Dr. Flood is a Professor at Stanford University who is fellowship trained in Pain Medicine and Obstetric Anesthesiology. She specializes in the treatment of chronic pelvic pain and multiple aspects of women's health including the prevention of chronic pain after childbirth. Research interests include the role of multimodal treatment in chronic pain conditions and prevention of persistent opioid use. Her research has spanned from detailed pharmacodynamic analysis, clinical trials to population health.

Clinical Focus

  • Anesthesia
  • Pain Medicine
  • Women's Health
  • Obstetric Anesthesiology
  • Pharmacology
  • opioid weaning

Academic Appointments

Administrative Appointments

  • Professor of Anesthesiology, Peri operative and Pain Medicine, Stanford University (2014 - Present)

Professional Education

  • Board Certification: American Board of Anesthesiology, Anesthesia (1996)
  • Board Certification: American Board of Anesthesiology, Pain Medicine (2016)
  • Fellowship: Stanford Hospital and Clinics - Pain Mgmt (2016) CA
  • Residency: New York Presbyterian Hospital (1994) NY
  • Internship: New York Presbyterian Hospital (1991) NY
  • Medical Education: Columbia Univ/Col Phys and Surg (1990)

Clinical Trials

  • Genetic and Demographic Factors That Influence the Pain and Progress of Labor Recruiting

    The purpose of this study is to try to understand why the experience of labor differs among women. The investigators want to understand why some women have longer or shorter labors and why the amount of pain women experience is different. The investigators hope to be able to consider women more individually in terms of their pain and progress of labor.

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  • Prevention of Persistent Opioid Use in Mothers Not Recruiting

    Our previous work has identified the group of women at risk for prolonged pain, opioid use and poor functional recovery after childbirth. The optimal intervention to mitigate this risk is unknown. We propose to test an analgesic adjutant that is commonly used for post-operative pain compared to placebo to improve post-partum recovery.

    Stanford is currently not accepting patients for this trial. For more information, please contact Pamela Flood, MD, MA, 201-370-3933.

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2022-23 Courses

All Publications

  • Chronic disabling postpartum headache after unintentional dural puncture during epidural anaesthesia: a prospective cohort study. British journal of anaesthesia Ansari, J. R., Barad, M., Shafer, S., Flood, P. 2021; 127 (4): 600-607


    BACKGROUND: Unintentional dural puncture with an epidural needle complicates approximately 1% of epidural anaesthetics and causes an acute headache in 60-80% of these patients. Several retrospective studies suggest an increased risk of chronic headache. We assessed the relationship between unintentional dural puncture and chronic disabling headache, defined as one or more functionally limiting headaches within a 2-week interval ending 2, 6, and 12 months postpartum.METHODS: In this prospective observational study, parturients who experienced unintentional dural puncture were matched 1:4 with control patients. Patients completed questionnaires regarding characteristics of headache and back pain pre-pregnancy, during pregnancy, immediately postpartum, and at 2, 6, and 12 months postpartum. The primary outcome was prevalence of disabling headache in the past 2 weeks, assessed at 2 months postpartum. Secondary outcomes included prevalence and characteristics of headache and back pain at these time points.RESULTS: We enrolled 99 patients. At 2 and 6 months postpartum, the prevalence of disabling headache was greater among patients with unintentional dural puncture than matched controls (2 months, 74% vs 38%, relative risk 1.9, 95% confidence interval 1.2-2.9, P=0.009; 6 months, 56% vs 25%, relative risk 2.1, 95% confidence interval 1.1-4.0, P=0.033). There was no difference in the prevalence of back pain at any time point.CONCLUSIONS: Our prospective trial confirms retrospective studies that chronic headache is more prevalent among women who experienced unintentional dural puncture compared with controls who received uncomplicated neuraxial anaesthesia. This finding has implications for the. patient consent process and recommendations for long-term follow-up of patients who experience unintentional dural puncture.

    View details for DOI 10.1016/j.bja.2021.05.020

    View details for PubMedID 34548152

  • Gender Differences in Compensation in Anesthesiology in the United States: Results of a National Survey of Anesthesiologists. Anesthesia and analgesia Hertzberg, L. B., Miller, T. R., Byerly, S., Rebello, E., Flood, P., Malinzak, E. B., Doyle, C. A., Pease, S., Rock-Klotz, J. A., Kraus, M. B., Pai, S. 2021


    BACKGROUND: A gender-based compensation gap among physicians is well documented. Even after adjusting for age, experience, work hours, productivity, and academic rank, the gender gap remained and widened over the course of a physician's career. This study aimed to examine if a significant gender pay gap still existed for anesthesiologists in the United States.METHODS: In 2018, we surveyed 28,812 physician members of the American Society of Anesthesiologists to assess the association of compensation with gender and to identify possible causes of wage disparities. Gender was the primary variable examined in the model, and compensation by gender was the primary outcome. Compensation was defined as the amount reported as direct compensation on a W-2, 1099, or K-1, plus all voluntary salary reductions (eg, 401[k], health insurance). The survey directed respondents to include salary, bonuses, incentive payments, research stipends, honoraria, and distribution of profits to employees. Respondents had the option of providing a point estimate of their compensation or selecting a range in $50,000 increments. Potential confounding variables that could affect compensation were identified based on a scoping literature review and the consensus expertise of the authors. We fitted a generalized ordinal logistic regression with 7 ranges of compensation. For the sensitivity analyses, we used linear regressions of log-transformed compensation based on respondent point estimates and imputed values.RESULTS: The final analytic sample consisted of 2081 observations (response rate, 7.2%). This sample represented a higher percentage of women and younger physicians compared to the demographic makeup of anesthesiologists in the United States. The adjusted odds ratio associated with gender equal to woman was an estimated 0.44 (95% confidence interval, 0.37-0.53), indicating that for a given compensation range, women had a 56% lower odds than men of being in a higher compensation range. Sensitivity analyses found the relative percentage difference in compensation for women compared to men ranged from -8.3 to -8.9. In the sensitivity analysis based on the subset of respondents (n = 1036) who provided a point estimate of compensation, the relative percentage difference (-8.3%; 95% confidence interval, -4.7 to -11.7) reflected a $32,617 lower compensation for women than men, holding other covariates at their means.CONCLUSIONS: Compensation for anesthesiologists showed a significant pay gap that was associated with gender even after adjusting for potential confounding factors, including age, hours worked, geographic practice region, practice type, position, and job selection criteria.

    View details for DOI 10.1213/ANE.0000000000005676

    View details for PubMedID 34375316

  • Labor prior to cesarean delivery associated with higher post-discharge opioid consumption. PloS one Ende, H. B., Landau, R., Cole, N. M., Burns, S. M., Bateman, B. T., Bauer, M. E., Booth, J. L., Flood, P., Leffert, L. R., Houle, T. T., Tsen, L. C. 2021; 16 (7): e0253990


    BACKGROUND: Severe acute post-cesarean delivery (CD) pain has been associated with an increased risk for persistent pain and postpartum depression. Identification of women at increased risk for pain can be used to optimize post-cesarean analgesia. The impact of labor prior to CD (intrapartum CD) on acute post-operative pain and opioid use is unclear. We hypothesized that intrapartum CD, which has been associated with both increased inflammation and affective distress related to an unexpected surgical procedure, would result in higher postoperative pain scores and increased opioid intake.METHODS: This is a secondary analysis of a prospective cohort study examining opioid use up to 2 weeks following CD. Women undergoing CD at six academic medical centers in the United States 9/2014-3/2016 were contacted by phone two weeks following discharge. Participants completed a structured interview that included questions about postoperative pain scores and opioid utilization. They were asked to retrospectively estimate their maximal pain score on an 11-point numeric rating scale at multiple time points, including day of surgery, during hospitalization, immediately after discharge, 1st week, and 2nd week following discharge. Pain scores over time were assessed utilizing a generalized linear mixed-effects model with the patient identifier being a random effect, adjusting for an a priori defined set of confounders. A multivariate negative binomial model was utilized to assess the association between intrapartum CD and opioid utilization after discharge, also adjusting for the same confounders. In the context of non-random prescription distribution, this model was constructed with an offset for the number of tablets dispensed.RESULTS: A total of 720 women were enrolled, 392 with and 328 without labor prior to CD. Patients with intrapartum CD were younger, less likely to undergo repeat CD or additional surgical procedures, and more likely to experience a complication of CD. Women with intrapartum CD consumed more opioid tablets following discharge than women without labor (median 20, IQR 10-30 versus 17, IQR 6-30; p = 0.005). This association persisted after adjustment for confounders (incidence rate ratio 1.16, 95% CI 1.05-1.29; p = 0.004). Pain scores on the day of surgery were higher in women with intrapartum CD (difference 0.91, 95% CI 0.52-1.30; adj. p = <0.001) even after adjustment for confounders. Pain scores at other time points were not meaningfully different between the two groups.CONCLUSION: Intrapartum CD is associated with worse pain on the day of surgery but not other time points. Opioid requirements following discharge were modestly increased following intrapartum CD.

