sample of parents (n = 92) who had used the parent bed to stay overnight with their child. Parental stress was measured with the Parental Stressor Scale: Pediatric Intensive Care (PSS: PICU). Stress scores were significantly lower (p = .02) for parents who utilized the parent beds in the new PICUs. New PICU environments that facilitate continual parental presence may reduce parental stress related to a child's hospitalization.

    View details for PubMedID 17708180

  • Discussion 1: Management of pain in the neonate JOURNAL OF PERINATOLOGY Anand, K. S., Westrup, B. 2007; 27: S19-S20
  • Management of abdominal compartment syndrome during extracorporeal life support PEDIATRIC CRITICAL CARE MEDICINE Okhuysen-Cawley, R., Prodhan, P., Imamura, M., Dedman, A., Anand, K. S. 2007; 8 (2): 177-179


    To describe the successful use of a peritoneal dialysis catheter for emergent decompression of abdominal compartment syndrome during extracorporeal life support for septic shock.Case report.Pediatric intensive care unit at a freestanding tertiary children's hospital.Two-year-old toddler with influenza A complicated by methicillin-resistant Staphylococcus aureus pneumonia and septic shock.Placement of peritoneal dialysis catheter.Changes in hemodynamic and respiratory parameters. Improvement in extracorporeal membrane oxygenation venous drainage with subsequent survival.Although the standard therapy for abdominal compartment syndrome is decompressive laparotomy, a minimally invasive percutaneous approach may be effective and should be considered in selected patients.

    View details for DOI 10.1097/01.PCC.0000257102.53488.5E

    View details for Web of Science ID 000244768300013

    View details for PubMedID 17273121

  • Reduction of bloodstream infections associated with catheters in paediatric intensive care unit: stepwise approach BRITISH MEDICAL JOURNAL Bhutta, A., Gilliam, C., Honeycutt, M., Schexnayder, S., Green, J., Moss, M., Anand, K. S. 2007; 334 (7589): 362-365


    Bloodstream infections associated with catheters were the most common nosocomial infections in one paediatric intensive care unit in 1994-7, with rates well above the national average.Clinical data were collected prospectively to assess the rates of infection from 1994 onwards. The high rates in 1994-7 led to the stepwise introduction of interventions over a five year period. At quarterly intervals, prospective data continued to be collected during this period and an additional three year follow-up period.A 292 bed tertiary care children's hospital.We aimed to reduce our infection rates to below the national mean rates for similar units by 2000 (a 25% reduction).A stepwise introduction of interventions designed to reduce infection rates, including maximal barrier precautions, transition to antibiotic impregnated central venous catheters, annual handwashing campaigns, and changing the skin disinfectant from povidone-iodine to chlorhexidine. Effects of change Significant decreases in rates of infection occurred over the intervention period. These were sustained over the three year follow-up. Annual rates decreased from 9.7/1000 days with a central venous catheter in 1997 to 3.0/1000 days in 2005, which translates to a relative risk reduction of 75% (95% confidence interval 35% to 126%), an absolute risk reduction of 6% (2% to 10%), and a number needed to treat of 16 (10 to 35).A stepwise introduction of interventions leading to a greater than threefold reduction in nosocomial infections can be implemented successfully. This requires a multidisciplinary team, support from hospital leadership, ongoing data collection, shared data interpretation, and introduction of evidence based interventions.

    View details for DOI 10.1136/bmj.39064.457025.DE

    View details for Web of Science ID 000244560400035

    View details for PubMedID 17303886

    View details for PubMedCentralID PMC1800983

  • Consciousness, cortical function, and pain perception in nonverbal humans BEHAVIORAL AND BRAIN SCIENCES Anand, K. S. 2007; 30 (1): 82-+
  • Response to PAIN editorial re: Boyle et al. (2006) PAIN Boyle, E. M., Freer, Y., Wong, C., McIntosh, N., Anand, K. S. 2007; 127 (3): 302

    View details for DOI 10.1016/j.pain.2006.09.019

    View details for Web of Science ID 000244012100014

    View details for PubMedID 17055647

  • Web-based method for translating neurodevelopment from laboratory species to humans NEUROINFORMATICS Clancy, B., Kersh, B., Hyde, J., Darlington, R. B., Anand, K. S., Finlay, B. L. 2007; 5 (1): 79-94


    Biomedical researchers and medical professionals are regularly required to compare a vast quantity of neurodevelopmental literature obtained from an assortment of mammals whose brains grow at diverse rates, including fast developing experimental rodent species and slower developing humans. In this article, we introduce a database-driven website, which was created to address this problem using statistical-based algorithms to integrate hundreds of empirically derived developing neural events in 10 mammalian species ( The site, based on a statistical model that has evolved over the past decade, currently incorporates 102 different neurodevelopmental events obtained from 10 species: hamsters, mice, rats, rabbits, spiny mice, guinea pigs, ferrets, cats, rhesus monkeys, and humans. Data are arranged in a Structured Query Language database, which allows comparative brain development measured in postconception days to be converted and accessed in real time, using Hypertext Preprocessor language. Algorithms applied to the database also allow predictions for dates of specific neurodevelopmental events where empirical data are not available, including for the human embryo and fetus. By designing a web-based portal, we seek to make these comparative data readily available to all those who need to efficiently estimate the timing of neurodevelopmental events in the human fetus, laboratory species, or across several different species. In an effort to further refine and expand the applicability of this database, we include a mechanism to submit additional data.

    View details for DOI 10.1385/NI:5:1:79

    View details for Web of Science ID 000245930400006

    View details for PubMedID 17426354

  • Effects of low-dose naloxone on opioid therapy in pediatric patients: a retrospective case-control study INTENSIVE CARE MEDICINE Cheung, C. S., van Dijk, M., Green, J. W., Tibboel, D., Anand, K. S. 2007; 33 (1): 190-194


    To develop novel therapies that prevent opioid tolerance in critically ill children we examined the effects of low-dose naloxone infusions on patients' needs for analgesia or sedation.Matched case-control study in a pediatric intensive care unit at a university children's hospital.We compared 14 pediatric ICU patients receiving low-dose naloxone and opioid infusions with 12 matched controls receiving opioid infusions.Opioid analgesia and sedative requirements were assessed as morphine- and midazolam-equivalent doses, respectively. No differences were observed between groups in opioid doses at baseline or during naloxone, but in the postnaloxone period opioid doses tended to be lower in the naloxone group. Compared to baseline the naloxone group required more opioids during naloxone but fewer opioids after naloxone. Total sedative doses were comparable at baseline in both groups, with no differences in the postnaloxone period. The naloxone group required less sedation after naloxone but sedation doses were unchanged in controls. The two groups did not differ in pain scores, sedation scores, or opioid side effects.Naloxone did not reduce the need for opioid during the infusion period but tended to reduce opioid requirements in the postnaloxone period without additional need for sedation. Randomized clinical trials may examine the effects of low-dose naloxone on opioid tolerance and side effects in pediatric ICU patients requiring prolonged opioid analgesia.

    View details for DOI 10.1007/s00134-006-0387-z

    View details for Web of Science ID 000243464300030

    View details for PubMedID 17089146

  • Response to David Bowsher's comment: The hump from cerebral neurovascular events to the subjective feeling of pain in neonates PAIN Bartocci, M., Anand, K. S., Lagercrantz, H. 2006; 126 (1-3): 321-322
  • Evaluation and development of potentially better practices to improve pain management of neonates PEDIATRICS Sharek, P. J., Powers, R., Koehn, A., Anand, K. J. 2006; 118: S78-S86


    Despite increased knowledge, improved options, and regulatory mandates, pain management of neonates remains inadequate, promoted by the ineffective translation of research data into clinical practice. The Neonatal Intensive Care Quality Improvement Collaborative 2002 was created to provide participating NICUs the tools necessary to translate research, related to prevention and treatment of neonatal pain, into practice. The objective for this study was to use proven quality improvement methods to develop a process to improve neonatal pain management collaboratively.Twelve members of the Neonatal Intensive Care Quality Improvement Collaborative 2002 formed an exploratory group to improve neonatal pain management. The exploratory group established group and site-specific goals and outcome measures for this project. Group members crafted a list of potentially better practices on the basis of the available literature, encouraged implementation of the potentially better practices at individual sites, developed a database for sharing information, and measured baseline outcomes.The goal "improve the assessment and management of infants experiencing pain in the NICU" was established. In addition, each site within the group identified local goals for improvement in neonatal pain management. Data from 7 categories of neonates (N = 277) were collected within 48 hours of NICU admission to establish baseline data for clinical practices. Ten potentially better practices were developed for prioritized pain conditions, and 61 potentially better practices were newly implemented at the 12 participating sites. Various methods were used for pain assessment at the participating centers. At baseline, heel sticks were used more frequently than peripheral intravenous insertions or venipunctures, with substantial variability in the number of avoidable procedures between centers. Pain was assessed in only 17% of procedures, and analgesic interventions were performed in 19% of the procedures at baseline.Collaborative use of quality improvement methods resulted in the creation of self-directed, efficient, and effective processes to improve neonatal pain management. Group establishment of potentially better practices, collective and site-specific goals, and extensive baseline data resulted in accelerated implementation of clinical practices that would not likely occur outside a collaborative setting.

    View details for DOI 10.1542/peds.2006-0913D

    View details for PubMedID 17079627

  • Pharmacological therapy for analgesia and sedation in the newborn ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Anand, K. S., Hall, R. W. 2006; 91 (6): F448-F453


    Rapid advances have been made in the use of pharmacological analgesia and sedation for newborns requiring neonatal intensive care. Practical considerations for the use of systemic analgesics (opioids, non-steroidal anti-inflammatory agents, other drugs), local and topical anaesthetics, and sedative or anaesthetic agents (benzodiazepines, barbiturates, other drugs) are summarised using an evidence-based medicine approach, while avoiding mention of the underlying basic physiology or pharmacology. These developments have inspired more humane approaches to neonatal intensive care. Despite these advances, little is known about the clinical effectiveness, immediate toxicity, effects on special patient populations, or long-term effects after neonatal exposure to analgesics or sedatives. The desired or adverse effects of drug combinations, interactions with non-pharmacological interventions or use for specific conditions also remain unknown. Despite the huge gaps in our knowledge, preliminary evidence for the use of neonatal analgesia and sedation is available, but must be combined with a clear definition of clinical goals, continuous physiological monitoring, evaluation of side effects or tolerance, and consideration of long-term clinical outcomes.

    View details for DOI 10.1136/adc.2005.082263

    View details for Web of Science ID 000241577300016

    View details for PubMedID 17056842

    View details for PubMedCentralID PMC2672765

  • Assessing postoperative pain in neonates: A multicenter observational study PEDIATRICS Taylor, B. J., Robbins, J. M., Gold, J. I., Logsdon, T. R., Bird, T. M., Anand, K. S. 2006; 118 (4): E992-E1000


    A multicenter observational study was conducted to evaluate the practices of postoperative pain assessment and management in neonates to identify specific targets for improvement in clinical practice.Ten participating NICUs collected data for the 72 hours after a surgical operation on 25 consecutive neonates (N = 250), including demographics, principal diagnoses, operative procedure, other painful procedures, pain assessments, interventions (pharmacologic and nonpharmacologic), and adverse events in neonates who underwent minor and major surgery. Descriptive and logistic-regression analyses were performed by using SPSS and Stata.The neonates studied had a birth weight of 2.4 +/- 1.0 kg (mean +/- SD) and gestational age of 36 +/- 4.3 weeks; 57% were male, and length of hospital stay was 23.5 +/- 30.0 days. Participating hospitals used 7 different numeric pain scales, with nursing pain assessments documented for 88% (n = 220) of the patients and physician pain assessments documented for 9% (n = 23) of the patients. Opioids (84% vs 60%) and benzodiazepines (24% vs 11%) were used more commonly after major surgery than minor surgery, and a small proportion (7% major surgery, 12% minor surgery) received no analgesia. Logistic-regression analyses showed that physician pain assessment was the only significant predictor of postsurgical analgesic use, whereas major surgery and postnatal age in days did not seem to contribute. Physician pain assessment was documented for 23 patients; 22 of these received postoperative analgesia.Documentation of postoperative pain assessment and management in neonates was extremely variable among the participating hospitals. Pain assessment by physicians must be emphasized, in addition to developing evidence-based guidelines for postoperative care and educating professional staff to improve postoperative pain control in neonates.

    View details for DOI 10.1542/peds.2005-3203

    View details for Web of Science ID 000240959300080

    View details for PubMedID 17015519

  • Assessment of persistent pain or distress and adequacy of analgesia in preterm ventilated infants PAIN Boyle, E. M., Freer, Y., Wong, C., McIntosh, N., Anand, K. S. 2006; 124 (1-2): 87-91


    Indicators of persistent pain in preterm neonates are poorly defined. In the setting of a double blind, placebo-controlled trial investigating morphine use in ventilated preterm infants (NEOPAIN Trial) we aimed to identify factors that may be useful in assessing persistent pain. Twenty-two babies (morphine 12; placebo 10) were assessed for comfort, pain or distress and clinical staff described the factors they had considered. This assessment was performed during the first period of duty with the baby. Based on this, they stated which study drug they believed the infant was receiving. Eighty-nine assessments were made in total (1-14 per baby). The drug was correctly identified on 71% of occasions. Staff considered one or more of the following factors: infant activity; response to routine care; known pain-related behaviours; posture/quality of movements; respiratory effort; synchrony with ventilator; blood pressure and heart rate. Four factors most frequently identified babies receiving placebo: facial expressions of pain, high activity levels, poor response to handling and poor synchrony with ventilation. Absence of pain-related behaviour was less discriminating. Observation of a good response to handling, good synchrony with ventilation, a "settled" baby, normal blood pressure and heart rate were poor discriminators. Hypotension and poor respiratory drive were noted exclusively in babies receiving morphine infusions. Facial expressions of pain, high activity levels, poor response to routine care, and poor ventilator synchrony were associated with placebo versus morphine therapy, and may be considered useful markers for persistent pain in preterm infants.