    View details for DOI 10.1371/journal.pone.0253990

    View details for PubMedID 34242277

  • Genetics and Gender in Acute Pain and Perioperative Opioid Analgesia. Anesthesiology clinics Kwon, A. H., Flood, P. 2020; 38 (2): 341–55


    Experimental and clinical acute pain research in relation to biological sex and genetics started in the 1980s. Research methods became more powerful and sensitive with the advancement in affordable gene sequencing methods and high-throughput genetic assays. Decades of research has identified several potential pharmaceutical targets, providing insights into future research direction, and understanding of acute pain and opioid analgesic effects in the clinical setting. However, there is insufficient evidence to make generalized recommendations for using genetic tests for clinical practice of acute pain management.

    View details for DOI 10.1016/j.anclin.2020.01.003

    View details for PubMedID 32336388

  • Impact of patient choice for different postcesarean delivery analgesic protocols on opioid consumption: a randomized prospective clinical trial. Regional anesthesia and pain medicine Carvalho, B., Sutton, C. D., Kowalczyk, J. J., Flood, P. D. 2019


    BACKGROUND: Choice of postcesarean delivery analgesic protocol may improve pain experience and reduce analgesic requirements.METHODS: Cesarean delivery patients were randomly assigned either to choose their postcesarean delivery analgesia protocol or to have no choice and receive routine care. Choices were low (50 mug intrathecal morphine), medium (identical to routine care: 150 mug intrathecal morphine), or high (300 mug intrathecal morphine with 600mg oral gabapentin). All groups received scheduled acetaminophen and ibuprofen. The primary outcome was oxycodone requirements 0-48hours postdelivery in those offered versus not offered a choice.RESULTS: Of 160 women enrolled, 120 were offered a choice and 40 were not offered a choice. There was no difference in oxycodone requirements or pain associated with choice, but those who had a choice expressed more satisfaction than those who did not have a choice (mean (95%CI) difference 5% (0% to 10 %), p=0.005). In the choice group, the high dose group required more oxycodone (5 (0 to 15)mg 0-24hours after delivery and 15 (10 to 25) mg at 24-48hours; p=0.05 and p=0.001) versus the low and medium groups. The low dose group had less pruritus (p=0.001), while the high dose group had more vomiting (p=0.01) requiring antiemetic treatment (p=0.04).CONCLUSION: Having a choice compared with no choice routine care did not reduce oxycodone requirements or pain scores. However, women have insight into their analgesic needs; women offered a choice and who chose the higher dose analgesic protocol required more oxycodone, and women who chose the lower dose protocol required less oxycodone. Despite providing additional analgesic (six times more intrathecal morphine plus gabapentin in high dose vs low dose protocols), we still did not equalize postcesarean oxycodone requirement differences between groups.TRIAL REGISTRATION NUMBER: NCT02605187.

    View details for PubMedID 30867278

  • Comparative Effectiveness of Cognitive Behavioral Therapy for Chronic Pain and Chronic Pain Self-Management within the Context of Voluntary Patient-Centered Prescription Opioid Tapering: The EMPOWER Study Protocol. Pain medicine (Malden, Mass.) Darnall, B. D., Mackey, S. C., Lorig, K. n., Kao, M. C., Mardian, A. n., Stieg, R. n., Porter, J. n., DeBruyne, K. n., Murphy, J. n., Perez, L. n., Okvat, H. n., Tian, L. n., Flood, P. n., McGovern, M. n., Colloca, L. n., King, H. n., Van Dorsten, B. n., Pun, T. n., Cheung, M. n. 2019


    Evidence to date, while sparse, suggests that patients taking long-term opioids require special considerations and protections to prevent potential iatrogenic harms from opioid de-prescribing, such as increased pain or suffering. Following this study protocol, the EMPOWER study seeks to address multiple unmet needs of patients with chronic pain who desire to reduce long-term opioid therapy, and provide the clinical evidence on effective methodology.EMPOWER applies patient-centered methods for voluntary prescription opioid reduction conducted within a comprehensive, multi-state, 3-arm randomized controlled comparative effectiveness study of three study arms (1) group cognitive behavioral therapy for chronic pain; (2) group chronic pain self-management; and (3) usual care (taper only). Specialized electronic data capture systems collect patient reported symptoms and satisfaction data weekly and monthly during the taper, with real-time clinical alerts and electronic feedback loops informing, documenting, and steering needed care actions.The EMPOWER study seeks to provide granular evidence on patient response to voluntary opioid tapering, and will provide evidence to inform clinical systems changes, clinical care, patient satisfaction, and patient outcomes for opioid reduction.

    View details for DOI 10.1093/pm/pnz285

    View details for PubMedID 31876947

  • Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU CRITICAL CARE MEDICINE Devlin, J. W., Skrobik, Y., Gelinas, C., Needham, D. M., Slooter, A. C., Pandharipande, P. P., Watson, P. L., Weinhouse, G. L., Nunnally, M. E., Rochwerg, B., Balas, M. C., van den Boogaard, M., Bosma, K. J., Brummel, N. E., Chanques, G., Denehy, L., Drouot, X., Fraser, G. L., Harris, J. E., Joffe, A. M., Kho, M. E., Kress, J. P., Lanphere, J. A., McKinley, S., Neufeld, K. J., Pisani, M. A., Payen, J., Pun, B. T., Puntillo, K. A., Riker, R. R., Robinson, B. H., Shehabi, Y., Szumita, P. M., Winkelman, C., Centofanti, J. E., Price, C., Nikayin, S., Misak, C. J., Flood, P. D., Kiedrowski, K., Alhazzani, W. 2018; 46 (9): E825–E873


    To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017.Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified.The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation.We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

    View details for PubMedID 30113379

  • Patient-Centered Prescription Opioid Tapering in Community Outpatients with Chronic Pain JAMA Internal Medicine Darnall, B., Ziadni, M., Stieg, R., Mackey, I., Kao, M., Flood, P. 2018; Feb 19
  • Recovery after Nulliparous Birth A Detailed Analysis of Pain Analgesia and Recovery of Function ANESTHESIOLOGY Komatsu, R., Carvalho, B., Flood, P. D. 2017; 127 (4): 684–94


    The majority of parturients in the United States first return for evaluation by their obstetric practitioner 6 weeks after delivery. As such, there is little granular data on the pain experience, analgesic requirements, and functional recovery during the postpartum period. This prospective observational study was performed to evaluate these factors to provide expectations for patients.A total of 213 nulliparous women were enrolled and assessed daily until they completed 3 outcomes: (1) pain resolution; (2) opioid cessation; and (3) self-assessed functional recovery from delivery. The primary endpoint, pain- and opioid-free functional recovery, was the time required to reach all three of the endpoints. Pain burden was assessed as the area under the curve created by plotting the daily numerical pain rating scale against the days required to attain pain resolution. Times to attain study endpoints after cesarean delivery and vaginal delivery were compared using survival analysis.After vaginal delivery, days required for pain and opioid-free functional recovery (median [interquartile range (IQR)]) were 19 [11 to 26], for opioid cessation 0 [0 to 2], termination of all analgesic (including nonsteroidal antiinflammatories and acetaminophen) 11 [5 to 17], and pain resolution 14 [7 to 24]. Achievement of these endpoints after cesarean delivery required 27 [19 to 40], 9 [5 to 12], 16 [11 to 24], and 21 [14 to 27] days, respectively.There is clinically significant variability between healthy nulliparous parturients in the pain experience, opioid use, and functional recovery after childbirth following vaginal and cesarean delivery. Recovery to predelivery function is similar after vaginal and cesarean delivery, and approximately half of the variance was explained by pain burden.

    View details for PubMedID 28926443

    View details for PubMedCentralID PMC5657561

  • Calcium chloride for the prevention of uterine atony during cesarean delivery: A pilot randomized controlled trial and pharmacokinetic study. Journal of clinical anesthesia Ansari, J. R., Kalariya, N., Carvalho, B., Flood, P., Guo, N., Riley, E. 2022; 80: 110796


    To assess the feasibility, patient tolerance, pharmacokinetics, and potential effectiveness of a randomized controlled trial protocol investigating intravenous calcium chloride for the prevention of uterine atony during cesarean delivery.Double-blind, randomized controlled pilot trial with nested population pharmacokinetic analysis.This study was performed at Lucile Packard Children's Hospital, from August 2018 to September 2019.Forty patients with at least two risk factors for uterine atony at the time of cesarean delivery.One gram of intravenous calcium chloride (n = 20 patients) or a saline placebo control (n = 20 patients), in addition to standard care with oxytocin, upon umbilical cord clamping.The primary efficacy-related outcome was the presence of uterine atony defined as the use of a second-line uterotonic medication, surgical interventions for atony, or hemorrhage with blood loss >1000 mL. Blood loss, uterine tone numerical rating scores, serial venous blood calcium levels, hemodynamics, and potential side effects were also assessed.The study protocol proved feasible. The incidence of atony was 20% in parturients who received calcium compared to 50% in the placebo group (relative risk 0.38, P = 0.07, 95% CI 0.15-1.07, NNT 3.3). Calcium recipients tolerated the drug infusion well, with no adverse events and an equal incidence of potential side effects in the calcium and placebo groups. Ionized calcium concentration rose significantly in all patients who received calcium infusion, from baseline 1.18 mmol/L to peak levels 1.50-1.60 mmol/L. One-compartment population pharmacokinetics established clearance of 0.93 (95% CI 0.63-1.52) L/min and volume of distribution 76 (95% CI 49-94) L.In this pilot study, investigators found that intravenous calcium chloride was well-tolerated by the 20 patients assigned to receive the study drug and may be effective in prevention of uterine atony. A 1-g dose was sufficient to substantially increase calcium levels without any critically elevated lab values or concern for adverse side effects. These encouraging findings warrant further investigation of calcium as a novel agent to prevent uterine atony with an adequately powered clinical trial. Clinical trial registry NCT03867383