    View details for DOI 10.1016/j.pain.2006.03.019

    View details for Web of Science ID 000240581700015

    View details for PubMedID 16725260

  • Cortical pain responses in the infant brain: Response to Slater et al.'s Letter to the Editor PAIN Anand, K. S., Bartocci, M., Lagercrantz, H. 2006; 123 (3): 332-334
  • Pain control: Opioid dosing, population kinetics and side-effects SEMINARS IN FETAL & NEONATAL MEDICINE Simons, S. P., Anand, K. S. 2006; 11 (4): 260-267


    Neonates undergoing invasive procedures, postoperative pain or ventilatory support commonly receive opioids for treating pain and stress. Randomized clinical trials have examined the benefits and adverse effects of morphine or fentanyl for ventilated neonates and other indications. This paper summarizes the current evidence for opioid dosing in newborns, reviews their side-effects and explains the use of population kinetics and non-linear mixed-effects modeling to analyze the data from clinical trials. Opioid use should be reserved for severe pain postoperatively or during intensive care in neonates, using continuous infusions rather than intermittent boluses. The safety and efficacy data from prolonged opioid use, particularly on the long-term outcomes of neonates, is still lacking. The pharmacodynamics and pharmacogenetics of opioid use in infancy needs further investigation, using non-linear mixed-effects models to drive individualized therapy. The current interest in opioid research will reap rich dividends in providing pain relief for neonates and avoiding dangerous side effects.

    View details for DOI 10.1016/j.siny.2006.02.008

    View details for Web of Science ID 000238475700007

    View details for PubMedID 16621750

  • Collaborative Pediatric Critical Care Research Network (CPCCRN) PEDIATRIC CRITICAL CARE MEDICINE Willson, D. F., Dean, J., Newth, C., Pollack, M., Anand, K. S., Meert, K., Carcillo, J., Zimmerman, J., Nicholson, C. 2006; 7 (4): 301-307


    Pediatric critical care was formally recognized as a separate subspecialty in pediatrics in 1987. Since that time the numbers of pediatric intensivists, pediatric intensive care units, and pediatric intensive care beds in the United States have increased dramatically. Research efforts have lagged behind, however, as this new discipline has struggled to identify the necessary time, funding, and other resources to pursue clinical and laboratory investigation. In April 2004, the National Center for Medical Rehabilitation Research of the National Institute for Child Health and Human Development issued a request for applications to establish the Collaborative Pediatric Critical Care Research Network (CPCCRN). The CPCCRN provides an infrastructure to pursue collaborative clinical trials and descriptive studies in pediatric critical care medicine. Six pediatric centers involving seven intensive care units and a data-coordinating center were identified through a competitive application process. Network goals include the support of collaborative clinical trials otherwise impracticable in single institutions and the establishment of a framework for developing the scientific basis for pediatric critical care practice. This article describes how the CPCCRN was established, its organization, and its goals and future plans.

    View details for DOI 10.1097/01.PCC.0000227106.66902.4F

    View details for Web of Science ID 000240781400001

    View details for PubMedID 16738501

  • Pain activates cortical areas in the preterm newborn brain PAIN Bartocci, M., Bergqvist, L. L., Lagercrantz, H., Anand, K. J. 2006; 122 (1-2): 109-117


    To study the patterns of supraspinal pain processing in neonates, we hypothesized that acute pain causes haemodynamic changes associated with activation of the primary somatosensory cortex. Forty preterm neonates at 28-36 weeks of gestation (mean=32.0) and at 25-42 h (mean=30.7) of age were studied following standardized tactile (skin disinfection) and painful (venipuncture) stimuli. Changes in regional cerebral haemodynamics were monitored by near infrared spectroscopy (NIRS) over both somatosensory cortices in 29 newborns, and over the contralateral somatosensory and occipital areas in 11 newborns. Heart rate (HR) and peripheral oxygen saturation (SaO2) were recorded simultaneously with NIRS parameters: oxygenated [HbO2], deoxygenated, and total hemoglobin. Tactile stimulation produced no changes in HR or SaO2. HR increased in the first 20s (p<0.001), while SaO2 decreased during the 40s after venipuncture (p<0.0001). Following tactile or painful stimulation, [HbO2] increased bilaterally regardless of which hand was stimulated (p<0.0001). Pain-induced [HbO2] increases in the contralateral somatosensory cortex (p<0.05) were not mirrored in the occipital cortex (p>0.1). Pain-related [HbO2] increases were more pronounced in male neonates (p<0.05 on left, p<0.001 on right), inversely correlated with gestational age (r=-0.53 on left, p<0.01; r=-0.42 on right, p<0.05) and directly correlated with postnatal age (r=0.75 on left, p<0.0001; r=0.67 on right, p<0.0001). Painful and tactile stimuli elicit specific haemodynamic responses in the somatosensory cortex, implying conscious sensory perception in preterm neonates. Somatosensory cortical activation occurs bilaterally following unilateral stimulation and these changes are more pronounced in male neonates or preterm neonates at lower gestational ages.

    View details for DOI 10.1016/j.pain.2006.01.015

    View details for Web of Science ID 000237549100018

    View details for PubMedID 16530965

  • Variation in pediatric intensive care therapies and outcomes by race, gender, and insurance status PEDIATRIC CRITICAL CARE MEDICINE Lopez, A. M., Tilford, J. M., Anand, K. S., Jo, C., Green, J. W., Aitken, M. E., Fiser, D. H. 2006; 7 (1): 2-6


    The differential allocation of medical resources to adult patients according to characteristics such as race, gender, and insurance status raises the serious concern that such issues apply to critically ill children as well.This study examined whether medical resources and outcomes for children admitted to pediatric intensive care units differed according to race, gender, or insurance status.An observational analysis was conducted with use of prospectively collected data from a multicenter cohort. Data were collected on 5,749 consecutive admissions for children from three pediatric intensive care units located in large urban children's hospitals.Children aged

    View details for DOI 10.1097/01.PCC.0000192319.55850.81

    View details for Web of Science ID 000240412400002

    View details for PubMedID 16395066

  • Morphine, hypotension, and intraventricular hemorrhage PEDIATRICS Anand, K. J., Hall, R. W. 2006; 117 (1): 250-252

    View details for DOI 10.1542/peds.2005-2250

    View details for Web of Science ID 000234406100044

    View details for PubMedID 16396892

  • Hospitalizations for critically ill children with traumatic brain injuries: A longitudinal analysis CRITICAL CARE MEDICINE Tilford, J. M., Aitken, M. E., Anand, K. S., Green, J. W., Goodman, A. C., Parker, J. G., Killingsworth, J. B., Fiser, D. H., Adelson, P. 2005; 33 (9): 2074-2081


    This study examines the incidence, utilization of procedures, and outcomes for critically ill children hospitalized with traumatic brain injury over the period 1988-1999 to describe the benefits of improved treatment.Retrospective analysis of hospital discharges was conducted using data from the Health Care Cost and Utilization Project Nationwide Inpatient Sample that approximates a 20% sample of U.S. acute care hospitals.Hospital inpatient stays from all types of U.S. community hospitals.The study sample included all children aged 0-21 with a primary or secondary ICD-9-CM diagnosis code for traumatic brain injury and a procedure code for either endotracheal intubation or mechanical ventilation.None.Deaths occurring during hospitalization were used to calculate mortality rates. Use of intracranial pressure monitoring and surgical openings of the skull were investigated as markers for the aggressiveness of treatment. Patients were further classified by insurance status, household income, and hospital characteristics. Over the 12-yr study period, mortality rates decreased 8 percentage points whereas utilization of intracranial pressure monitoring increased by 11 percentage points. The trend toward more aggressive management of traumatic brain injury corresponded with improved hospital outcomes over time. Lack of insurance was associated with vastly worse outcomes. An estimated 6,437 children survived their traumatic brain injury hospitalization because of improved treatment, and 1,418 children died because of increased mortality risk associated with being uninsured. Improved treatment was valued at approximately dollar 17 billion, whereas acute care hospitalization costs increased by dollar 1.5 billion (in constant 2000 dollars). Increased mortality in uninsured children was associated with a dollar 3.76 billion loss in economic benefits.More aggressive management of pediatric traumatic brain injury appears to have contributed to reduced mortality rates over time and saved thousands of lives. Additional lives could be saved if mortality rates could be equalized between insured and uninsured children.

    View details for DOI 10.1097/01.CCM.0000171839.65687.F5

    View details for Web of Science ID 000237504200026

    View details for PubMedID 16148483

  • Morphine administration and short-term pulmonary outcomes among ventilated preterm infants PEDIATRICS Bhandari, Bergqvist, L. L., Kronsberg, S. S., Barton, B. A., Anand, K. J., NEOPAIN Trial Investigators Grp 2005; 116 (2): 352-359


    The use of opioid therapy for sedation and analgesia among ventilated infants varies among care providers. The impact of opioid therapy early in the neonatal course of respiratory distress syndrome (RDS) on pulmonary outcomes is not known.We tested the hypothesis that preterm neonates randomized to the morphine infusion group would have improved ventilatory outcomes, measured as shorter durations of ventilator or oxygen therapy, fewer air leaks, and lower incidence of bronchopulmonary dysplasia.All 898 subjects (gestational age [GA] of > or =23 to < or =32 weeks) who were enrolled in the Neurologic Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial formed the study cohort (morphine: 449 patients; placebo: 449 patients). Subjects received the masked study drug until they were weaned from the ventilator or for 14 days, whichever occurred earlier. Outcome measures included air leaks, duration of ventilation or oxygen therapy, hospitalization, bronchopulmonary dysplasia, and death.Subjects in the 2 groups had similar baseline characteristics (mean +/- SD, morphine versus placebo: GA: 27.3 +/- 2.3 vs 27.4 +/- 2.3 weeks; birth weight: 1037 +/- 340 vs 1054 +/- 354 g). Infants in the morphine group required ventilator therapy significantly longer, compared with the placebo group (median [interquartile range]: 7 days [4-20 days] vs 6 days [3-19 days]). This difference in ventilation duration was significant for infants with GA of 27 to 29 weeks (6 days [4-12 days] vs 5 days [2-9 days]) and 30 to 32 weeks (4 days [3-6 days] vs 3 days [2-5 days]). Infants who received additional analgesia with intermittent morphine doses in both groups were sicker than those who were not given open-label morphine. After adjustment for birth weight, Clinical Risk Index for Babies scores, maternal chorioamnionitis, RDS requiring surfactant, and patent ductus arteriosus in a logistic regression model, the use of additional analgesia with morphine was associated independently with increased air leaks and longer durations of high-frequency ventilation, nasal continuous positive airway pressure, and oxygen therapy.Morphine infusions do not improve short-term pulmonary outcomes among ventilated preterm neonates. Additional morphine doses were associated with worsening respiratory outcomes among preterm neonates with RDS.

    View details for DOI 10.1542/peds.2004-2123

    View details for Web of Science ID 000230915600025

    View details for PubMedID 16061589

  • Anesthetics and brain toxicity CURRENT OPINION IN ANESTHESIOLOGY Soriano, S. G., Anand, K. S. 2005; 18 (3): 293-297


    Recent experimental data from rodent studies have demonstrated accelerated neurodegeneration in rat pups exposed to commonly used anesthetic drugs. These provocative findings certainly question and undermine the safe use of anesthetic drugs, particularly in pediatric anesthesia, and have prompted many to investigate the neurotoxic effect of anesthetic drugs on the developing brain. This review will address the scientific evidence for the anesthetic-induced neurotoxicity and its applicability in humans.Several investigators have shown that prolonged administration of anesthetic drugs, including ketamine, isoflurane, nitrous oxide and midazolam, produced increased neurodegeneration in 7-day-old rat pups. The combination of the latter three drugs led to altered learning behavior in adulthood. Despite these unequivocal findings in rodents, similar changes cannot be reproduced in other species. Furthermore, withholding anesthesia during painful procedures in neonatal rats resulted in significant long-term aberrant responses to sensory stimulation and pain thresholds.Taken together, these studies question the applicability of these data to the anesthetic management of the neonate. Further investigations in this area are needed before withholding anesthetics in the anesthetic management of pediatric surgical patients.

    View details for DOI 10.1097/

    View details for Web of Science ID 000209516800011

    View details for PubMedID 16534354

  • Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates PEDIATRICS Carbajal, R., Lenclen, R., Jugie, M., Paupe, A., Barton, B. A., Anand, K. J. 2005; 115 (6): 1494-1500


    Morphine alleviates prolonged pain, reduces behavioral and hormonal stress responses induced by surgery among term neonates, and improves ventilator synchrony and sedation among ventilated preterm neonates, but its analgesic effects on the acute pain caused by invasive procedures remain unclear.To investigate the analgesic efficacy of intravenously administered morphine on heel stick-induced acute pain among preterm neonates.This study was nested within a prospective, randomized, double-blind, multicenter, placebo-controlled trial (the NEOPAIN Trial).A tertiary-care NICU in a teaching hospital.Forty-two preterm neonates undergoing ventilation.Neonates were randomized to either the morphine (loading dose of 100 microg/kg, followed by infusions of 10-30 microg/kg per hour according to gestation, N = 21) or placebo (5% dextrose infusions, N = 21) group. Pain responses to 3 heel sticks were evaluated, ie, before the loading dose (T1), 2 to 3 hours after the loading dose (T2), and 20 to 28 hours after the loading dose (T3).Pain was assessed with the Douleur Aiguë Nouveau-né (DAN) scale (behavioral pain scale) and the Premature Infant Pain Profile (PIPP) (multidimensional pain scale); plasma morphine levels were measured at T3.Infants in the placebo and morphine groups had similar gestational ages (mean +/- SD: 27.2 +/- 1.7 vs 27.3 +/- 1.8 weeks) and birth weights (972 +/- 270 vs 947 +/- 269 g). Mean +/- SD DAN pain scores at T1, T2, and T3 were 4.8 +/- 4.0, 4.6 +/- 2.9, and 4.7 +/- 3.6, respectively, for the placebo group and 4.5 +/- 3.8, 4.4 +/- 3.7, and 3.1 +/- 3.4 for the morphine group. The within-group factor (pain at T1, T2, and T3) was not statistically different over time. The between-group analysis (infants receiving placebo versus those receiving morphine) showed no significant differences. Mean +/- SD PIPP pain scores at T1, T2, and T3 were 11.5 +/- 4.8, 11.1 +/- 3.7, and 9.1 +/- 4.0, respectively, for the placebo group and 10.0 +/- 3.6, 8.8 +/- 4.9, and 7.8 +/- 3.6 for the morphine group. The within-group factor was statistically different over time. The between-group analysis showed no significant differences. Mean +/- SD plasma morphine levels at T3 were 0.44 +/- 1.79 ng/mL and 63.36 +/- 33.35 ng/mL for the placebo and morphine groups, respectively. There was no correlation between plasma morphine levels and pain scores at T3 (DAN, R = -0.05; PIPP, R = -0.02).Despite its routine use in the NICU, morphine given as a loading dose followed by continuous intravenous infusions does not appear to provide adequate analgesia for the acute pain caused by invasive procedures among ventilated preterm neonates.

    View details for DOI 10.1542/peds.2004-1425

    View details for Web of Science ID 000229504800006

    View details for PubMedID 15930209

  • Analgesia and sedation during mechanical ventilation in neonates Aranda, J. V., Carlo, W., Hummel, P., Thomas, R., Lehr, V. T., Anand, K. J. ELSEVIER. 2005: 877-899


    Endotracheal intubation and mechanical ventilation are major components of routine intensive care for very low birth weight newborns and sick full-term newborns. These procedures are associated with physiologic, biochemical, and clinical responses indicating pain and stress in the newborn. Most neonates receive some form of analgesia and sedation during mechanical ventilation, although there are marked variations in clinical practice. Clinical guidelines for pharmacologic analgesia and sedation in newborns based on robust scientific data are lacking, as are measures of clinical efficacy.This article represents a preliminary attempt to develop a scientific rationale for analgesia sedation in mechanically ventilated newborns based on a systematic analysis of published clinical trials.The current literature was reviewed with regard to the use of opioids (fentanyl, morphine, diamorphine), sedative-hypnotics (midazolam), nonsteroidal anti-inflammatory drugs (ibuprofen, indomethacin), and acetaminophen in ventilated neonates. Original meta-analyses were conducted that collated the data from randomized clinical comparisons of morphine or fentanyl with placebo, or morphine with fentanyl.The results of randomized trials comparing fentanyl, morphine, or midazolam with placebo, and fentanyl with morphine were inconclusive because of small sample sizes. Meta-analyses of the randomized controlled trials indicated that morphine and fentanyl can reduce behavioral and physiologic measures of pain and stress in mechanically ventilated preterm neonates but may prolong the duration of ventilation or produce other adverse effects. Randomized trials of midazolam compared with placebo reported significant adverse effects (P < 0.05) and no apparent clinical benefit; the findings of a meta-analysis suggest that there are insufficient data to justify use of IV midazolam for sedation in ventilated neonates.Despite ongoing research in this area, huge gaps in our knowledge remain. Well-designed and adequately powered clinical trials are needed to establish the safety, efficacy, and short- and long-term outcomes of analgesia and sedation in the mechanically ventilated newborn.

    View details for DOI 10.1016/j.clinthera.2005.06.019

    View details for Web of Science ID 000230531000017

    View details for PubMedID 16117990

  • Analgesia and anesthesia for neonates: Study design and ethical issues Anand, K. J., Aranda, J. V., Berde, C. B., Buckman, S., Capparelli, E. V., Carlo, W. A., Hummel, P., Lantos, P., Johnston, C. C., Lehr, V. T., Lynn, A. M., Maxwell, L. G., Oberlander, T. F., Raju, T. N., Soriano, S. G., Taddio, A., Walco, G. A. ELSEVIER. 2005: 814-843


    The purpose of this article is to summarize the clinical, methodologic, and ethical considerations for researchers interested in designing future trials in neonatal analgesia and anesthesia, hopefully stimulating additional research in this field.The MEDLINE, PubMed, EMBASE, and Cochrane register databases were searched using subject headings related to infant, newborn, neonate, analgesia, anesthesia, ethics, and study design. Cross-references and personal files were searched manually. Studies reporting original data or review articles related to these topics were assessed and critically evaluated by experts for each topical area. Data on population demographics, study characteristics, and cognitive and behavioral outcomes were abstracted and synthesized in a systematic manner and refined by group members. Data synthesis and results were reviewed by a panel of independent experts and presented to a wider audience including clinicians, scientists, regulatory personnel, and industry representatives at the Newborn Drug Development Initiative workshop. Recommendations were revised after extensive discussions at the workshop and between committee members.Designing clinical trials to investigate novel or currently available approaches for analgesia and anesthesia in neonates requires consideration of salient study designs and ethical issues. Conditions requiring treatment include pain/stress resulting from invasive procedures, surgical operations, inflammatory conditions, and routine neonatal intensive care. Study design considerations must define the inclusion and exclusion criteria, a rationale for stratification, the confounding effects of comorbid conditions, and other clinical factors. Significant ethical issues include the constraints of studying neonates, obtaining informed consent, making risk-benefit assessments, defining compensation or rewards for participation, safety considerations, the use of placebo controls, and the variability among institutional review boards in interpreting federal guidelines on human research. For optimal study design, investigators must formulate well-defined study questions, choose appropriate trial designs, estimate drug efficacy, calculate sample size, determine the duration of the studies, identify pharmacokinetic and pharmacodynamic parameters, and avoid drug-drug interactions. Specific outcome measures may include scoring on pain assessment scales, various biomarkers and their patterns of response, process outcomes (eg, length of stay, time to extubation), intermediate or long-term outcomes, and safety parameters.Much more research is needed in this field to formulate a scientifically sound, evidence-based, and clinically useful framework for management of anesthesia and analgesia in neonates. Newer study designs and additional ethical dilemmas may be defined with accumulating data in this field.

    View details for DOI 10.1016/j.clinthera.2005.06.021

    View details for Web of Science ID 000230531000015

    View details for PubMedID 16117988

  • Analgesia and local anesthesia during invasive procedures in the neonate Anand, K. J., Johnston, C. C., Oberlander, T. F., Taddio, A., Lehr, V. T., Walco, G. A. ELSEVIER. 2005: 844-876


    Preterm and full-term neonates admitted to the neonatal intensive care unit or elsewhere in the hospital are routinely subjected to invasive procedures that can cause acute pain. Despite published data on the complex behavioral, physiologic, and biochemical responses of these neonates and the detrimental short- and long-term clinical outcomes of exposure to repetitive pain, clinical use of pain-control measures in neonates undergoing invasive procedures remains sporadic and suboptimal. As part of the Newborn Drug Development Initiative, the US Food and Drug Administration and the National Institute of Child Health and Human Development invited a group of international experts to form the Neonatal Pain Control Group to review the therapeutic options for pain management associated with the most commonly performed invasive procedures in neonates and to identify research priorities in this area.The goal of this article was to review and synthesize the published clinical evidence for the management of pain caused by invasive procedures in preterm and full-term neonates.Clinical studies examining various therapies for procedural pain in neonates were identified by searches of MEDLINE (1980-2004), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2004), the reference lists of review articles, and personal files. The search terms included specific drug names, infant-newborn, infant-preterm, and pain, using the explode function for each key word. The English-language literature was reviewed, and case reports and small case series were discarded.The most commonly performed invasive procedures in neonates included heel lancing, venipuncture, IV or arterial cannulation, chest tube placement, tracheal intubation or suctioning, lumbar puncture, circumcision, and SC or IM injection. Various drug classes were examined critically, including opioid analgesics, sedative/hypnotic drugs, nonsteroidal anti-inflammatory drugs and acetaminophen, injectable and topical local anesthetics, and sucrose. Research considerations related to each drug category were identified, potential obstacles to the systematic study of these drugs were discussed, and current gaps in knowledge were enumerated to define future research needs. Discussions relating to the optimal design for and ethical constraints on the study of neonatal pain will be published separately. Well-designed clinical trials investigating currently available and new therapies for acute pain in neonates will provide the scientific framework for effective pain management in neonates undergoing invasive procedures.

    View details for DOI 10.1016/j.clinthera.2005.06.018

    View details for Web of Science ID 000230531000016

    View details for PubMedID 16117989

  • Morphine, hypotension, and adverse outcomes among preterm neonates: Who's to blame? Secondary results from the NEOPAIN trial PEDIATRICS Hall, R. W., Kronsberg, S. S., Barton, B. A., Kaiser, Anand, K. J., NEOPAIN Trial Investigators Grp 2005; 115 (5): 1351-1359


    Hypotension occurs commonly among preterm neonates, but its cause and consequences remain unclear. Secondary data analyses from the NEOPAIN trial identified the clinical factors associated with hypotension and examined the contributions of morphine treatment or hypotension to severe intraventricular hemorrhage (IVH) (grades 3 and 4), any IVH (grades 1-4), or death.In the NEOPAIN trial, 898 ventilated neonates between 23 and 32 weeks of gestation were enrolled, with equal numbers randomized to receive masked morphine or placebo infusions. Additional doses of open-label morphine were administered as necessary by medical staff members. IVH was diagnosed with centralized readings of early and late cranial ultrasonograms. Hypotension was assessed before study drug infusion, during the loading dose, and at 24 and 72 hours during study drug infusion. Logistic regression analyses with stepdown elimination identified the predictor factors associated with the hypotension, severe IVH, any IVH, or death outcomes at each time point.Hypotension was associated with 23 to 26 weeks of gestation, morphine infusions, severity of illness, additional morphine doses, and prior hypotension. Severe IVH was associated with shorter gestation, higher Clinical Risk Index for Babies scores, no prenatal steroids, pulmonary hemorrhage, hypotension before the loading dose, and morphine doses before intubation and at 25 to 72 hours. Neonatal deaths were associated with 23 to 26 weeks of gestation, higher Clinical Risk Index for Babies scores, pulmonary hemorrhage, patent ductus arteriosus, thrombocytopenia, and hypotension before the loading dose. Morphine infusions were not a significant factor in logistic models for severe IVH, any IVH, or death.Preemptive morphine infusions, additional morphine, and lower gestational age were associated with hypotension among preterm neonates. Severe IVH, any IVH, and death were associated with preexisting hypotension, but morphine therapy did not contribute to these outcomes. Morphine infusions, although they cause hypotension, can be used safely for most preterm neonates but should be used cautiously for 23- to 26-week neonates and those with preexisting hypotension.

    View details for DOI 10.1542/peds.2004-1398

    View details for Web of Science ID 000228833500038

    View details for PubMedID 15867047

  • Does neonatal surgery lead to increased pain sensitivity in later childhood? PAIN Peters, J. W., Schouw, R., Anand, K. J., van Dijk, M., Duivenvoorden, H. J., Tibboel, D. 2005; 114 (3): 444-454


    Does pain or tissue damage in early life lead to hyperalgesia persisting into childhood? We performed a cross-sectional study in 164 infants to investigate whether major surgery within the first 3 months of life increases pain sensitivity to subsequent surgery and to elucidate whether subsequent surgery in the same dermatome or in a different dermatome leads to differences in pain sensitivity. All infants received standard intraoperative and postoperative pain management, with rescue analgesia guided by a treatment algorithm. Differences in pain sensitivity during surgery were assessed by the intraoperative fentanyl intake and by (nor)epinephrine plasma concentrations. Differences in postoperative pain sensitivity were assessed by the observational pain measures COMFORT and VAS, and by morphine intake and (nor)epinephrine plasma concentrations. Infants previously operated upon in the same dermatome needed more intraoperative fentanyl, had higher COMFORT and VAS scores, had greater (nor)epinephrine plasma concentrations, and needed also more morphine than did infants with no prior surgery. In contrast, infants who previously underwent surgery in another dermatome had only significant higher postoperative analgesic requirements and norepinephrine plasma concentrations in comparison with infants with no prior surgery. These preliminary differences may indicate the occurrence of spinal and supraspinal changes following neonatal surgery. We conclude that the long-term consequences of surgery in early infancy are greater in areas of prior tissue damage and that these effects may portend limited clinical but important neurobiological differences.