    View details for DOI 10.1016/j.jclinane.2022.110796

    View details for PubMedID 35447502

  • In Response. Anesthesia and analgesia Malinzak, E. B., Hertzberg, L. B., Doyle, C. A., Flood, P., Kraus, M. B., Rebello, E., Pai, S., Pease, S. 2022; 134 (4): e23-e24

    View details for DOI 10.1213/ANE.0000000000005914

    View details for PubMedID 35299224

  • Engagement in Prescription Opioid Tapering Research: the EMPOWER Study and a Coproduction Model of Success. Journal of general internal medicine Mardian, A., Perez, L., Pun, T., Cheung, M., Porter, J., De Bruyne, K., Kao, M., Flood, P., Moore, N., Colloca, L., Cramer, E., Ashton-James, C. E., Lorig, K., Mackey, S. C., Darnall, B. D. 2021


    Patients with chronic pain experience stigma within the healthcare system. This stigma is compounded for those taking long-term prescription opioids. Often, public messaging and organizational policies have telegraphed that opioid treatment is a problem to be solved by focusing only on medication reduction efforts. Lack of data has contributed to misperceptions and poor opioid policies. In part, data collection remains poor because patients feel fractured from systems of care and are often not interested in engaging with opioid reduction mandates and research. Similarly, clinicians may fail to engage with opioid stewardship and research due to complexities that exceed their training or capacities. The EMPOWER study applies a coproduction model that engages researchers, patients, clinicians, managers, and other health system users. Key stakeholders shaped the design of the study to best ensure acceptability and engagement of the "end users"-patients who enroll in the study and the clinicians who implement the opioid tapers. Targeting the needs of any stakeholder group in isolation is suboptimal. Accordingly, we detail the EMPOWER patient-centered opioid tapering clinical research framework and specific strategies to address stakeholder concerns. We also discuss how this framework may be applied to enhance engagement in healthcare research broadly.

    View details for DOI 10.1007/s11606-021-07085-w

    View details for PubMedID 34389937

  • Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III. Critical care medicine Ward, D. S., Absalom, A. R., Aitken, L. M., Balas, M. C., Brown, D. L., Burry, L., Colantuoni, E., Coursin, D., Devlin, J. W., Dexter, F., Dworkin, R. H., Egan, T. D., Elliott, D., Egerod, I., Flood, P., Fraser, G. L., Girard, T. D., Gozal, D., Hopkins, R. O., Kress, J., Maze, M., Needham, D. M., Pandharipande, P., Riker, R., Sessler, D. I., Shafer, S. L., Shehabi, Y., Spies, C., Sun, L. S., Tung, A., Urman, R. D. 2021


    OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators.DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process.PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process.MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization.CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

    View details for DOI 10.1097/CCM.0000000000005049

    View details for PubMedID 33938718

  • A Brief Screening Tool for Opioid Use Disorder: EMPOWER Study Expert Consensus Protocol. Frontiers in medicine You, D. S., Mardian, A. S., Darnall, B. D., Chen, C. A., De Bruyne, K., Flood, P. D., Kao, M., Karnik, A. D., McNeely, J., Porter, J. G., Schwartz, R. P., Stieg, R. L., Mackey, S. C. 2021; 8: 591201


    Growing concerns about the safety of long-term opioid therapy and its uncertain efficacy for non-cancer pain have led to relatively rapid opioid deprescribing in chronic pain patients who have been taking opioid for years. To date, empirically supported processes for safe and effective opioid tapering are lacking. Opioid tapering programs have shown high rates of dropouts and increases in patient distress and suicidal ideation. Therefore, safe strategies for opioid deprescribing that are more likely to succeed are urgently needed. In response to this demand, the EMPOWER study has been launched to examine the effectiveness of behavioral medicine strategies within the context of patient-centered opioid tapering in outpatient settings ( The EMPOWER protocol requires an efficient process for ensuring that collaborative opioid tapering would be offered to the most appropriate patients while identifying patients who should be offered alternate treatment pathways. As a first step, clinicians need a screening tool to identify patients with Opioid Use Disorder (OUD) and to assess for OUD severity. Because such a tool is not available, the study team composed of eight chronic pain and/or addiction experts has extended a validated screening instrument to develop a brief and novel consensus screening tool to identify OUD and assess for OUD severity for treatment stratification. Our screening tool has the potential to assist busy outpatient clinicians to assess OUD among patients receiving long-term opioid therapy for chronic pain.

    View details for DOI 10.3389/fmed.2021.591201

    View details for PubMedID 33869240

  • A systematic review of patient-reported outcome measures used to assess postpartum pain using Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines. British journal of anaesthesia Sultan, P. n., Ando, K. n., Sultan, E. n., Hawkins, J. E., Chitneni, A. n., Sharawi, N. n., Sadana, N. n., Blake, L. E., Singh, P. M., Flood, P. n., Carvalho, B. n. 2021


    We performed a systematic review using Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines to identify the best available patient-reported outcome measure (PROM) of postpartum pain.This review follows COSMIN guidelines. We searched four databases with no date limiters, for previously identified validated PROMs used to assess postpartum pain. PROMs evaluating more than one author-defined domain of postpartum pain were assessed. We sought studies evaluating psychometric properties. An overall rating was then assigned based upon COSMIN analysis, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the level of evidence for psychometric properties of included PROMs. These assessments were used to make recommendations and identify the best PROM to assess postpartum pain.We identified 19 studies using seven PROMs (involving 3511 women), which evaluated postpartum pain. All included studies evaluated ≥1 psychometric property of the included PROMs. An adequate number of pain domains was assessed by the Brief Pain Inventory (BPI), Short Form-BPI (SF-BPI), and McGill Pain Questionnaire (MPQ). The SF-BPI was the only PROM to demonstrate adequate content validity and at least a low-level of evidence for sufficient internal consistency, resulting in a Class A recommendation (the best performing instrument, recommended for use).SF-BPI is the best currently available PROM to assess postpartum pain. However, it fails to assess several important domains and only just met the criteria for a Class A recommendation. Future studies are warranted to develop, evaluate, and implement a new PROM designed to specifically assess postpartum pain.

    View details for DOI 10.1016/j.bja.2021.03.035

    View details for PubMedID 34016441

  • Did she have an epidural? The long-term consequences of postdural puncture headache and the role of unintended dural puncture. Headache Barad, M., Carroll, I., Reina, M. A., Ansari, J., Flood, P. 2021


    This narrative literature review examines the long-term impact of postdural puncture headache (PDPH) in postpartum women following an unintended dural puncture (UDP) with a large bore needle commonly used for epidural catheter placement. It seeks to bridge the knowledge gap for the neurologist as to the mounting body of obstetric anesthesia literature on the development of chronic headache after PDPH with this unique needle.Headache is the most common complication of dural puncture, and the risk is greatest in the parturient population. Preexisting risk factors for this population include youth and sex, and after UDP with a large bore needle, almost 70%-80% report a headache. Additionally, there appears to be a significant cohort who experience long-term, persistent headache after UDP.We performed a narrative review of literature using PubMed, searching terms that included long-term follow-up after UDP with a large bore needle in the postpartum population.In women who had UDP with a large bore needle used for epidural catheter placement at delivery, the rate of chronic debilitating headache is around 30% in the months following delivery and may persist for up to a year or longer.Based on the existing literature, we have mounting evidence that UDP with the large bore needle used to place an epidural catheter should be understood as a high-risk inciting event for the development of long-term headaches not simply a high risk of acute PDPH. Additionally, consideration should be given to stratifying the etiology of PDPH, based on needle type, and recognizing the entity of chronic PDPH, thus allowing for improvements in research and diagnosis.

    View details for DOI 10.1111/head.14221

    View details for PubMedID 34570902

  • Factors associated with persistent pain after childbirth: a narrative review. British journal of anaesthesia Komatsu, R., Ando, K., Flood, P. D. 2020


    A systematic literature search was performed to identify studies that reported risk factors for persistent pain after childbirth. Many studies have sought to identify risk factors for post-delivery pain in different populations, using different methodologies and different outcome variables. Studies of several different but interrelated post-partum pain syndromes have been conducted. Factors strongly and specifically associated with persistent incisional scar pain after Caesarean delivery include a coexisting persistent pain problem in another part of the body and severe acute postoperative pain. For persistent vaginal and perineal pain, operative vaginal delivery and the magnitude of perineal trauma have been consistently linked. History of pregnancy-related and pre-pregnancy back pain and heavier body weight are robust risk factors for persistent back pain after pregnancy. Unfortunately, limitations, particularly small samples and lack of a priori sample size calculation designed to detect specific effect sizes for risk of persistent pain outcomes, preclude definitive conclusions about many other predictors and the strength of outcome associations. In future studies, assessments of specific phenotypes using a rigorous analysis with appropriate predetermined sample sizes and validated instruments are needed to allow elucidation of stronger and reliable associations. Interventional studies targeting the most robustly associated, modifiable risk factors, such as acute post-partum pain, may lead to solutions for the prevention and treatment of these common problems that impact a large population.

    View details for DOI 10.1016/j.bja.2019.12.037

    View details for PubMedID 31955857

  • A Bun in the Oven How to Use TIVA in Obstetrics TAKING ON TIVA: DEBUNKING MYTHS AND DISPELLING MISUNDERSTANDINGS Flood, P., Ansari, J., Irwin, M. G., Wong, G. T., Lam, S. W. 2020: 139-145
  • Patient-centered prescription opioid tapering in community outpatients with chronic pain: 2- to 3-year follow-up in a subset of patients Pain Reports Ziadni, M. S., A, C. L., Krishnamurthy, P., Flood, P., Stieg, R. L., Darnall, B. D. 2020; 5 (5): e851
  • "My Surgical Success": Effect of a Digital Behavioral Pain Medicine Intervention on Time to Opioid Cessation After Breast Cancer Surgery-A Pilot Randomized Controlled Clinical Trial PAIN MEDICINE Darnall, B. D., Ziadni, M. S., Krishnamurthy, P., Flood, P., Heathcote, L. C., Mackey, I. G., Taub, C., Wheeler, A. 2019; 20 (11): 2228–37

    View details for DOI 10.1093/pm/pnz094

    View details for Web of Science ID 000504316200017

  • Determinants of women's dissatisfaction with anaesthesia care in labour and delivery. Anaesthesia Yurashevich, M., Carvalho, B., Butwick, A. J., Ando, K., Flood, P. D. 2019


    Patient-centred care and factors associated with patient satisfaction with anaesthesia have been widely studied. However, the most important considerations in the setting of obstetric anaesthesia are uncertain. Identification of, and addressing, factors that contribute to patient dissatisfaction may improve quality of care. We sought to identify factors associated with<100% satisfaction with obstetric anaesthesia care. At total of 4297 women treated by anaesthetists provided satisfaction data 24h after vaginal and 48h after caesarean delivery. As 78% of women were 100% satisfied, we studied factors associated with the dichotomous variable, 100% satisfied vs. < 100% satisfied. We evaluated patient characteristics and peripartum factors using multivariable sequential logistic regression. The following factors were strongly associated with maternal dissatisfaction after vaginal delivery: pain intensity during the first stage of labour; pain intensity during the second stage of labour; postpartum pain intensity; delay >15min in providing epidural analgesia and postpartum headache (all p<0.0001). Pruritus (p=0.005) also contributed to dissatisfaction after vaginal delivery, whereas non-Hispanic ethnicity was negatively associated with dissatisfaction (p=0.01). After caesarean delivery, the intensity of postpartum pain (p<0.0001), headache (p=0.001) and pruritus (p=0.001) were linked to dissatisfaction. Hispanic ethnicity also had a negative relationship with dissatisfaction after caesarean delivery (p=0.005). Thus, inadequate or delayed analgesia and treatment-related side-effects are associated with maternal dissatisfaction with obstetric anaesthesia care. Development of protocols to facilitate identification of ineffective analgesia and provide an appropriate balance between efficacy and side-effects, are important goals to optimise maternal satisfaction.

    View details for DOI 10.1111/anae.14756

    View details for PubMedID 31264207

  • Women's health in Northwestern Syria: Findings from Healthy-Syria 2017 study. Avicenna journal of medicine Terkawi, A. S., Bakri, B., Alsadek, A. S., Alsibaee, R. H., Alasfar, E. M., Albakour, A. H., Aljouja, A. Y., Alshaikhwais, N. A., Fares, F. A., Flood, P. D., Jnaid, H., Najib, A. A., Saloom, D. A., Zahra, N. A., Altirkawi, K. A. 2019; 9 (3): 94–106


    Objectives: Since the uprising in 2011, there have been limited health-care data from inside Syria regarding women's health. This study aimed to provide an updated account of women's health, including pregnancy, perinatal care, childbirth, and other conditions to identify obstacles and challenges to health-care delivery in Northwestern Syria.Methods: This is a prospective data registry study, using a medical electronic records system that builds on the International Classification of Diseases, Tenth Revision (ICD-10) codes. We collected data from one medical center in Northwestern Syria during 2017. We conducted a survey to understand patients' knowledge of and barriers limiting antenatal care (ANC).Results: We studied 7213 patients' health status and surveyed 134 regarding ANC. Prenatal care, delivery, and miscarriage treatment represented the most common (70%) reasons for women's health-care visits, followed by menstrual disorders (17%). From 2057 delivery records, 70% delivered vaginally and 30% required cesarean delivery. Our findings showed that 1169 (24%) of the pregnant women (4936) in 2017 were adolescents, of them 22 (0.44%) were 14 years old. Regarding ANC visits, 85% of respondents did not have a single ANC visit in the first trimester, 82% had no visits in the second trimester, and 44% had no visits in the third trimester. Thirty-one percent had no ANC visit throughout the entire pregnancy. Only 13% had postnatal care (PNC) visits. Women who live in the refugee camp are 2.7 times less likely to meet the World Health Organization (WHO) criteria for focused ANC (FANC = 4 visits) compared to those who reside in town (P < 0.001), with only 14% having met the FANC. The major barrier to ANC is related to transportation (34%), followed by factors related to the study center (29%) and knowledge and education (19%). We estimated the number of obstetrics-gynecology doctors per 1000 populations to be 0.02.Conclusions: We found a huge deficiency in ANC and PNC visits, a high adolescent birth rate, and a higher cesarean-to-vaginal delivery ratio than what is recommended by the WHO. We also found a severe shortage in the number of obstetrician-gynecologists serving this population.

    View details for DOI 10.4103/ajm.AJM_190_18

    View details for PubMedID 31404201

  • Postpartum chronic pelvic pain and pelvic girdle pain. Minerva anestesiologica Komatsu, R., Ando, K., Flood, P. D. 2019

    View details for DOI 10.23736/S0375-9393.19.13893-X

    View details for PubMedID 31238646

  • Response to BotulinumtoxinA in a migraine cohort with multiple comorbidities and widespread pain. Regional anesthesia and pain medicine Barad, M., Sturgeon, J. A., Fish, S., Dexter, F., Mackey, S., Flood, P. D. 2019; 44 (6): 660–68


    BACKGROUND: The phase III research evaluating migraine prophylaxis therapy (PREEMPT) protocol was developed in low-risk migraine patients. We studied longitudinal response to treatment in a sequential retrospective observational cohort to evaluate predictors of effectiveness in patients with multiple overlapping pain syndromes treated in a quaternary pain management clinic.METHODS: We evaluated indicators of individual response in 402 consecutive chronic migraine patients who provided demographic information and used the Collaborative Health Outcomes Information Registry.RESULTS: The patients were middle aged 47 (38-56) median (IQR) years old and 83% women. They reported multiple complex pain problems with 11 (6-18) regions represented on a pain body map. Evaluated with National Institutes of Health Patient-Reported Outcomes Measurement Information System measures, they reported higher scores for sleep impairment and disturbance, anxiety, depression, fatigue, pain behavior, pain interference and worse function and satisfaction with social roles compared with the general US population; p<0.001for all domains. Within 120days of treatment, 62% of patients reported reduced headache frequency. The best multivariable model developed for prediction of reduced headache frequency in response to treatment included lower treatment number, lower pain interference score, and less depression (p=0.001, 0.002, and 0.009). Depression may have been an obstacle to successful treatment; there was no association between depression score and number of treatments (p=0.54).CONCLUSIONS: Our findings point to the importance of identifying and addressing pain interference and depression early in chronic migraine management and, more broadly, highlights the importance of multidisciplinary evaluation and treatment in chronic migraine.

    View details for DOI 10.1136/rapm-2018-100196

    View details for PubMedID 31101743

  • "My Surgical Success": Effect of a Digital Behavioral Pain Medicine Intervention on Time to Opioid Cessation After Breast Cancer Surgery-A Pilot Randomized Controlled Clinical Trial. Pain medicine (Malden, Mass.) Darnall, B. D., Ziadni, M. S., Krishnamurthy, P., Flood, P., Heathcote, L., Mackey, I. G., Taub, C. J., Wheeler, A. 2019


    OBJECTIVE: This study aims to assess the feasibility of digital perioperative behavioral pain medicine intervention in breast cancer surgery and evaluate its impact on pain catastrophizing, pain, and opioid cessation after surgery.DESIGN AND SETTING: A randomized controlled clinical trial was conducted at Stanford University (Palo Alto, CA, USA) comparing a digital behavioral pain medicine intervention ("My Surgical Success" [MSS]) with digital general health education (HE).PARTICIPANTS: A convenience sample of 127 participants were randomized to treatment group. The analytic sample was 68 patients (N=36 MSS, N=32 HE).MAIN OUTCOMES: The primary outcome was feasibility and acceptability of a digital behavioral pain medicine intervention (80% threshold for acceptability items). Secondary outcomes were pain catastrophizing, past seven-day average pain intensity, and time to opioid cessation after surgery for patients who initiated opioid use.RESULTS: The attrition rate for MSS intervention (44%) was notably higher than for HE controls (18%), but it was lower than typical attrition rates for e-health interventions (60-80%). Despite greater attrition for MSS, feasibility was demonstrated for the 56% of MSS engagers, and the 80% threshold for acceptability was met. We observed a floor effect for baseline pain catastrophizing, and no significant group differences were found for postsurgical pain catastrophizing or pain intensity. MSS was associated with 86% increased odds of opioid cessation within the 12-week study period relative to HE controls (hazard ratio = 1.86, 95% confidence interval = 1.12-3.10, P=0.016).CONCLUSIONS: Fifty-six percent of patients assigned to MSS engaged with the online platform and reported high satisfaction. MSS was associated with significantly accelerated opioid cessation after surgery (five-day difference) with no difference in pain report relative to controls. Perioperative digital behavioral pain medicine may be a low-cost, accessible adjunct that could promote opioid cessation after breast cancer surgery.