    View details for DOI 10.1016/j.pain.2005.01.014

    View details for Web of Science ID 000228232400016

    View details for PubMedID 15777869

  • Of mice and men: Should we extrapolate rodent experimental data to the care of human neonates? ANESTHESIOLOGY Soriano, S. G., Anand, K. J., Rovnaghi, C. R., Hickey, P. R. 2005; 102 (4): 866-868
  • The pharmacological treatment of neonatal pain SEMINARS IN FETAL & NEONATAL MEDICINE Tibboel, D., Anand, K. J., van den Anker, J. N. 2005; 10 (2): 195-205


    Optimal analgesia remains a major challenge for all involved in the care of (critically) ill newborns. The rapid changes in liver metabolism involving maturation of liver enzymes and renal clearance of drugs render (extreme) very low birth weight infants different from newborns of later postconceptional age with regards to the use of opioids such as morphine and fentanyl. Acute and/or procedural pain has been investigated fairly recently in randomized controlled trials and there are now guidelines. The long-term effects of opioid use in this particular age group of vulnerable babies await further evaluation.

    View details for DOI 10.1016/j.siny.2004.11.002

    View details for Web of Science ID 000231354200009

    View details for PubMedID 15701584

  • Effect of inborn versus outborn delivery on clinical outcomes in ventilated preterm neonates: secondary results from the NEOPAIN trial. Journal of perinatology : official journal of the California Perinatal Association Palmer, K. G., Kronsberg, S. S., Barton, B. A., Hobbs, C. A., Hall, R. W., Anand, K. J. 2005; 25 (4): 270-5


    OBJECTIVE: The objective of this study was to evaluate the effect of birth center (inborn versus outborn) on morbidity and mortality for preterm neonates (23 to 32 weeks) using data collected prospectively within a uniform protocol.STUDY DESIGN: Secondary analyses of data from the NEurologic Outcomes and Pre-emptive Analgesia In Neonates (NEOPAIN) trial (n=898) were performed to evaluate the effect of inborn versus outborn delivery on neonatal outcomes, including the occurrence of severe intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), chronic lung disease (CLD), and mortality.RESULTS: Outborn babies were more likely to have severe IVH (p=0.0005); this increased risk persisted after controlling for severity of illness. When adjustments for antenatal steroids were added, the effect of birth center was no longer significant. Neither the occurrences of PVL or CLD nor mortality were significantly different between the inborn and outborn infants.CONCLUSION: Outborn babies are more likely to have severe IVH than inborn babies, perhaps because their mothers are less likely to receive antenatal steroids. Improvements in antenatal steroid administration to high-risk women may substantially reduce neonatal morbidity.

    View details for DOI 10.1038/

    View details for PubMedID 15616613

  • Gastric suction at birth JOURNAL OF PEDIATRICS Conklin, L. S., Perlman, J. M., Wyckoff, M. H. 2005; 146 (1): 152-153

    View details for DOI 10.1016/j.jpeds.2004.08.030

    View details for Web of Science ID 000226337700041

    View details for PubMedID 15644853

  • NEOPAIN: a question of survival LANCET Pechlaner, C. 2004; 364 (9433): 498
  • Anesthetic agents and the immature brain: Are these toxic or therapeutic? ANESTHESIOLOGY Anand, K. J., Phil, D., Soriano, S. G. 2004; 101 (2): 527-530
  • Neonatal research and the validity of informed consent obtained in the perinatal period. Journal of perinatology : official journal of the California Perinatal Association Ballard, H. O., Shook, L. A., Desai, N. S., Anand, K. J. 2004; 24 (7): 409-15


    BACKGROUND: Consent for participation in clinical research is considered valid if it is informed, understood, and voluntary. In the case of minors, parents give permission for their child to participate in research studies after being presented with all information needed to make an informed decision. Although informed consent is a vital component of clinical research, there is little information evaluating its validity in neonatal intensive-care populations. The objective of this project was to determine the validity of informed consent obtained from parents of infants enrolled in the multicenter randomized research study, neurologic outcomes and pre-emptive analgesia in the neonate (NEOPAIN).DESIGN/METHODS: Parents of infants who survived to discharge and had signed consent for their newborn to participate in the NEOPAIN study at the University of Kentucky were asked 20 open-ended questions to determine their level of understanding about the NEOPAIN study. The NEOPAIN consent form, which had been approved by the University of Kentucky Medical Institutional Review Board (IRB), was used to formulate these questions. Questions addressed the timing of consent, parental understanding of the purpose, benefits, and risks of the study, the voluntary nature of the project, and their willingness to enroll in future studies if the opportunity presented. Answers were scored on a Likert scale, with 1 for no understanding and 5 for complete understanding.RESULTS: Five of 64 parents (7.8%) had no recollection of the NEOPAIN study or of signing consent. Of those who remembered the study, only 67.8% understood the purpose of the study, with a higher proportion of the mothers than fathers knowing the purpose of the study (73.3% vs 57.1%), (p=0.029). Of those who understood the purpose of the study 95% were able to verbalize the benefits, but only 5% understood any potential risks. No parents reported feeling pressured or coerced to sign consent for the project and all parents reported they would enroll their child in additional studies if asked.CONCLUSIONS: Valid consent in the antenatal/perinatal population is difficult, if not impossible, to obtain. To maximize validity of consent in the antenatal/perinatal population every effort should be made to include mothers in the consent process. Additional attention during the consent process should be given to possible risks of the study.

    View details for DOI 10.1038/

    View details for PubMedID 15152271

  • Tracheal intubation in neonates, infants, and children: Is there a right way? CRITICAL CARE MEDICINE Anand, K. J., Suresh, S. 2004; 32 (2): 614-616
  • Routine morphine infusion in preterm newborns who received ventilatory support - A randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Simons, S. H., van Dijk, M., van Lingen, R., Roofthooft, D., Duivenvoorden, H. J., Jongeneel, N., Bunkers, C., Smink, E., Anand, K. J., van den Anker, J. N., Tibboel, D. 2003; 290 (18): 2419-2427


    Newborns admitted to neonatal intensive care units (NICUs) undergo a variety of painful procedures and stressful events. Because the effect of continuous morphine infusion in preterm neonates has not been investigated systematically, there is confusion regarding whether morphine should be used routinely in this setting.To evaluate the effects of continuous intravenous morphine infusion on pain responses, incidence of intraventricular hemorrhage (IVH), and poor neurologic outcome (severe IVH, periventricular leukomalacia, or death).A randomized, double-blind, placebo-controlled trial conducted between December 2000 and October 2002 in 2 level III NICUs in the Netherlands of 150 newborns who had received ventilatory support (inclusion criteria: postnatal age younger than 3 days and ventilation for less than 8 hours; exclusion criteria: severe asphyxia, severe IVH, major congenital malformations, and administration of neuromuscular blockers).Intravenous morphine (100 microg/kg and 10 microg/kg per hour) or placebo infusion was given for 7 days (or less because of clinical necessity in several cases).The analgesic effect of morphine, as assessed using validated scales; the effect of morphine on the incidence of IVH; and poor neurologic outcome.The analgesic effect did not differ between the morphine and placebo groups, judging from the following median (interquartile range) pain scores: Premature Infant Pain Profile, 10.1 (8.2-11.6) vs 10.0 (8.2-12.0) (P =.94); Neonatal Infant Pain Scale, 4.8 (3.7-6.0) vs 4.8 (3.2-6.0) (P =.58); and visual analog scale, 2.8 (2.0-3.9) vs 2.6 (1.8-4.3) (P =.14), respectively. Routine morphine infusion decreased the incidence of IVH (23% vs 40%, P =.04) but did not influence poor neurologic outcome (10% vs 16%, P =.66). In addition, analyses were adjusted for the use of additional open-label morphine (27% of morphine group vs 40% of placebo group, P =.10).Lack of a measurable analgesic effect and absence of a beneficial effect on poor neurologic outcome do not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support. Follow-up is needed to evaluate the long-term effects of morphine infusions on the neurobehavioral outcomes of prematurity.

    View details for DOI 10.1001/jama.290.18.2419

    View details for Web of Science ID 000186518300028

    View details for PubMedID 14612478

  • Do we still hurt newborn babies? - A prospective study of procedural pain and analgesia in neonates ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Simons, S. H., van Dijk, M., Anand, K. S., Roofthooft, D., van Lingen, R. A., Tibboel, D. 2003; 157 (11): 1058-1064


    Despite an increasing awareness regarding pain management in neonates and the availability of published guidelines for the treatment of procedural pain, preterm neonates experience pain leading to short- and long-term detrimental effects.To assess the frequency of use of analgesics in invasive procedures in neonates and the associated pain burden in this population.For 151 neonates, we prospectively recorded all painful procedures, including the number of attempts required, and analgesic therapy used during the first 14 days of neonatal intensive care unit admission. These data were linked to estimates of the pain of each procedure, obtained from the opinions of experienced clinicians.On average, each neonate was subjected to a mean +/- SD of 14 +/- 4 procedures per day. The highest exposure to painful procedures occurred during the first day of admission, and most procedures (63.6%) consisted of suctioning. Many procedures (26 of 31 listed on a questionnaire) were estimated to be painful (pain scores >4 on a 10-point scale). Preemptive analgesic therapy was provided to fewer than 35% of neonates per study day, while 39.7% of the neonates did not receive any analgesic therapy in the neonatal intensive care unit.Clinicians estimated that most neonatal intensive care unit procedures are painful, but only a third of the neonates received appropriate analgesic therapy. Despite the accumulating evidence that neonatal procedural pain is harmful, analgesic treatment for painful procedures is limited. Systematic approaches are required to reduce the occurrence of pain and to improve the analgesic treatment of repetitive pain in neonates.

    View details for DOI 10.1001/archpedi.157.11.1058

    View details for Web of Science ID 000186551800003

    View details for PubMedID 14609893

  • Postoperative pain in the neonate: age-related differences in morphine requirements and metabolism INTENSIVE CARE MEDICINE Bouwmeester, N. J., Hop, W. C., van Dijk, M., Anand, K. J., van den Anker, J. N., Tibboel, D. 2003; 29 (11): 2009-2015


    To investigate age-related differences in morphine requirements and metabolism in full-term neonates.Randomized double-blind study in the pediatric surgical intensive care unit.Sixty-eight neonates (52 aged under 7 days, 16 aged 7 day or older) following major surgery.After surgery patients were randomly assigned to continuous morphine (10 micro g/kg per hour) or intermittent morphine (30 micro g/kg per 3 hours). Additional morphine was administered on guidance of pain scores.Pain was measured by the Comfort behavioral scale and visual analogue scale. Morphine and morphine-6-glucuronide (M6G) plasma concentrations were determined before and 0, 6, 12, and 24 h after surgery. The younger neonates differed significantly from the older neonates in morphine requirement (median 10 vs. 10.8 micro g/kg per hour), morphine plasma concentration [23.0 vs. 15.3 ng/ml), and M6G/morphine ratio (0.6 vs. 1.5). Pain scores did not differ between age groups or morphine treatment groups. Neonates who were mechanically ventilated longer than 24 h had significantly higher morphine plasma concentrations than the spontaneously breathing neonates 12 and 24 h after surgery (29.1 vs. 13.1 ng/ml and 26.9 vs. 12.0 ng/ml, respectively). Morphine plasma concentrations were not correlated with analgesia or respiratory depression. Five neonates (intermittent morphine) showed respiratory insufficiency; however, the difference between the groups was not significant.Neonates aged 7 days or younger require significantly less morphine postoperatively than older neonates. The two morphine regimens (continuous, intermittent) were equally effective and safe. Mechanical ventilation decreases morphine metabolism and clearance.

    View details for DOI 10.1007/s00134-003-1899-4

    View details for Web of Science ID 000186423500025

    View details for PubMedID 12897995

  • Early exposure to marijuana and risk of later drug use JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Anand, K. J. 2003; 290 (3): 330

    View details for DOI 10.1001/jama.290.3.330-a

    View details for Web of Science ID 000184078800014

    View details for PubMedID 12865369

  • Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants BRITISH JOURNAL OF ANAESTHESIA Bouwmeester, N. J., van den Anker, J. N., Hop, W. C., Anand, K. J., Tibboel, D. 2003; 90 (5): 642-652


    To investigate clinical variables such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation that might affect morphine requirements and plasma concentrations of morphine and its metabolites.In a double-blind study, neonates and infants stratified for age [group I 0-4 weeks (neonates), group II > or =4-26 weeks, group III > or =26-52 weeks, group IV > or =1-3 yr] admitted to the paediatric intensive care unit after abdominal or thoracic surgery received morphine 100 micro g kg(-1) after surgery, and were randomly assigned to either continuous morphine 10 micro g kg(-1) h(-1) or intermittent morphine boluses 30 micro g kg(-1) every 3 h. Pain was measured using the COMFORT behavioural scale and a visual analogue scale. Additional morphine was administered on guidance of the pain scores. Morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) plasma concentrations were measured before, directly after, and at 6, 12 and 24 h after surgery.Multiple regression analysis of different variables revealed that age was the most important factor affecting morphine requirements and plasma morphine concentrations. Significantly fewer neonates required additional morphine doses compared with all other age groups (P<0.001). Method of morphine administration (intermittent vs continuous) had no significant influence on morphine requirements. Neonates had significantly higher plasma concentrations of morphine, M3G and M6G (all P<0.001), and significantly lower M6G/morphine ratio (P<0.03) than the older children. The M6G/M3G ratio was similar in all age groups.Neonates have a narrower therapeutic window for postoperative morphine analgesia than older age groups, with no difference in the safety or effectiveness of intermittent doses compared with continuous infusions in any of these age groups. In infants >1 month of age, analgesia is achieved after morphine infusions ranging from 10.9 to 12.3 micro g kg(-1) h(-1) at plasma concentrations of <15 ng ml(-1).