    View details for PubMedID 31087093

  • Impact of patient choice for different postcesarean delivery analgesic protocols on opioid consumption: a randomized prospective clinical trial REGIONAL ANESTHESIA AND PAIN MEDICINE Carvalho, B., Sutton, C., Kowalczyk, J. J., Flood, P. 2019; 44 (5): 578–85
  • International Stakeholder Community of Pain Experts and Leaders Call for an Urgent Action on Forced Opioid Tapering PAIN MEDICINE Darnall, B. D., Juurlink, D., Kerns, R. D., Mackey, S., Van Dorsten, B., Humphreys, K., Gonzalez-Sotomayor, J. A., Furlan, A., Gordon, A. J., Gordon, D. B., Hoffman, D. E., Katz, J., Kertesz, S. G., Satel, S., Lawhern, R. A., Nicholson, K. M., Polomano, R. C., Williamson, O. D., McAnally, H., Kao, M., Schug, S., Twillman, R., Lewis, T. A., Stieg, R. L., Lorig, K., Mallick-Searle, T., West, R. W., Gray, S., Ariens, S. R., Potter, J., Cowan, P., Kollas, C. D., Laird, D., Ingle, B., Grove, J., Wilson, M., Lockman, K., Hodson, F., Palackdharry, C. S., Fillingim, R. B., Fudin, J., Barnhouse, J., Manhapra, A., Henson, S. R., Singer, B., Ljosenvoor, M., Griffith, M., Doctor, J. N., Hardin, K., London, C., Mankowski, J., Anderson, A., Ellsworth, L., Budzinski, L., Brandt, B., Hartley, G., Heck, D., Zobrosky, M. J., Cheek, C., Wilson, M., Laux, C. E., Datz, G., Dunaway, J., Schonfeld, E., Cady, M., LeDantec-Boswell, T., Craigie, M., Sturgeon, J., Flood, P., Giummarra, M., Whelan, J., Thorn, B. E., Martin, R. L., Schatman, M. E., Gregory, M. D., Kirz, J., Robinson, P., Marx, J. G., Stewart, J. R., Keck, P. S., Hadland, S. E., Murphy, J. L., Lumley, M. A., Brown, K. S., Leong, M. S., Fillman, M., Broatch, J. W., Perez, A., Watford, K., Kruska, K., You, D., Ogbeide, S., Kukucka, A., Lawson, S., Ray, J. B., Martin, T., Lakehomer, J. B., Burke, A., Cohen, R. I., Grinspoon, P., Rubenstein, M. S., Sutherland, S., Walters, K., Lovejoy, T. 2019; 20 (3): 429–33

    View details for DOI 10.1093/pm/pny228

    View details for Web of Science ID 000467966600003

  • International Stakeholder Community of Pain Experts and Leaders Call for an Urgent Action on Forced Opioid Tapering. Pain medicine (Malden, Mass.) Darnall, B. D., Juurlink, D., Kerns, R. D., Mackey, S., Van Dorsten, B., Humphreys, K., Gonzalez-Sotomayor, J. A., Furlan, A., Gordon, A. J., Gordon, D. B., Hoffman, D. E., Katz, J., Kertesz, S. G., Satel, S., Lawhern, R. A., Nicholson, K. M., Polomano, R. C., Williamson, O. D., McAnally, H., Kao, M., Schug, S., Twillman, R., Lewis, T. A., Stieg, R. L., Lorig, K., Mallick-Searle, T., West, R. W., Gray, S., Ariens, S. R., Sharpe Potter, J., Cowan, P., Kollas, C. D., Laird, D., Ingle, B., Julian Grove, J., Wilson, M., Lockman, K., Hodson, F., Palackdharry, C. S., Fillingim, R. B., Fudin, J., Barnhouse, J., Manhapra, A., Henson, S. R., Singer, B., Ljosenvoor, M., Griffith, M., Doctor, J. N., Hardin, K., London, C., Mankowski, J., Anderson, A., Ellsworth, L., Davis Budzinski, L., Brandt, B., Harkootley, G., Nickels Heck, D., Zobrosky, M. J., Cheek, C., Wilson, M., Laux, C. E., Datz, G., Dunaway, J., Schonfeld, E., Cady, M., LeDantec-Boswell, T., Craigie, M., Sturgeon, J., Flood, P., Giummarra, M., Whelan, J., Thorn, B. E., Martin, R. L., Schatman, M. E., Gregory, M. D., Kirz, J., Robinson, P., Marx, J. G., Stewart, J. R., Keck, P. S., Hadland, S. E., Murphy, J. L., Lumley, M. A., Brown, K. S., Leong, M. S., Fillman, M., Broatch, J. W., Perez, A., Watford, K., Kruska, K., Sophia You, D., Ogbeide, S., Kukucka, A., Lawson, S., Ray, J. B., Wade Martin, T., Lakehomer, J. B., Burke, A., Cohen, R. I., Grinspoon, P., Rubenstein, M. S., Sutherland, S., Walters, K. R., Lovejoy, T. 2018

    View details for PubMedID 30496540

  • Aerobic Exercise Training and Inducible Inflammation: Results of a Randomized Controlled Trial in Healthy, Young Adults. Journal of the American Heart Association Sloan, R. P., Shapiro, P. A., McKinley, P. S., Bartels, M., Shimbo, D., Lauriola, V., Karmally, W., Pavlicova, M., Choi, C. J., Choo, T., Scodes, J. M., Flood, P., Tracey, K. J. 2018; 7 (17): e010201


    Background Consensus panels regularly recommend aerobic exercise for its health-promoting properties, due in part to presumed anti-inflammatory effects, but many studies show no such effect, possibly related to study differences in participants, interventions, inflammatory markers, and statistical approaches. This variability makes an unequivocal determination of the anti-inflammatory effects of aerobic training elusive. Methods and Results We conducted a randomized controlled trial of 12weeks of aerobic exercise training or a wait list control condition followed by 4weeks of sedentary deconditioning on lipopolysaccharide (0, 0.1, and 1.0ng/mL)-inducible tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and on toll-like receptor 4 in 119 healthy, sedentary young adults. Aerobic capacity by cardiopulmonary exercise testing was measured at study entry (T1) and after training (T2) and deconditioning (T3). Despite a 15% increase in maximal oxygen consumption, there were no changes in inflammatory markers. Additional analyses revealed a differential longitudinal aerobic exercise training effect by lipopolysaccharide level in inducible TNF -alpha ( P=0.08) and IL-6 ( P=0.011), showing T1 to T2 increases rather than decreases in inducible (lipopolysaccharide 0.1, 1.0 versus 0.0ng/mL) TNF- alpha (51% increase, P=0.041) and IL-6 (42% increase, P=0.11), and significant T2 to T3 decreases in inducible TNF- alpha (54% decrease, P=0.007) and IL-6 (55% decrease, P<0.001). There were no significant changes in either group at the 0.0ng/mL lipopolysaccharide level for TNF- alpha or IL-6. Conclusions The failure to support the primary hypotheses and the unexpected post hoc findings of an exercise-training-induced proinflammatory response raise questions about whether and under what conditions exercise training has anti-inflammatory effects. Clinical Trial Registration URL : . Unique identifier: NCT 01335737.

    View details for PubMedID 30371169

  • Aerobic Exercise Training and Inducible Inflammation: Results of a Randomized Controlled Trial in Healthy, Young Adults JOURNAL OF THE AMERICAN HEART ASSOCIATION Sloan, R. P., Shapiro, P. A., McKinley, P. S., Bartels, M., Shimbo, D., Lauriola, V., Karmally, W., Pavlicova, M., Choi, C., Choo, T., Scodes, J. M., Flood, P., Tracey, K. J. 2018; 7 (17)
  • Methodologic Innovation in Creating Clinical Practice Guidelines: Insights From the 2018 Society of Critical Care Medicine Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption Guideline Effort CRITICAL CARE MEDICINE Devlin, J. W., Skrobik, Y., Rochwerg, B., Nunnally, M. E., Needham, D. M., Gelinas, C., Pandharipande, P. P., Slooter, A. C., Watson, P. L., Weinhouse, G. L., Kho, M. E., Centofanti, J., Price, C., Harmon, L., Misak, C. J., Flood, P. D., Alhazzani, W. 2018; 46 (9): 1457–63


    To describe novel guideline development strategies created and implemented as part of the Society of Critical Care Medicine's 2018 clinical practice guidelines for pain, agitation (sedation), delirium, immobility (rehabilitation/mobility), and sleep (disruption) in critically ill adults.We involved critical illness survivors from start to finish, used and expanded upon Grading of Recommendations, Assessment, Development and Evaluation methodology for making recommendations, identified evidence gaps, and developed communication strategies to mitigate challenges.Thirty-two experts from five countries, across five topic-specific sections; four methodologists, two medical librarians, four critical illness survivors, and two Society of Critical Care Medicine support staff.Unique approaches included the following: 1) critical illness survivor involvement to help ensure patient-centered questions and recommendations; 2) qualitative and semiquantitative approaches for developing descriptive statements; 3) operationalizing a three-step approach to generating final recommendations; and 4) systematic identification of evidence gaps.Critical illness survivors contributed to prioritizing topics, questions, and outcomes, evidence interpretation, recommendation formulation, and article review to ensure that their values and preferences were considered in the guidelines. Qualitative and semiquantitative approaches supported formulating descriptive statements using comprehensive literature reviews, summaries, and large-group discussion. Experts (including the methodologists and guideline chairs) developed and refined guideline recommendations through monthly topic-specific section conference calls. Recommendations were precirculated to all members, presented to, and vetted by, most members at a live meeting. Final electronic voting provided links to all forest plots, evidence summaries, and "evidence to decision" frameworks. Written comments during voting captured dissenting views and were integrated into evidence to decision frameworks and the guideline article. Evidence gaps, reflecting clinical uncertainty in the literature, were identified during the evidence to decision process, live meeting, and voting and formally incorporated into all written recommendation rationales. Frequent scheduled "check-ins" mitigated communication gaps.Our multifaceted, interdisciplinary approach and novel methodologic strategies can help inform the development of future critical care clinical practice guidelines.

    View details for PubMedID 29985807

  • Executive Summary: Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU CRITICAL CARE MEDICINE Devlin, J. W., Skrobik, Y., Gelinas, C., Needham, D. M., Slooter, A. C., Pandharipande, P. P., Watson, P. L., Weinhouse, G. L., Nunnally, M. E., Rochwerg, B., Balas, M. C., van den Boogaard, M., Bosma, K. J., Brummel, N. E., Chanques, G., Denehy, L., Drouot, X., Fraser, G. L., Harris, J. E., Joffe, A. M., Kho, M. E., Kress, J. P., Lanphere, J. A., McKinley, S., Neufeld, K. J., Pisani, M. A., Payen, J., Pun, B. T., Puntillo, K. A., Riker, R. R., Robinson, B. H., Shehabi, Y., Szumita, P. M., Winkelman, C., Centofanti, J. E., Price, C., Nikayin, S., Misak, C. J., Flood, P. D., Kiedrowski, K., Alhazzani, W. 2018; 46 (9): 1532–48

    View details for PubMedID 30113371

  • Patient-Centered Prescription Opioid Tapering in Community Outpatients With Chronic Pain. JAMA internal medicine Darnall, B. D., Ziadni, M. S., Stieg, R. L., Mackey, I. G., Kao, M. C., Flood, P. 2018; 178 (5): 707-708

    View details for DOI 10.1001/jamainternmed.2017.8709

    View details for PubMedID 29459978

    View details for PubMedCentralID PMC5876887

  • Effect of Maternal Body Mass Index on Postpartum Hemorrhage. Anesthesiology Butwick, A. J., Abreo, A. n., Bateman, B. T., Lee, H. C., El-Sayed, Y. Y., Stephansson, O. n., Flood, P. n. 2018


    It is unclear whether obesity is a risk factor for postpartum hemorrhage. The authors hypothesized that obese women are at greater risk of hemorrhage than women with a normal body mass index.The authors conducted a cohort study of women who underwent delivery hospitalization in California between 2008 and 2012. Using multilevel regression, the authors examined the relationships between body mass index with hemorrhage (primary outcome), atonic hemorrhage, and severe hemorrhage (secondary outcomes). Stratified analyses were performed according to delivery mode.The absolute event rate for hemorrhage was 60,604/2,176,673 (2.8%). In this cohort, 4% of women were underweight, 49.1% of women were normal body mass index, 25.9% of women were overweight, and 12.7%, 5.2%, and 3.1% of women were in obesity class I, II, and III, respectively. Compared to normal body mass index women, the odds of hemorrhage and atonic hemorrhage were modestly increased for overweight women (hemorrhage: adjusted odds ratio [aOR], 1.06; 99% CI, 1.04 to 1.08; atonic hemorrhage: aOR, 1.07; 99% CI, 1.05 to 1.09) and obesity class I (hemorrhage: aOR, 1.08; 99% CI, 1.05 to 1.11; atonic hemorrhage; aOR, 1.11; 99% CI, 1.08 to 1.15). After vaginal delivery, overweight and obese women had up to 19% increased odds of hemorrhage or atonic hemorrhage; whereas, after cesarean delivery, women in any obesity class had up to 14% decreased odds of severe hemorrhage.The authors' findings suggest that, at most, maternal obesity has a modest effect on hemorrhage risk. The direction of the association between hemorrhage and body mass index may differ by delivery mode.

    View details for PubMedID 29346134

  • New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on alpha 7 nAChRs CURRENT NEUROPHARMACOLOGY Bagdas, D., Gurun, M. S., Flood, P., Papke, R. L., Damaj, M. 2018; 16 (4): 415–25


    Nicotine and nicotinic acetylcholine receptors (nAChRs) have been explored for the past three decades as targets for pain control. The aim of this review is to introduce readers particularly to α7 nAChRs in a perspective of pain and its modulation.Developments for α7 nAChR modulators and recent animal studies related to pain are reviewed.Accumulating evidences suggest that selective ligands for α7 nAChRs hold promise in the treatment of chronic pain conditions as they lack many of side effects associated with other nicotinic receptor types.This review provides the reader recent insights on α7 nAChRs from structure and function to the latest findings on the pharmacology and therapeutic targeting of these receptors for the treatment of pain and inflammation.

    View details for PubMedID 28820052

  • Patient choice compared with no choice of intrathecal morphine dose for caesarean analgesia: a randomized clinical trial. British journal of anaesthesia Carvalho, B., Mirza, F., Flood, P. 2017; 118 (5): 762-771


    The study aimed to determine whether a patient's choice for their intrathecal morphine (ITM) dose reflects their opioid requirements and pain after caesarean delivery and if giving women a choice of ITM dose would reduce opioid use and improve pain scores compared with women who did not have a choice.A total of 120 women undergoing caesarean delivery with spinal anaesthesia were enrolled in this randomized, double-blind study. Patients were randomly assigned to a choice of 100 or 200 μg ITM or no choice. The study involved deception, such that all participants were still randomly assigned 100 or 200 μg ITM regardless of choice. Rescue opioid use over the 48-h study period was the primary outcome measure. Pain at rest and movement and side effect (pruritus, nausea, and vomiting) data were collected 3, 6, 12, 24, 36 and 48 h postoperatively. Data are presented as median [95% confidence interval (CI)].Women who requested the larger ITM dose required more supplemental opioid [median 0.8 (95% CI 0.4-1.3)] mg morphine equivalents at each assessment interval; P  < 0.001] and reported more pain with movement [median 1.2 (95% CI 0.5-1.9)] verbal numerical rating score of 0-10 points] than patients who requested the smaller ITM dose ( P  = 0.0008), regardless of the ITM dose given. There was no difference in opioid use whether the patient was offered a perceived choice or not.Women who were given a choice and chose the larger ITM dose correctly anticipated a greater postoperative opioid requirement and more pain compared with women who chose the smaller dose. Simply being offered a choice did not impact opioid use or pain scores after caesarean (NCT01425762).

    View details for DOI 10.1093/bja/aex039

    View details for PubMedID 28486595

  • Inhibition Mediated by Glycinergic and GABAergic Receptors on Excitatory Neurons in Mouse Superficial Dorsal Horn Is Location-Specific but Modified by Inflammation. journal of neuroscience Takazawa, T., Choudhury, P., Tong, C., Conway, C. M., Scherrer, G., Flood, P. D., Mukai, J., MacDermott, A. B. 2017; 37 (9): 2336-2348


    The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers, including pain, itch, and temperature. Because the involvement of local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is so important in signal processing, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia. We found that excitatory interneurons and projection neurons in lamina I and IIo are dominantly inhibited by GABA while those in lamina IIi and III are dominantly inhibited by glycine. This was true of identified neuronal subpopulations: neurokinin 1 receptor-expressing (NK1R+) neurons in lamina I were GABA-dominant while protein kinase C gamma-expressing (PKCγ+) neurons at the lamina IIi-III border were glycine-dominant. We found this pattern of synaptic inhibition to be consistent with the distribution of GABAergic and glycinergic neurons identified by immunohistochemistry. Following complete Freund's adjuvant injection into mouse hindpaw, the frequency of spontaneous excitatory synaptic activity increased and inhibitory synaptic activity decreased. Surprisingly, these changes were accompanied by an increase in GABA dominance in lamina IIi. Because this shift in inhibitory dominance was not accompanied by a change in the number of inhibitory synapses or the overall postsynaptic expression of glycine receptor α1 subunits, we propose that the dominance shift is due to glycine receptor modulation and the depressed function of glycine receptors is partially compensated by GABAergic inhibition.SIGNIFICANCE STATEMENT Pain associated with inflammation is a sensation we would all like to minimize. Persistent inflammation leads to cellular and molecular changes in the spinal cord dorsal horn, including diminished inhibition, which may be responsible for enhance excitability. Investigating inhibition in the dorsal horn following peripheral inflammation is essential for development of improved ways to control the associated pain. In this study, we have elucidated regional differences in inhibition of excitatory interneurons in mouse dorsal horn. We have also discovered that the dominating inhibitory neurotransmission within specific regions of dorsal horn switches following peripheral inflammation and the accompanying hypersensitivity to thermal and mechanical stimuli. Our novel findings contribute to a more complete understanding of inflammatory pain.