    View details for DOI 10.1093/bja/aeg121

    View details for Web of Science ID 000182664200012

    View details for PubMedID 12697593

  • Prematurity and later cognitive outcomes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Doyle, L. W., Saigal, S., Streiner, D. L. 2002; 288 (20): 2542-2543

    View details for DOI 10.1001/jama.288.20.2542

    View details for Web of Science ID 000179394500018

    View details for PubMedID 12444858

  • Vulnerability of the developing brain - Neuronal mechanisms CLINICS IN PERINATOLOGY Bhutta, A. T., Anand, K. J. 2002; 29 (3): 357-+


    Despite the improved survival of tiny preterm neonates, their neurodevelopmental outcomes remain a cause for grave concern. The authors propose two primary mechanisms leading to enhanced neuronal cell death in the immature brain: (1) NMDA-mediated excitotoxicity resulting from repetitive or prolonged pain, and (2) enhanced naturally occurring neuronal apoptosis during early development due to multiple metabolic stresses or lack of social stimulation. The pattern and magnitude of abnormalities will depend on genetic variability as well as the timing, intensity, and duration of adverse environmental experiences. Thus, cumulative brain damage during infancy will finally lead to reductions in brain volume, abnormal behavioral and neuroendocrine regulation, and poor cognitive outcomes during childhood and adolescence. The public health and economic importance of preventing or ameliorating the subtle brain damage caused by these mechanisms cannot be overestimated. This certainly justifies concerted efforts by neuroscientists and clinicians to investigate the mechanisms underlying early neuronal injury, to minimize the impact of adverse experiences and environmental factors in neonates, and to develop novel therapeutic strategies for improving the cognitive and behavioral outcomes of ex-preterm neonates.

    View details for DOI 10.1016/S0095-5108(02)00011-8

    View details for Web of Science ID 000178353300002

    View details for PubMedID 12380463

  • Case of the month. Symptomatic chronic calcified subdural hematoma in a 5-year-old child. The Journal of the Arkansas Medical Society Narsinghani, U., Burson, G., Schmidt, M. B., Anand, K. S. 2002; 98 (9): 300-3


    Head trauma is a frequent cause of morbidity and mortality in the pediatric population. The pathophysiology and clinical outcomes of head trauma differ between children and adults. Traumatic mass lesions such as subdural and epidural hematomas occur less frequently in children and, when present, are associated with lower mortality. Subdural hematoma is the collection of blood on the cortical surface beneath the dura with bleeding from bridging veins or cortical arteries. These hematomas are usually associated with trauma. Chronic subdural hematomas are much more common in infants and frequently exist as a single entity; it is rare for chronic subdural fluid accumulations to occur after one year of age. Specific traumatic events are usually unrecognized or unreported. In rare instances, subdural hematoma may indicate an underlying bleeding disorder, hematological malignancy or benign expansion of subarachnoid space. We report the dramatic presentation of a strikingly large calcified chronic subdural hematoma in a 5-year-old with increased intracranial pressure and subfalcine herniation.

    View details for PubMedID 11881264

  • Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence BRAIN RESEARCH REVIEWS Liu, J. G., Anand, K. J. 2001; 38 (1-2): 1-19


    Prolonged opioid exposure occurs frequently as a result of clinical use or drug abuse. Research using different ligands, cell lines, and animal models in the past three decades has elucidated some correlation between the biochemical events and behavioral changes resulting from opioid tolerance, dependence and addiction. For the most part, opioid tolerance and dependence are associated with up-regulation of the cAMP pathway, mediated by the supersensitization of adenylyl cyclase and by the altered coupling of opioid receptors to stimulatory G proteins. Neuroadaptive changes in signal transduction following prolonged opioid exposure are mediated by protein kinase systems, such as protein kinase C (PKC), cyclic AMP-dependent protein kinase (PKA), Ca2+/camodulin-dependent protein kinase II (CaMKII), G protein-coupled receptor kinases (GRKs) and mitogen-activated protein kinases (MAPKs). Intermediate steps between opioid receptor activation and the second- or third-messenger cascades include GRK-mediated receptor endocytosis and intracellular trafficking, as well as interactions with excitatory amino acid receptors and regulation of nitric oxide synthesis. Thus, prolonged occupancy by opioid receptor agonists can have differential effects on opioid receptor internalization, down-regulation and desensitization, and in the supersensitization of adenylyl cyclase, which contribute to the development of opioid tolerance and dependence. We discuss the role of various protein kinases in the signaling mechanisms underlying these differences. Clearer understanding of the molecular mechanisms of opioid tolerance and dependence will help in the treatment of patients suffering from acute and chronic pain, or drug dependence and addiction.

    View details for DOI 10.1016/S0165-0173(01)00057-1

    View details for Web of Science ID 000173855100001

    View details for PubMedID 11750924

  • Fetuses, fentanyl and the stress response - Signals from the beginnings of pain? ANESTHESIOLOGY Anand, K. J., Maze, M. 2001; 95 (4): 823-825
  • Can we use methadone for analgesia in neonates? ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Chana, S. K., Anand, K. J. 2001; 85 (2): F79-F81

    View details for DOI 10.1136/fn.85.2.F79

    View details for Web of Science ID 000170833600001

    View details for PubMedID 11517197

    View details for PubMedCentralID PMC1721304

  • Opioid tolerance in neonates: a state-of-the-art review PAEDIATRIC ANAESTHESIA Suresh, S., Anand, K. J. 2001; 11 (5): 511-521
  • Hormonal and metabolic stress responses after major surgery in children aged 0-3 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine BRITISH JOURNAL OF ANAESTHESIA Bouwmeester, N. J., Anand, K. J., van Dijk, M., Hop, W. C., Boomsma, F., Tibboel, D. 2001; 87 (3): 390-399


    Children aged 0-3 yr were stratified for age and randomized to receive either continuous morphine (CM, 10 microg x kg(-1) x h(-1)) with three-hourly placebo boluses or intermittent morphine (IM, 30 microg x kg(-1) every 3 h) with a placebo infusion for postoperative analgesia. Plasma concentrations of epinephrine, norepinephrine, insulin, glucose and lactate were measured before and at the end of surgery and 6, 12 and 24 h after surgery. Pain was assessed with validated pain scales [the COMFORT scale and a visual analogue scale (VAS)] with the availability of additional morphine doses. Minor differences occurred between the randomized treatment groups, the oldest IM group (aged 1-3 yr) having a higher blood glucose concentration (P=0.003), mean arterial pressure (P=0.02) and COMFORT score (P=0.02) than the CM group. In the neonates, preoperative plasma concentrations of norepinephrine (P=0.01) and lactate (P<0.001) were significantly higher, while the postoperative plasma concentrations of epinephrine were significantly lower (P<0.001) and plasma concentrations of insulin significantly higher (P<0.005) than in the older age groups. Postoperative pain scores (P<0.003) and morphine consumption (P<0.001) were significantly lower in the neonates than in the older age groups. Our results show that continuous infusion of morphine does not provide any major advantages over intermittent morphine boluses for postoperative analgesia in neonates and infants.

    View details for DOI 10.1093/bja/87.3.390

    View details for Web of Science ID 000171452400004

    View details for PubMedID 11517122

  • Radiological case of the month - Lemierre syndrome ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Narsinghani, U., Schmidt, M. B., Jacobs, R. F., Anand, K. S. 2001; 155 (8): 965-966

    View details for DOI 10.1001/archpedi.155.8.965

    View details for Web of Science ID 000170237100018

    View details for PubMedID 11483128

  • Interactions of inflammatory pain and morphine in infant rats - Long-term behavioral effects PHYSIOLOGY & BEHAVIOR Bhutta, A. T., Rovnaghi, C., Simpson, P. M., Gossett, J. M., Scalzo, F. M., Anand, K. J. 2001; 73 (1-2): 51-58


    Neonatal rat pups exposed to repetitive acute pain show decreases in pain threshold and altered behavior during adulthood. A model using prolonged inflammatory pain in neonatal rats may have greater clinical relevance for investigating the long-term behavioral effects of neonatal pain in ex-preterm neonates. Neonatal rat pups were exposed to repeated formalin injections on postnatal (P) days 1-7 (P1-P7), with or without morphine pretreatment, and were compared with untreated controls. Behavioral testing during adulthood assessed pain thresholds using hot-plate (HP) and tail-flick (TF) tests, alcohol preference, and locomotor activity (baseline and postamphetamine). Adult rats exposed to neonatal inflammatory pain exhibited longer HP latencies than controls and male rats had longer HP thresholds compared to females. Male rats exposed to neonatal morphine alone exhibited longer TF latencies than controls. Both neonatal morphine treatment and neonatal inflammatory pain decreased ethanol preference, but their effects were not additive. During adulthood, male rats exposed to neonatal inflammatory pain exhibited less locomotor activity than untreated controls. We conclude that neonatal formalin and morphine treatment have specific patterns of long-term behavioral effects in adulthood, some of which are attenuated when the two treatments are combined.

    View details for DOI 10.1016/S0031-9384(01)00432-2

    View details for Web of Science ID 000169239400007

    View details for PubMedID 11399294

  • Statistical models to predict the need for postoperative intensive care and hospitalization in pediatric surgical patients INTENSIVE CARE MEDICINE Anand, K. J., Hopkins, S. E., Wright, J. A., Ricketts, R. R., Flanders, W. D. 2001; 27 (5): 873-883


    To develop statistical models for predicting postoperative hospital and ICU stay in pediatric surgical patients based on preoperative clinical characteristics and operative factors related to the degree of surgical stress. We hypothesized that preoperative and operative factors will predict the need for ICU admission and may be used to forecast the length of ICU stay or postoperative hospital stay.Prospective data collection from 1,763 patients.Tertiary care children's hospital.All pediatric surgical patients, including those undergoing day surgery. Patients undergoing dental or ophthalmologic surgical procedures were excluded.None.A logistic regression model predicting ICU admission was developed from all patients. Poissonregression models were developed from 1,161 randomly selected patients and validated from the remaining 602 patients. The logistic regression model for ICU admission was highlypredictive (area under the receiver operating characteristics (ROC) curve = 0.981). In the data set used for development of Poisson regression models, significant correlations occurred between the observed and predicted ICU stay (Pearson r = 0.468, p < 0.0001, n = 131) and between the observed and predicted hospital stay for patients undergoing general (r = 0.695, p < 0.0001), orthopedic (r = 0.717, p < 0.0001), cardiothoracic (r = 0.746, p < 0.0001), urologic (r = 0.458, p < 0.0001), otorhinolaryngologic (r = 0.962, p < 0.0001), neurosurgical (r = 0.7084, p < 0.0001) and plastic surgical (r = 0.854, p < 0.0001) procedures. In the validation data set, correlations between predicted and observed hospital stay were significant for general (p < 0.0001), orthopedic (p < 0.0001), cardiothoracic (p = 0.0321) and urologic surgery (p = 0.0383). The Poisson models for length of ICU stay, otorhinolaryngology, neurosurgery or plastic surgery could not be validated because of small numbers of patients.Preoperative and operative factors may be used to develop statistical models predicting the need for ICU admission in pediatric surgical patients, and hospital stay following general surgical, orthopedic, cardiothoracic and urologic procedures. These statistical models need to be refined and validatedfurther, perhaps using data collection from multiple institutions.

    View details for DOI 10.1007/s001340100929

    View details for Web of Science ID 000169279000012

    View details for PubMedID 11430544

  • Abnormal cognition and behavior in preterm neonates linked to smaller brain volumes TRENDS IN NEUROSCIENCES Bhutta, A. T., Anand, K. J. 2001; 24 (3): 129-130


    Volumetric measurements of the brain regions in eight-year-old children indicate that the poor cognitive and behavioral outcomes noted in ex-preterm neonates are associated with reduced volumes of specific regions in the brain. Recent literature suggests that this reduction might result from enhanced apoptosis or excitotoxic damage to highly susceptible immature neurons.

    View details for DOI 10.1016/S0166-2236(00)01747-1

    View details for Web of Science ID 000168765900001

    View details for PubMedID 11182440

  • Life-threatening respiratory failure following accidental infusion of polyethylene glycol electrolyte solution into the lung JOURNAL OF TOXICOLOGY-CLINICAL TOXICOLOGY Narsinghani, U., Chadha, M., Farrar, H. C., Anand, K. S. 2001; 39 (1): 105-107


    Functional fecal retention is the most common cause of encopresis in children. Hospitalization may be required to clear the bowel following failure of outpatient management. Although the safety and efficacy of polyethylene glycol electrolyte solution is well established in children older than 6 months (1), its use should be carefully monitored in patients with altered mental status or impaired airway protective reflexes. We report the accidental infusion of NuLytely into the lungs of an 11-year-old female patient who consequently developed life-threatening acute lung injury. She rapidly developed respiratory failure requiring emergent tracheal intubation and suctioning, followed by mechanical ventilation. Careful monitoring is needed to avoid this potential complication if polyethylene glycol solution is infused via a nasogastric tube.