    View details for DOI 10.1523/JNEUROSCI.2354-16.2017

    View details for PubMedID 28130358

    View details for PubMedCentralID PMC5354347

  • AEROBIC EXERCISE TRAINING IMPROVES AFFECT IN NORMAL HEALTHY YOUNG ADULTS Sloan, R., McKinley, P., Shapiro, P., Puterman, E., Bartels, M., Diaz, K., McIntyre, K., Pavlicova, M., Scodes, J., Flood, P. OXFORD UNIV PRESS INC. 2017: S1534-S1535
  • Patterns of Opioid Prescription and Use After Cesarean Delivery. Obstetrics and gynecology Bateman, B. T., Cole, N. M., Maeda, A. n., Burns, S. M., Houle, T. T., Huybrechts, K. F., Clancy, C. R., Hopp, S. B., Ecker, J. L., Ende, H. n., Grewe, K. n., Raposo Corradini, B. n., Schoenfeld, R. E., Sankar, K. n., Day, L. J., Harris, L. n., Booth, J. L., Flood, P. n., Bauer, M. E., Tsen, L. C., Landau, R. n., Leffert, L. R. 2017; 130 (1): 29–35


    To define the amount of opioid analgesics prescribed and consumed after discharge after cesarean delivery.We conducted a survey at six academic medical centers in the United States from September 2014 to March 2016. Women who had undergone a cesarean delivery were contacted by phone 2 weeks after discharge and participated in a structured interview about the opioid prescription they received on discharge and their oral opioid intake while at home.A total of 720 women were enrolled; of these, 615 (85.4%) filled an opioid prescription. The median number of dispensed opioid tablets was 40 (interquartile range 30-40), the median number consumed was 20 (interquartile range 8-30), and leftover was 15 (interquartile range 3-26). Of those with leftover opioids, 95.3% had not disposed of the excess medication at the time of the interview. There was an association between a larger number of tablets dispensed and the number consumed independent of patient characteristics. The amount of opioids dispensed did not correlate with patient satisfaction, pain control, or the need to refill the opioid prescription.The amount of opioid prescribed after cesarean delivery generally exceeds the amount consumed by a significant margin, leading to substantial amounts of leftover opioid medication. Lower opioid prescription correlates with lower consumption without a concomitant increase in pain scores or satisfaction.

    View details for PubMedID 28594763

    View details for PubMedCentralID PMC5600205

  • No Pain Labor & Delivery: A Global Health Initiative's Impact on Clinical Outcomes in China ANESTHESIA AND ANALGESIA Hu, L., Flood, P., Li, Y., Tao, W., Zhao, P., Xia, Y., Pian-Smith, M. C., Stellaccio, F. S., Ouanes, J. P., Hu, F., Wong, C. A. 2016; 122 (6): 1931-1938


    The availability of labor analgesia is highly variable in the People's Republic of China. There are widespread misconceptions, by both parturients and health care providers, that labor epidural analgesia is harmful to mother and baby. Meanwhile, China has one of the highest cesarean delivery rates in the world, exceeding 50%. The goal of the nongovernmental No Pain Labor & Delivery (NPLD) is to facilitate sustainable increases in vaginal delivery rates by increasing access to safe neuraxial labor analgesia, thereby decreasing the cesarean delivery rate. NPLD was launched in 2008 with the stated goal of improving labor outcome in China by increasing the absolute labor epidural analgesia rate by 10%. NPLD established 10 training centers over a 10-year period. We hypothesized that increased availability of labor analgesia would result in reduced requests for cesarean delivery and better labor outcomes for mother and baby. Multidisciplinary teams of Western clinicians and support staff traveled to China for 8 to 10 days once a year. The approach involved establishing 24/7 obstetric anesthesia coverage in Chinese hospitals through education and modeling multidisciplinary approaches, including problem-based learning discussions, bedside teaching, daily debriefings, simulation training drills, and weekend conferences. As of November 2015, NPLD has engaged with 31 hospitals. At 24 of these sites, 24/7 obstetric anesthesia coverage has been established and labor epidural analgesia rates have exceeded 50%. Lower rates of cesarean delivery, episiotomy, postpartum blood transfusion, and better neonatal outcomes were documented in 3 impact studies comprising approximately 55,000 deliveries. Changes in practice guidelines, medical policy, and billing codes have been implemented in conjunction with the modernization of perinatal practice that has occurred concurrently in China since the first NPLD trip in 2008.

    View details for DOI 10.1213/ANE.0000000000001328

    View details for Web of Science ID 000376463000032

    View details for PubMedID 27195636

  • Does Ondansetron Modify Sympathectomy Due to Subarachnoid Anesthesia? Meta-analysis, Meta-regression, and Trial Sequential Analysis ANESTHESIOLOGY Terkawi, A. S., Mavridis, D., Flood, P., Wetterslev, J., Terkawi, R. S., Bin Abdulhak, A. A., Nunemaker, M. S., Tiouririne, M. 2016; 124 (4): 846-869


    Disagreement among many underpowered studies has led to an equivocal understanding of the efficacy of the 5-HT3 antagonist ondansetron in preventing the consequences of sympathectomy after subarachnoid anesthesia. The authors assessed the efficacy of ondansetron with respect to the overall quality and statistical power of the meta-analyses.The authors used a standard and a newer method of meta-analysis, trial sequential analysis (TSA), to estimate adjusted CIs based on how much information has been accrued. They also used random-effects meta-analyses techniques, small trial bias assessment, selection models, sensitivity analyses, and the Grading of Recommendations on Assessment, Development, and Evaluation system. These results from the aforementioned techniques were compared, and importance of consideration of these factors was discussed.Fourteen randomized placebo-controlled trials (1,045 subjects) were identified and analyzed. By using conventional meta-analyses, the authors determined that ondansetron was associated with reduction in the incidence of hypotension (relative risk = 0.62 [95% CI, 0.46 to 0.83], P = 0.001; TSA-adjusted CI, 0.34 to 1.12; I = 60%, P = 0.002) and bradycardia (relative risk = 0.44 [95% CI, 0.26 to 0.73], P = 0.001; TSA-adjusted CI, 0.05 to 3.85; I = 0%, P = 0.84). However, the authors found indications of bias among these trials. TSAs demonstrated that the meta-analysis lacked adequate information size and did not achieve statistical significance when adjusted for sparse data and repetitive testing. The Grading of Recommendations on Assessment, Development, and Evaluation system showed that the results had low to very low quality of evidence.The analyses fail to confirm evidence that ondansetron reduces the incidence of hypotension and bradycardia after subarachnoid anesthesia due to the risk of bias and information sizes less than the required. As results from meta-analysis are given significant weight, it is important to carefully evaluate the quality of the evidence that is input.

    View details for DOI 10.1097/ALN.0000000000001039

    View details for Web of Science ID 000373352000018

    View details for PubMedID 26835645

  • (527) An internet-based perioperative pain psychology treatment program: results of a randomized controlled trial in breast oncology surgery patients. journal of pain Darnall, B., Wheeler, A., Taub, C., MACKEY, I., Wapnir, I., Schultz, C., RICO, T., Flood, P. 2016; 17 (4S): S106-?

    View details for DOI 10.1016/j.jpain.2016.01.334

    View details for PubMedID 28162332

  • Pharmacokinetics and Pharmacodynamics of Drugs Commonly Used in Pregnancy and Parturition. Anesthesia and analgesia Ansari, J., Carvalho, B., Shafer, S. L., Flood, P. 2016; 122 (3): 786-804


    The majority of pregnant women will be treated with a medication other than a vitamin supplement during their pregnancy. Almost half of these medications will be category C or D according to the former US Food and Drug Administration classification system, indicating a lack of human studies with animal studies suggesting adverse fetal effects (category C) or evidence of risk in humans (category D). Changes in maternal physiology alter drug bioavailability, distribution, clearance, and thus the drug half-life in often unpredictable ways. For many drugs, good pharmacokinetic and pharmacodynamic data in pregnancy and parturition are lacking. For other drugs, recent studies demonstrate major pharmacokinetic or pharmacodynamic changes that require dose adjustment in pregnancy, but current dosing guidelines do not reflect these data. In this review, we address the principles that underlie changes in pharmacology and physiology in pregnancy and provide information on drugs that anesthesiologists commonly encounter in treating pregnant patients.