    View details for DOI 10.1081/CLT-100102888

    View details for Web of Science ID 000170067300016

    View details for PubMedID 11327218

  • Developmental neurobiology of pain in neonatal rats LAB ANIMAL Narsinghani, U., Anand, K. J. 2000; 29 (9): 27-39


    The authors examine the biological basis for the behavioral evidence of pain perception in neonatal rats, and discuss the potential link to a greater understanding of chronic pain

    View details for Web of Science ID 000089869900007

    View details for PubMedID 11381240

  • End-of-life decisions in the neonatal intensive care unit: Medical infanticide or palliative terminal care? CRITICAL CARE MEDICINE Schmitz, M. L., Taylor, B. J., Anand, K. J. 2000; 28 (7): 2668-2671
  • Has the increased survival of premature infants affected resource utilization in pediatric intensive cave units? CRITICAL CARE MEDICINE Anand, K. J., Tilford, J. M. 2000; 28 (3): 900-902
  • Effects of perinatal pain and stress BIOLOGICAL BASIS FOR MIND BODY INTERACTIONS Anand, K. J., Mayer, E. A., Saper, C. B. 2000; 122: 117-129


    Neonatal intensive care exposes preterm neonates to a series of repeated, randomly occurring invasive procedures and handling, resulting in acute pain, chronic pain, and prolonged stress during a critical window associated with epochal brain development. Characteristics of the immature pain system in preterm neonates (such as a low pain threshold, prolonged periods of windup, overlapping receptive fields, immature descending inhibition) predisposes them to greater clinical and behavioral sequelae from inadequately treated pain than older age groups. Evidence for developmental plasticity in the neonatal brain suggests that repetitive painful experiences during this period or prolonged exposure to analgesic drugs may alter neuronal and synaptic organization permanently. Traditionally, clinicians have chosen the perspective that routine use of analgesic or sedative drugs in preterm neonates may create more problems than minimal therapy. However, the immediate and long-term consequences of inadequately treated pain have forced them to reconsider the risk-benefit ratios for such therapy. Whereas the short-term consequences of prolonged analgesic therapy in human neonates are well-known (tolerance, withdrawal, ventilator dependency), long-term consequences are relatively unknown. Advances in the study of repetitive pain associated with routine NICU care have challenged the perspective that prolonged pain and stress were inevitable consequences of premature birth.

    View details for Web of Science ID 000085937700009

    View details for PubMedID 10737054

  • Long-term effects of pain in infants JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Porter, F. L., Grunau, R. E., Anand, K. J. 1999; 20 (4): 253-261


    Pain and stress have been shown to induce significant physiological and behavioral reactions in newborn infants, even in those born prematurely. Infants who are born prematurely or seriously ill are commonly exposed to multiple painful and stressful events as part of their prolonged hospitalizations and required medical procedures. There is now evidence that these early events not only induce acute changes, but that permanent structural and functional changes may also result. This article reviews the growing body of evidence of likely long-term effects of early pain and stress on the human infant. It is hoped that a better understanding of this literature will promote more responsive and sensitive management of infants and young children during their encounters with the medical community and will ultimately facilitate the healthy growth and development of all children.

    View details for DOI 10.1097/00004703-199908000-00008

    View details for Web of Science ID 000082064300008

    View details for PubMedID 10475600

  • Is hypertonic saline an effective alternative to mannitol in the treatment of elevated intracranial pressure in pediatric patients? JOURNAL OF INTENSIVE CARE MEDICINE Vats, A., Chambliss, C. R., Anand, K. J., Pettignano, R. 1999; 14 (4): 184-188
  • Long-term behavioral effects of repetitive pain in neonatal rat pups PHYSIOLOGY & BEHAVIOR Anand, K. J., Coskun, Thrivikraman, K. V., Nemeroff, C. B., Plotksy, P. M. 1999; 66 (4): 627-637


    Human preterm neonates are subjected to repetitive pain during neonatal intensive care. We hypothesized that exposure to repetitive neonatal pain may cause permanent or long-term changes because of the developmental plasticity of the immature brain. Neonatal rat pups were stimulated one, two, or four times each day from P0 to P7 with either needle prick (noxious groups N1, N2, N4) or cotton tip rub (tactile groups T1, T2, T4). In groups N2, N4, T2, T4 stimuli were applied to separate paws at hourly intervals;each paw was stimulated only once a day. Identical rearing occurred from P7 to P22 days. Pain thresholds were measured on P16, P22, and P65 (hot-plate test), and testing for defensive withdrawal, alcohol preference, air-puff startle, and social discrimination tests occurred during adulthood. Adult rats were exposed to a hot plate at 62 degrees C for 20 s, then sacrificed and perfused at 0 and 30 min after exposure. Fos expression in the somatosensory cortex was measured by immunocytochemistry. Weight gain in the N2 group was greater than the T2 group on P16 (p < 0.05) and P22 (p < 0.005); no differences occurred in the other groups. Decreased pain latencies were noted in the N4 group [5.0 +/- 1.0 s vs. 6.2 +/- 1.4 s on P16 (p < 0.05); 3.9 +/- 0.5 s vs. 5.5 +/- 1.6 s on P22 (p < 0.005)], indicating effects of repetitive neonatal pain on subsequent development of the pain system. As adults, N4 group rats showed an increased preference for alcohol (55 +/- 18% vs. 32 +/- 21%; p = 0.004); increased latency in exploratory and defensive withdrawal behavior (p < 0.05); and a prolonged chemosensory memory in the social discrimination test (p < 0.05). No significant differences occurred in corticosterone and ACTH levels following air-puff startle or in pain thresholds at P65 between N4 and T4 groups. Fos expression at 30 min after hot-plate exposure was significantly greater in all areas of the somatosensory cortex in the T4 group compared with the N4 group (p < 0.05), whereas no differences occurred just after exposure. These data suggest that repetitive pain in neonatal rat pups may lead to an altered development of the pain system associated with decreased pain thresholds during development. Increased plasticity of the neonatal brain may allow these and other changes in brain development to increase their vulnerability to stress disorders and anxiety-mediated adult behavior. Similar behavioral changes have been observed during the later childhood of expreterm neonates who were exposed to prolonged periods of neonatal intensive care.

    View details for DOI 10.1016/S0031-9384(98)00338-2

    View details for Web of Science ID 000080685000012

    View details for PubMedID 10386907

    View details for PubMedCentralID PMC4211637

  • Consciousness, behavior, and clinical impact of the definition of pain PAIN FORUM Anand, K. J., Rovnaghi, C., Walden, M., Churchill, J. 1999; 8 (2): 64-73
  • Analgesia and sedation in preterm neonates who require ventilatory support - Results from the NOPAIN trial ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Anand, K. J., McIntosh, N., Lagercrantz, H., Pelausa, E., Young, T. E., Vasa, R. 1999; 153 (4): 331-338


    Preterm neonates are exposed to multiple painful procedures after birth and exhibit acute physiological responses to pain. Occurrence of early intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intraventricular hemorrhage and periventricular leukomalacia. We proposed that such neurologic outcomes in preterm neonates who require ventilatory support may be reduced by morphine analgesia or midazolam sedation compared with a placebo.To define the incidence of clinical outcomes in the target study population, to estimate the effect size and adverse effects associated with analgesia and sedation, and to calculate the sample size for a definitive test of this hypothesis.Sixty-seven preterm neonates were randomized in a pilot clinical trial from 9 centers. Neonates of 24 to 32 weeks gestation were eligible if they had been intubated and required ventilatory support for less than 8 hours and if they were enrolled within 72 hours after birth. Exclusion criteria included major congenital anomalies, severe intrapartum asphyxia, and participation in other research studies. Severity of illness was assessed by the Clinical Risk Index for Babies, and neonates were randomized to receive continuous infusions of morphine sulfate, midazolam hydrochloride, or 10% dextrose (placebo). Masked study medications were continued as long as clinically necessary, then weaned and stopped according to predefined criteria. Levels of sedation (COMFORT scores) and responses to pain (Premature Infant Pain Profile scores) were measured before, during, and 12 hours after discontinuation of drug infusion. Cranial ultrasound examinations were performed as part of routine practice, and poor neurologic outcomes were defined as neonatal death, severe intraventricular hemorrhage (grade III or IV), or periventricular leukomalacia.No significant differences occurred in the demographic, clinical, and socioeconomic variables related to mothers and neonates in the 3 groups or in the severity of illness at birth as measured by Clinical Risk Index for Babies scores. Two neonates in the placebo group and 1 neonate in the midazolam group died; no deaths occurred in the morphine group. Poor neurologic outcomes occurred in 24% of neonates in the placebo group, 32% in the midazolam group, and 4% in the morphine group (likelihood ratio chi2 = 7.04, P = .03). Secondary clinical outcomes and neurobehavioral outcomes at 36 weeks' postconceptional age were similar in the 3 groups. Responses elicited by endotracheal tube suction (Premature Infant Pain Profile scores) were significantly reduced during the morphine (P<.001) and midazolam (P = .002) infusions compared with the placebo group.This pilot trial suggests that preemptive analgesia given by continuous low-dose morphine infusion may reduce the incidence of poor neurologic outcomes in preterm neonates who require ventilatory support. Limitations in the sample size of this pilot study suggest that these results should be confirmed in a large multicenter randomized trial.

    View details for Web of Science ID 000079629700002

    View details for PubMedID 10201714

  • Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION van Lingen, R. A., Deinum, J. T., Quak, J. M., Kuizenga, A. J., van Dam, J. G., Anand, K. J., Tibboel, D., Okken, A. 1999; 80 (1): F59-F63


    To investigate the pharmacokinetics, metabolism, and dose-response relation of a single rectal dose of paracetamol in preterm infants in two different age groups.Preterm infants stratified by gestational age groups 28-32 weeks (group 1) and 32-36 weeks (group 2) undergoing painful procedures were included in this study. Pain was assessed using a modified facies pain score.Twenty one infants in group 1 and seven in group 2 were given a single rectal dose of 20 mg/kg body weight. Therapeutic concentrations were reached in 16/21 and 1/7 infants in groups 1 and 2, respectively. Peak serum concentrations were significantly higher in group 1. Median time to reach peak concentrations was similar in the two groups. As serum concentration was still in the therapeutic range for some infants in group 1, elimination half life (T1/2) could not be determined in all infants: T1/2 was 11.0 +/- 5.7 in 11 infants in group 1 and 4.8 +/- 1.2 hours in group 2. Urinary excretion was mainly as paracetamol sulphate. The glucuronide:sulphate ratio was 0.12 +/- 0.09 (group 1) and 0.28 +/- 0.35 (group 2). The pain score did not correlate with therapeutic concentrations.A 20 mg/kg single dose of paracetamol can be safely given to preterm infants in whom sulphation is the major pathway of excretion. Multiple doses in 28-32 week old neonates would require an interval of more than 8 hours to prevent progressively increasing serum concentrations.

    View details for DOI 10.1136/fn.80.1.F59

    View details for Web of Science ID 000078014000013

    View details for PubMedID 10325815

    View details for PubMedCentralID PMC1720876

  • Opioid tolerance in neonates: Mechanisms, diagnosis, assessment, and management SEMINARS IN PERINATOLOGY Suresh, S., Anand, K. J. 1998; 22 (5): 425-433


    Opioid tolerance and withdrawal have been challenges for decades. The neurochemical mechanisms of tolerance and dependence are clinically important only because they can affect weaning schedules and the adjustment of doses for neonates. Analgesic effects are characterized by an increased depolarization threshold for the neuron, shorter duration of the action potential generated, and reduced release of neurotransmitters. Tolerance and withdrawal are associated with the reversal of these cellular effects. Adverse clinical effects associated with the use of opioids in neonates include respiratory depression, chest wall rigidity, urinary retention, and decreased gastrointestinal motility. The physiological systems most prominently affected by opioid withdrawal include the central nervous system, gastrointestinal system, and the autonomic nervous system. Opioid withdrawal symptoms in neonates can be assessed by using easily available scoring systems, although these need to be validated for different populations. Management of opioid withdrawal includes the use of other opioids, benzodiazepines and alpha-2 adrenergic receptor antagonist, clonidine. Careful titration of opioids with attention given to appropriate weaning schedules can reduce the incidence of withdrawal in neonates.

    View details for DOI 10.1016/S0146-0005(98)80058-X

    View details for Web of Science ID 000076657700008

    View details for PubMedID 9820567

  • Neonatal analgesia and anesthesia - Introduction SEMINARS IN PERINATOLOGY Anand, K. J. 1998; 22 (5): 347-349

    View details for DOI 10.1016/S0146-0005(98)80051-7

    View details for Web of Science ID 000076657700001

    View details for PubMedID 9820560

  • Practical approach to analgesia and sedation in the Neonatal Intensive Care Unit SEMINARS IN PERINATOLOGY Menon, G., Anand, K. J., McIntosh, N. 1998; 22 (5): 417-424


    The anatomic and physiological bases for nociception are present even in very preterm neonates. Neonates show the same behavioral, endocrine, and metabolic responses to noxious stimuli as older subjects. Preterm infants appear to be more sensitive to painful stimuli and have heightened responses to successive stimuli. Infants receiving intensive care are subjected to frequent stressful procedures and also chronic noxious influences related to the environment of care. Inflammatory conditions such as necrotizing enterocolitis may also cause pain. Untreated pain in babies is associated with increased major morbidity and mortality. Nonpharmacological interventions, including environmental modification and comforting during procedures reduce stress. Intravenous opiates are the mainstay of pharmacological analgesia. A pure sedative agent can provide physiological stability in settings in which there are less acutely painful stimuli or when there are adverse effects from, or tolerance to, opiates. Local anesthesia of skin and mucous membranes is helpful for invasive procedures. Antipyretic analgesics such as acetaminophen have a role in inflammatory pain.

    View details for DOI 10.1016/S0146-0005(98)80057-8

    View details for Web of Science ID 000076657700007

    View details for PubMedID 9820566

  • Bilateral vocal cord paralysis after meningitis due to Streptococcus pneumoniae SOUTHERN MEDICAL JOURNAL Clack, Z. A., Anand, K. J., Fortenberry, J. D., Chambliss, C. R. 1998; 91 (7): 660-662


    We report the clinical course of a 15-month-old boy who had fever, decreased activity, and weakness, with severe respiratory distress during transport to the hospital. Laboratory evaluation confirmed the diagnosis of meningitis due to Streptococcus pneumoniae. He was intubated on arrival and required 4 days of ventilatory support. Soon after extubation, he had marked stridor and dyspnea that were unresponsive to standard therapy with nebulized racemic epinephrine and intravenous dexamethasone. Magnetic resonance imaging of the brain revealed nonspecific findings, and airway endoscopy showed bilateral vocal cord paralysis. Repeated endoscopy showed no improvement in vocal cord function and a deficient swallowing mechanism. Tracheostomy was done to facilitate airway management before discharge from the pediatric intensive care unit. We propose that the diagnosis of vocal cord paralysis must be considered in patients with meningitis and respiratory compromise.

    View details for DOI 10.1097/00007611-199807000-00010

    View details for Web of Science ID 000074784400009

    View details for PubMedID 9671838

  • Physiological, hormonal, and behavioral response to a single fentanyl dose in intubated and ventilated preterm neonates JOURNAL OF PEDIATRICS Guinsburg, R., Kopelman, B. I., Anand, K. J., de Almeida, M. F., Peres, C. D., Miyoshi, M. H. 1998; 132 (6): 954-959


    To study the responses of ventilated preterm neonates to a single dose of opioid.In a randomized, double-blind, controlled trial, 22 mechanically ventilated preterm infants (< or = 32 weeks) were observed before medication and at 30 and 60 minutes after administration of fentanyl (3 micrograms/kg) or placebo. Heart rate, blood pressure, arterial blood gases, ventilator settings, and behavioral measures (Neonatal Facial Coding System and Modified Postoperative Comfort Score) were recorded during each period. Blood cortisol, growth hormone, glucose, and lactate were measured before and at 60 minutes after analgesia. Behavioral measures were assessed at the bedside and from video films recorded during each observation period.Patients presented high basal levels of cortisol, growth hormone, and lactate. Behavioral scales indicated the presence of pain before any medication. In the fentanyl group, the maximum and minimum heart rate decreased and growth hormone level increased after analgesia. At the video analysis of behavioral measures, postoperative comfort score increased and neonatal facial coding system score decreased in the fentanyl group.Single doses of fentanyl analgesia can reduce the physiologic/behavioral measures of pain and stress associated with mechanical ventilation in preterm infants.

    View details for DOI 10.1016/S0022-3476(98)70390-7

    View details for Web of Science ID 000074065100010

    View details for PubMedID 9627585

  • Lidocaine iontophoresis for topical anesthesia before intravenous line placement in children Zempsky, W. T., Anand, K. J., Sullivan, K. M., Fraser, D., Cucina, K. MOSBY-ELSEVIER. 1998: 1061-1063


    In a double-blind randomized trial including 42 children aged 7 to 18 years, less pain occurred with intravenous placement after iontophoresis of 2% lidocaine with epinephrine, as reported by patients (p = 0.005), parents (p = 0.001), intravenous personnel (p = 0.009), and investigators (p = 0.0002) compared with placebo therapy. Lidocaine iontophoresis provides rapid and effective topical anesthesia for intravenous access in children.

    View details for DOI 10.1016/S0022-3476(98)70413-5

    View details for Web of Science ID 000074065100033

    View details for PubMedID 9627608

  • Clinical importance of pain and stress in preterm neonates BIOLOGY OF THE NEONATE Anand, K. J. 1998; 73 (1): 1-9


    Clinical and laboratory investigations of neonatal pain suggest that preterm neonates have an increased sensitivity to pain and that acute painful stimuli lead to the development of prolonged periods of hyperalgesia. Non-noxious stimuli during these periods of hyperalgesia may expose preterm neonates to established or chronic pain. Acute physiologic changes caused by painful or stressful stimuli can be implicated as important factors in the causation or subsequent extension of early intraventricular hemorrhage (IVH) or the ischemic changes leading to periventricular leukomalacia (PVL). Therapeutic interventions that provide comfort/analgesia in preterm neonates were correlated with a decreased incidence of severe IVH. Long-term follow-up studies of preterm neonates may substantiate the preliminary data associating repetitive painful experiences with some of the neurobehavioral and developmental sequelae resulting from neonatal intensive care.

    View details for DOI 10.1159/000013953

    View details for Web of Science ID 000071243300001

    View details for PubMedID 9458936

  • A cross-sectional survey of pain and pharmacological analgesia in Canadian Neonatal Intensive Care Units CLINICAL JOURNAL OF PAIN Johnston, C. C., Collinge, J. M., Henderson, S. J., Anand, K. J. 1997; 13 (4): 308-312


    To determine current practices for the use of analgesia term and preterm neonates cared for in Neonatal Intensive Care Units (NICUs).One-week survey of medical charts of current patients.NICUs in Canada.A total of 14 of 38 invited NICUs participated. These units were not different on number of beds, admissions per year, or university affiliation from the nonparticipating units.Daily logs were kept of the frequency and type of procedures and analgesia administration for all ill neonates in each NICU during the study period.The sample consisted of 239 patients. A total of 2,134 invasive procedures were performed. Medication was given specifically 18 times for 17 invasive procedures (0.8%). For another 129 invasive procedures, the patient was receiving analgesia for reasons other than the procedure. Sixteen patients had surgery during the survey period, and another 14 had surgery prior to but within 4 days of the survey. Fifty-one patients received anaesthesia or analgesia specifically related to surgery (39 times), procedures (35 times), or other reasons (34 times), a total of 108 courses. Opioids were the most frequently used medications and were given for all reasons, by continuous infusion, intermittent bolus, or sometimes both methods for the same patient.Postoperative pain in neonates in Canadian NICUs appears to be consistently treated, primarily with opioid analgesics, but analgesia, opioid or nonopioid is rarely given for nonsurgical invasive procedures.

    View details for DOI 10.1097/00002508-199712000-00008

    View details for Web of Science ID 000071110800005

    View details for PubMedID 9430811

  • Pain management in the pediatric intensive care unit. Current opinion in pediatrics Chambliss, C. R., Anand, K. J. 1997; 9 (3): 246-53


    Critically ill pediatric patients are frequently exposed to acute, established, and chronic pain as a result of their disease processes or intensive care therapies. Despite the availability of many drugs and techniques for providing analgesia, these painful conditions are not adequately treated in a large proportion of children. This article reviews some of the reasons for provision of adequate analgesia and sedation, describes the various classes of drugs commonly used in the pediatric intensive care unit, and lists the techniques and indications for regional and topical anesthesia as well as specific clinical applications for adjuvant analgesic agents. Analgesic approaches that do not have an established record of safety and efficacy in pediatric patients are not reviewed. We propose that adequate and early analgesic interventions will minimize patient's discomfort, maintain metabolic homeostasis, and improve a patient's tolerance of intensive care unit therapies and nursing interventions. Adequate analgesia can be provided to even the sickest child using the drugs, techniques, and novel approaches reviewed.

    View details for DOI 10.1097/00008480-199706000-00011

    View details for PubMedID 9229164

  • Pediatric. Tolerance, dependence, and strategies for compassionate withdrawal of analgesics and anxiolytics in the pediatric ICU. Critical care nurse Anand, K. J., Ingraham, J. 1996; 16 (6): 87-93

    View details for PubMedID 9004606

  • Laceration repair using a tissue adhesive in a children's emergency department PEDIATRICS Bruns, T. B., Simon, H. K., McLario, D. J., Sullivan, K. M., Wood, R. J., Anand, K. J. 1996; 98 (4): 673-675


    To determine the effectiveness of a tissue adhesive, Histoacryl Blue (HAB), for laceration repair in children.Prospective, randomized clinical trial.A tertiary care pediatric emergency center at Egleston Children's Hospital.Children who presented for laceration repair between October 1994 and February 1995 were prospectively evaluated. Patients less than 1 or greater than 18 years of age, those with lacerations greater than 5 cm, and those with lacerations located on the eyelids, ears, nose, lips, hands, feet, joints, or perineum were excluded.Following consent and routine wound management, including subcutaneous closure when deemed necessary, patients were randomized to receive skin sutures or HAB for cutaneous closure.Length of time required for laceration repair was recorded. Parental perception of the pain experienced by their child was assessed using a visual analogue scale. Photographic documentation of scar appearance at the 2-month follow-up visit was evaluated by plastic surgeons using a visual analogue scale.Sixty-one children were enrolled: HAB group (N = 30), suture group (N = 31). No differences occurred between groups in laceration length, depth, location, or patient demographics. Length of time required for repair was decreased (median, HAB 7 minutes vs suture 17.0 minutes) and parental assessment of their child's pain was significantly less in the HAB group. Parents were more likely to recommend HAB over suturing to other parents or guardians. Cosmetic outcome in the HAB group was assessed to be as good as, or better than, the cosmetic outcome in the suture group as evaluated by two plastic surgeons.The use of HAB for laceration repair is an acceptable alternative to conventional suturing with a comparable cosmetic outcome. Advantages include less pain to the child, no need for suture removal, and more efficient use of physician time. Parents were also more likely to recommend HAB over suturing for laceration repair.

    View details for Web of Science ID A1996VN09000004

    View details for PubMedID 8885944

  • New perspectives on the definition of pain - Response PAIN Merskey, H. 1996; 67 (1): 209
  • Intratracheal administration of fentanyl: Pharmacokinetics and local tissue effects INTENSIVE CARE MEDICINE Irazuzta, J. E., Ahmed, U., Gancayco, A., Ahmed, S. T., Zhang, J., Anand, K. J. 1996; 22 (2): 129-133


    To study the pharmacokinetics and local tissue effects resulting from the intratracheal administration of preservative-free fentanyl.Prospective, randomized, blinded and controlled animal study.University research laboratory.Eighteen adult male New Zealand rabbits.Preservative-free fentanyl citrate or normal saline was administered by the intratracheal (i.t.) and intravenous (i.v.) routes to randomized groups of rabbits. The animals were killed at 24, 48 and 72 h following administration.Plasma concentrations of fentanyl were measured before administration and at 2, 5, 10, 30, 60 and 120 min following administration by a specific radioimmunoassay. A detailed histological examination of the lung and tracheal tissue was performed to identify local side effects. There were no significant differences in the plasma fentanyl concentrations resulting from the i.v. or i.t. route of administration. In both groups, the concentrations of fentanyl were within the therapeutic range (i.t. 2.37 ng/ml, i.v. 2.53 ng/ml) by 2 min after injection and reached a maximum concentration within 5 min. The bioavailability of i.t. fentanyl was 71%. Microscopic examination of the respiratory system did not show significant differences between the two random groups overall. However, in the sub-group of animals killed at 24 h, more animals in the i.t. group showed signs of inflammation in the lung parenchyma.There is rapid absorption of fentanyl following i.t. administration. Pharmacokinetic parameters for fentanyl were not significantly altered by the route of administration. Although there were no signs that i.t. administration of preservative-free fentanyl produces lung injury, a transient and mild inflammatory response was detected at 24 h after administration.

    View details for DOI 10.1007/BF01720719

    View details for Web of Science ID A1996TZ33800007

    View details for PubMedID 8857120

  • Hypertonic saline (HS) is an effective agent in the management of increased intracranial pressure (ICP). Vats, A., Pettignano, R., Chambliss, C. R., Anand, K. J. SLACK INC. 1996: A18


    To review the definitions and scientific basis for opioid tolerance and dependence in neonates and older children; to assess objective methods for the clinical evaluation of opioid abstinence syndromes in this age group; and to suggest therapeutic strategies for the treatment of opioid abstinence in critically ill neonates and children.The published literature on opioid tolerance and dependence in pediatric patients was reviewed. Data from current clinical practices, nursing procedures, and ongoing clinical research were evaluated.Currently proposed mechanisms of opioid tolerance and dependence are assessed, with particular relevance to the developing human central nervous system. The validity and clinical role of currently available objective methods for the assessment of opioid abstinence in neonates and older infants are defined. The efficacy of various pharmacologic and nonpharmacologic modalities for the treatment of opioid abstinence is evaluated and compared, and a therapeutic approach based on receptor mechanisms, clinical monitoring data, and pharmacologic efficacy is suggested.Important parallels for therapeutically-induced opioid tolerance and withdrawal may be drawn from the assessment and management of neonates born from opioid-addicted mothers. Opioid withdrawal can be prevented with appropriate weaning schedules, diagnosed by objective clinical methods, and treated by a variety of pharmacologic and non-pharmacologic means. Pharmacologic therapy includes the use of opioids, with adjuvant drugs such as diazepam, clonidine, or chlorpromazine. The pathophysiology and assessment of therapeutically induced opioid tolerance and withdrawal merit further research in critically ill pediatric patients.

    View details for DOI 10.1097/00003246-199402000-00027

    View details for Web of Science ID A1994MX50500027

    View details for PubMedID 8306694

  • Neonatal pain management. Critical care nursing clinics of North America Clancy, G. T., Anand, K. J., Lally, P. 1992; 4 (3): 527-35


    Neonatal pain management is a challenge for the clinician. Research is just beginning to uncover the neonates' capability of expression of pain, explore pharmacologic management strategies, and identify the spectrum of intrusions that may precipitate pain or distress in the critically ill neonate. This article reviews the neonatal biologic, behavioral, and physiologic responses to pain and describes recommendations for clinical management and decision-making.

    View details for PubMedID 1388999


    View details for Web of Science ID A1992JC21400013

    View details for PubMedID 1603122



    Extreme hormonal and metabolic responses to stress are associated with increased morbidity and mortality in sick adults. We hypothesized that administering deep opioid anesthesia to critically ill neonates undergoing cardiac surgery would blunt their responses to stress and might improve clinical outcomes.In a randomized trial, 30 neonates were assigned to receive deep intraoperative anesthesia with high doses of sufentanil and postoperative infusions of opiates for 24 hours; 15 neonates were assigned to receive lighter anesthesia with halothane and morphine followed postoperatively by intermittent morphine and diazepam. Hormonal and metabolic responses to surgery were evaluated by assay of arterial blood samples obtained before, during, and after the operations.The neonates who received deep anesthesia (with sufentanil) had significantly reduced responses of beta-endorphin, norepinephrine, epinephrine, glucagon, aldosterone, cortisol, and other steroid hormones; their insulin responses and ratios of insulin to glucagon were greater during the operation. The neonates who received lighter anesthesia (with halothane plus morphine) had more severe hyperglycemia and lactic acidemia during surgery and higher lactate and acetoacetate concentrations postoperatively (P less than 0.025). The group that received deep anesthesia had a decreased incidence of sepsis (P = 0.03), metabolic acidosis (P less than 0.01), and disseminated intravascular coagulation (P = 0.03) and fewer postoperative deaths (none of 30 given sufentanil vs. 4 of 15 given halothane plus morphine, (P less than 0.01).In neonates undergoing cardiac surgery, the physiologic responses to stress are attenuated by deep anesthesia and postoperative analgesia with high doses of opioids. Deep anesthesia continued postoperatively may reduce the vulnerability of these neonates to complications and may reduce mortality.

    View details for DOI 10.1056/NEJM199201023260101

    View details for Web of Science ID A1992GX31500001

    View details for PubMedID 1530752



    Hormonal and metabolic responses were measured in 15 neonates who underwent repair of complex congenital heart defects during a standardized anesthetic protocol. Four of the 15 neonates died postoperatively in the intensive care unit. Analysis of arterial plasma samples obtained before, during, and 24 h after surgery showed that plasma epinephrine, norepinephrine, cortisol, glucagon, and beta endorphin increased in all patients (P less than 0.05). Insulin levels increased only at the end of surgery but remained elevated for 24 h postoperatively (P less than 0.02). Intraoperative metabolic changes were characterized by hyperglycemia and lactic acidemia that persisted postoperatively. This pattern of neonatal stress responses is distinct from and more extreme than that seen in adult cardiac surgical patients. The four neonates who died postoperatively tended to have higher stress responses intra- and postoperatively despite having been indistinguishable from survivors by the usual clinical and hemodynamic criteria. These preliminary results suggest that neonatal hormonal and metabolic responses to cardiac surgical operations in neonates are extreme and are associated with a high hospital mortality rate.

    View details for DOI 10.1097/00000542-199010000-00012

    View details for Web of Science ID A1990EB62300012

    View details for PubMedID 2221435



    Neonatal stress responses have been investigated only in recent years. Term neonates mount substantial hormonal and metabolic responses, which are distinct from those of adult patients. These responses can be altered significantly by the effects of prematurity, the effects of graded surgical stress, and the anesthetic techniques used during surgery. In addition, neonatal stress responses may have important implications for the clinical outcome following surgery in neonates.

    View details for DOI 10.1016/S0095-5108(18)30599-2

    View details for Web of Science ID A1990CY46000018

    View details for PubMedID 2180620



    Beginning with a brief description of mature anatomic pathways and neurotransmitters in the "pain system," this article details their development in the human fetus, neonate, and child. Special emphasis is given to the basic mechanisms and physiologic effects of opioid analgesia. The clinical implications of these data are described, particularly with regard to the maintenance of cardiovascular stability and hormonal-metabolic homeostasis in newborns and children undergoing surgery or other forms of stress.

    View details for Web of Science ID A1989AK18000003

    View details for PubMedID 2569180



    Only recently has the use of anesthesia and analgesia become widely accepted in the newborn infant. This is largely a result of the overwhelming evidence that neonates have the neurologic substrate for the perception of pain and display characteristic behavioral, physiologic, metabolic, and hormonal responses to noxious stimuli. The management of postoperative pain in the surgical neonate begins in the operating room, where techniques can be chosen that will ease the transition into the postoperative period. For postoperative analgesia, the most widely used and effective agents are the narcotics morphine and fentanyl. They may be administered either intermittently or continuously, and with proper precautions may be given to both intubated and nonintubated newborns. Other medications for analgesia and sedation are not as well studied in the newborn, but chloral hydrate and the benzodiazepines are useful for sedation, and acetaminophen may be used for analgesia alone or for potentiating the effect of narcotics. In addition, a number of creative nonpharmacologic techniques are being developed and promise to further decrease the discomfort experienced by postoperative neonates.

    View details for DOI 10.1016/S0095-5108(18)30654-7

    View details for Web of Science ID A1989T887700006

    View details for PubMedID 2656066



    Evidence of an endocrine and metabolic response to stress is evident from the mid trimester of fetal life. The ontogeny of this response is seen in the different patterns of response evident in the fetus, neonate, infant and child. These data raise important issues concerning the management of pain and stress in early life.

    View details for DOI 10.1007/BF00260885

    View details for Web of Science ID A1989T864300012

    View details for PubMedID 2723248



    Three groups of women were delivered by caesarean section before labour: for an abnormal fetal heart rate (FHR) trace (21 cases, group 1), or for maternal deterioration in severe pre-eclampsia without gross fetal heart rate abnormalities (20 cases, group 2), or to avoid mechanical difficulties in labour at term (30 cases, group 3). The mean gestational ages of the first two groups were 32 weeks with a high proportion of infants small-for-gestational-age. In group 1, FHR variation (mean range of pulse intervals) was less than half (20.6 SE 1.2 ms) of the normal value at the same age (44.4 SE 1.5 ms). This was associated with hypoxaemia (mean umbilical artery PO2 of 6 mmHg at delivery), with evidence of compensation shown by an elevated amniotic fluid erythropoietin. The fetuses were hypoglycaemic and had greater umbilical artery blood alanine concentrations, but no large changes in adenine nucleotide or endorphin plasma concentrations. Although there was a minor degree of respiratory acidaemia at birth, there was not significant metabolic acidaemia. The results demonstrate that the reduced variation of 'suboptimal' and 'decelerative' fetal heart rate records is associated with fetal hypoxaemia and evidence of nutritional deprivation, but not with asphyxia.

    View details for DOI 10.1111/j.1471-0528.1988.tb06501.x

    View details for Web of Science ID A1988Q566500005

    View details for PubMedID 3191052



    Measurement of the severity of surgery would greatly facilitate the design and interpretation of studies in neonates undergoing surgery. A scoring method, based on the amount of blood loss, superficial dissection, and visceral trauma, the site and duration of surgery, cardiac surgical factors, and associated stress factors for surgical neonates, was formulated and applied to 94 neonates undergoing surgery. Perioperative management was standardized for all patients and hormonal-metabolic variables were measured in blood samples drawn preoperatively at the end of the operation, and at six, 12, and 24 hours after operation. The stress scores were correlated significantly with the plasma epinephrine (P less than .0001), norepinephrine (P less than .0001), insulin (P less than .001), glucagon (P less than .005), and cortisol (P less than .02) responses, and with changes in blood glucose (P less than .0001), lactate (P less than .0001), pyruvate (P less than .0001), and alanine (P less than .005) during and after operation. Discriminant function analysis was used for further validation and this scoring method was found to predict accurately the severity of surgical stress in 89.4% cases. Discrepancies in the remaining cases were found to be related to specific clinical factors. On comparison of the hormonal and metabolic responses of neonates in the minor (N = 71), moderate (N = 12), and severe (N = 11) stress groups, increasing severity of surgical stress was found to be associated with greater and more prolonged changes in plasma catecholamines, blood glucose, and gluconeogenic substrates during and after operation. Clinical outcome following operation was also significantly different between the three stress groups.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for DOI 10.1016/S0022-3468(88)80193-3

    View details for Web of Science ID A1988M927400001

    View details for PubMedID 3290422



    Concern about the side effects of various anaesthetic agents in newborn infants has led to the widespread use of anaesthesia with unsupplemented nitrous oxide and oxygen with muscle relaxants in such patients. To investigate the efficacy of such a regimen 36 neonates undergoing operations were randomised to two groups: one group received anaesthesia with nitrous oxide and curare alone and the other was additionally given halothane. Concentrations of metabolites and hormones were measured before and at the end of operation and at six, 12, and 24 hours after operation and the values compared between the two groups. Neonates given halothane anaesthesia showed decreased hormonal responses to operation, with significant differences between the two groups in the changes in adrenaline, noradrenaline, and cortisol concentrations and the ratio of insulin to glucagon concentration. Changes in blood concentrations of glucose and total ketone bodies and plasma concentrations of non-esterified fatty acids were also decreased in neonates receiving halothane anaesthesia. Neonates given anaesthesia with unsupplemented nitrous oxide showed significantly greater increases in the urinary ratio of 3-methylhistidine to creatinine concentration and their clinical condition was also more unstable during and after operation. Unless specifically contraindicated potent anaesthesia with halothane or other anaesthetic agents should be given to all neonates undergoing surgical operations as it decreases their stress responses and improves their clinical stability during and after operation.

    View details for DOI 10.1136/bmj.296.6623.668

    View details for Web of Science ID A1988M446100007

    View details for PubMedID 3128362

    View details for PubMedCentralID PMC2545294


    View details for Web of Science ID A1987K889500033

    View details for PubMedID 2890834


    View details for DOI 10.1056/NEJM198711193172105

    View details for Web of Science ID A1987K867500005

    View details for PubMedID 3317037


    View details for DOI 10.1016/S0022-3476(87)80440-7

    View details for Web of Science ID A1987H605900043

    View details for PubMedID 3585618

  • Anaesthesia and surgery in children. Lancet (London, England) [Anonymous] 1987; 1 (8535): 750-1

    View details for PubMedID 2882168



    In a randomised controlled trial, preterm babies undergoing ligation of a patent ductus arteriosus were given nitrous oxide and d-tubocurarine, with (n = 8) or without (n = 8) the addition of fentanyl (10 micrograms/kg intravenously) to the anaesthetic regimen. Major hormonal responses to surgery, as indicated by changes in plasma adrenaline, noradrenaline, glucagon, aldosterone, corticosterone, 11-deoxycorticosterone, and 11-deoxycortisol levels, in the insulin/glucagon, molar ratio, and in blood glucose, lactate, and pyruvate concentrations were significantly greater in the non-fentanyl than in the fentanyl group. The urinary 3-methylhistidine/creatinine ratios were significantly greater in the non-fentanyl group on the second and third postoperative days. Compared with the fentanyl group, the non-fentanyl group had circulatory and metabolic complications postoperatively. The findings indicate that preterm babies mount a substantial stress response to surgery under anaesthesia with nitrous oxide and curare and that prevention of this response by fentanyl anaesthesia may be associated with an improved postoperative outcome.

    View details for Web of Science ID A1987F534500002

    View details for PubMedID 2879174



    The response to surgical injury is mediated through the hypothalamus and is characterised by the release of catecholamines, glucocorticoids, growth hormone and glucagon; the suppression of insulin secretion and changes in other endocrine systems. These hormonal responses trigger a cascade of metabolic adjustments leading to catabolism and substrate mobilization in the postoperative period. There is evidence that a severe and prolonged catabolic reaction to injury may be associated with an increased morbidity and mortality in high-risk adult patients. This article reviews the historical background of investigation in this field, together with recent advances in the understanding of the complex metabolic phenomena following surgery. These changes are discussed with particular reference to therapeutic manipulation of the stress response using anaesthetic, hormonal or nutrition regimens. It is concluded that further research in this field may provide major clinical benefits in the management of critically ill patients undergoing surgical stress.

    View details for Web of Science ID A1986E631000002

    View details for PubMedID 3097757



    Little is known of the ability of the human newborn infant to mount an endocrine and metabolic response to surgical trauma. Blood concentrations of glucose, lactate, pyruvate, alanine, hydroxybutyrate, acetoacetate, and glycerol together with plasma concentrations of insulin, glucagon, adrenaline, and nonadrenaline were measured in 33 infants (26 term, 7 preterm) subjected to surgery during the neonatal period. The results show that newborn infants can indeed mount a substantial endocrine and metabolic stress response, the main features of which are hyperglycemia and hyperlactatemia associated with the release of catecholamines and the inhibition of insulin secretion. There are specific differences between preterm and term neonates and between neonates anesthetised by different anesthetic techniques in the pattern of this response.

    View details for DOI 10.1016/S0022-3468(85)80390-0

    View details for Web of Science ID A1985ABL0500011

    View details for PubMedID 3973812