    View details for DOI 10.1213/ANE.0000000000001143

    View details for PubMedID 26891392

  • Are Epigenetic Changes the Key to the Elusive Mechanism for the Long-lasting Effects of Anesthetic Drugs that Persist after Emergence? ANESTHESIOLOGY Degos, V., Flood, P. 2016; 124 (3): 530-531

    View details for DOI 10.1097/ALN.0000000000000982

    View details for Web of Science ID 000370698900005

    View details for PubMedID 26649425

  • Molecular Interaction between Stress and Pain. Anesthesiology Flood, P. n., Clark, J. D. 2016; 124 (5): 994–95

    View details for PubMedID 26959842

  • Electrical Synapses High-speed Communication in the Maintenance of Neuropathic Pain ANESTHESIOLOGY Tawfik, V. L., Flood, P. 2016; 124 (1): 13-15

    View details for Web of Science ID 000366461300005

    View details for PubMedID 26566281

  • Electroencephalography of Seizure-Like Movements During General Anesthesia with Propofol: Seizures or Nonepileptic Events? A & A case reports Li, Y., Flood, P., Cornes, S. 2015; 5 (11): 195-198


    Seizure-like behavior is an uncommon yet worrisome phenomenon during anesthesia with propofol. The current case report describes a 23-year-old man admitted for elective surgery who experienced several seizure-like episodes after induction with propofol and during a desflurane-based general anesthetic that were so severe it was not possible to complete the procedure. A second surgery was rescheduled 2 days later with simultaneous scalp electroencephalographic (EEG) recording and general anesthesia with propofol and fentanyl. During the second operation, he again experienced numerous episodes of generalized shaking movements. Simultaneous intraoperative EEG recording showed a background of diffuse beta and alpha frequencies interspersed with periods of pseudoperiodic delta activity; electrographic seizures were not apparent. With this information, muscle relaxants were given and the procedure was performed without difficulty. This is the first report of apparent seizure-like activity during anesthesia with propofol of an otherwise relatively healthy adult, in which concurrent EEG recording demonstrates the nonepileptic nature. The current case demonstrates that, at least in some instances, these concerning movements are not seizure related. Concurrent EEG monitoring may be helpful to evaluate the nature of the episodes in select cases.

    View details for DOI 10.1213/XAA.0000000000000212

    View details for PubMedID 26588032

  • Large Heterogeneity in Mean Durations of Labor Analgesia Among Hospitals Reporting to the American Society of Anesthesiologists' Anesthesia Quality Institute ANESTHESIA AND ANALGESIA Flood, P., Dexter, F., Ledolter, J., Dutton, R. P. 2015; 121 (5): 1283-1289


    Variability in the mean durations of labor analgesia for vaginal delivery among hospitals is unknown. Such differences in means among hospitals would influence appropriate equitable fee-for-service payment to US anesthesia groups. Equitable payment is the foundational principle of relative value unit payment, which, for anesthesia in the United States, means use of the American Society of Anesthesiologist's Relative Value Guide.We analyzed data from the American Society of Anesthesiologists' Anesthesia Quality Institute to test whether there are large differences in mean durations of labor analgesia for vaginal delivery among US hospitals. We choose the statistical methodology for that analysis using detailed data from 2 individual hospitals. Analyses of the means were performed for the 172 hospitals reporting a total of at least 200 durations; having no greater than 5.0% of durations 1.0 hour or less; and at least 5 four-week periods each having a mean of at least one epidural every couple of days. The 172 hospitals provided for n = 5671 combinations of hospital and 4-week period and 551,707 labor epidurals, with an overall mean duration of 6.12 hours (SE, 0.001 hour).55.2% of the 172 hospitals had mean durations of labor analgesia for vaginal delivery that each differed (P < 0.001) from the overall mean. Among those 55.2% were the 9.9% of hospitals with means ≤5.12 hours. Those mean durations on the low end ranged from 2.68 (SE, 0.17) to 5.10 (SE, 0.07) hours. Also, among the 55.2% were the 12.2% of hospitals with means ≥7.12 hours. Those mean durations at the high end ranged from 7.13 (SE, 0.08) to 12.03 (SE, 0.23) hours. The heterogeneity in the mean durations among hospitals would have been greater had the inclusion criteria not been applied.Our results show that the number of labor epidurals alone is not a valid measure to quantify obstetrical anesthesia productivity. In addition, payment to US anesthesia groups for labor analgesia based solely on the number of labor epidurals initiated is not equitable. Previous work showed lack of validity and equality of payment based on face-to-face time with the patient (i.e., like a surgical anesthetic). The use of base and time units, with one time unit per hour, is a suitable payment system.

    View details for DOI 10.1213/ANE.0000000000000897

    View details for PubMedID 26284432

  • Beat-to-Beat Heart Rate and Blood Pressure Variability and Hypertensive Disease in Pregnancy AMERICAN JOURNAL OF PERINATOLOGY Flood, P., McKinley, P., Monk, C., Muntner, P., Colantonio, L. D., Goetzl, L., Hatch, M., Sloan, R. P. 2015; 32 (11): 1050-1058


    Objective The aim of this study is to determine the relationship between heart rate and/or blood pressure variability, measured at 28 weeks' gestation, and the incidence of pregnancy-induced hypertension or preeclampsia. Study Design Secondary analysis of data from a prospectively enrolled cohort of 385 active military women in whom spectral analysis of continuous heart rate and variability was measured at 28 weeks' gestation. The primary outcome was the predictive value of spectral analysis of heart rate and blood pressure for hypertensive diseases of pregnancy. Results High-frequency heart rate variability was reduced and low-frequency variability of systolic and diastolic blood pressure increased in women who would develop pregnancy-induced hypertension but not preeclampsia. Low-frequency variability of diastolic blood pressure remained a significant predictor of pregnancy-induced hypertension but not preeclampsia after adjustment for age, weight, and blood pressure in a multivariate model. Conclusion Early identification of pregnancy-induced hypertension can facilitate treatment to avoid maternal morbidity. Understanding the physiological underpinnings of the two very different diseases may lead to improved treatment and prevention. If proven effective in a broader population, the ability to differentiate pregnancy-induced hypertension from preeclampsia may reduce unnecessary iatrogenic interventions or inappropriate preterm delivery.

    View details for DOI 10.1055/s-0035-1548542

    View details for Web of Science ID 000361410300008

    View details for PubMedID 25970272

  • The Relationship Between Plasma Inflammatory Cytokines and Labor Pain ANESTHESIA AND ANALGESIA Rhee, K. Y., Goetzl, L., Unal, R., Cierny, J., Flood, P. 2015; 121 (3): 748-751


    Proinflammatory cytokines are increased in maternal blood at term pregnancy and are associated with cervical ripening and the initiation of labor. We hypothesize that maternal plasma cytokines also affect the sensitivity to labor pain.By using a previously validated model describing labor pain, we used a deidentified database derived from healthy nulliparous parturients who delivered singleton pregnancies at term. Numerical rating scores for pain were recorded after the onset of regular contractions using an 11-point scale. Maternal blood was drawn for the measurement of interleukin (IL)-1β, IL-4, IL-6, IL-8, and IL-10; interferon-γ; and tumor necrosis factor-α on admission or at the onset of painful contractions, whichever occurred later. Individual demographic, physiognomic, and cytokine variables that significantly affected labor pain at P < 0.05 were reported and included stepwise into a multivariable model.One hundred sixty parturients provided 411 numerical analog scores for pain that were evaluated with our model. The relationship between numerical analog scores and cervical dilation was significantly affected by the type of membrane rupture, membrane status, induction, oxytocin administration, maternal race, and plasma IL-1β concentration as individual variables. Only the association between the highest IL-1β quartile and slower acceleration of pain during labor remained significant in the multivariate model (P = 0.0003). Women with IL-1β concentration in the highest quartile arrived at the labor room with a more dilated cervix than those with lower plasma concentrations of IL-1β (5.1 ± 3.0 vs 4.1 ± 2.6 cm; P < 0.02) and had faster labor progress.Inflammatory cytokines including IL-1β play a role in cervical ripening. High maternal plasma concentrations of IL-1β may serve as a marker of advanced cervical ripening and readiness for labor that proceeds with less pain.

    View details for DOI 10.1213/ANE.0000000000000837

    View details for Web of Science ID 000360360400001

    View details for PubMedID 26097983

  • In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept PSYCHIATRY RESEARCH-NEUROIMAGING Rodriguez, C. I., Kegeles, L. S., Levinson, A., Ogden, R. T., Mao, X., Milak, M. S., Vermes, D., Xie, S., Hunter, L., Flood, P., Moore, H., Shungu, D. C., Simpson, H. B. 2015; 233 (2): 141-147


    We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy ((1)H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.

    View details for DOI 10.1016/j.pscychresns.2015.06.001

    View details for Web of Science ID 000359313300010

    View details for PubMedID 26104826

  • Intact Survival After Obstetric Hemorrhage and 55 Minutes of Cardiopulmonary Resuscitation. A & A case reports Anast, N., Kwok, J., Carvalho, B., Lipman, S., Flood, P. 2015; 5 (1): 9-12


    Cardiac arrest occurs in approximately 1:12,000 parturients. Among nonpregnant patients who have in-hospital cardiac arrest, those whose spontaneous circulation does not return within 15 to 20 minutes have a high risk of death and disability, so life support efforts are generally stopped after this period. However, among parturients, witnessed in-hospital arrest is often reversible and has a better prognosis. We describe a successful clinical outcome after maternal cardiac arrest and 55 minutes of advanced cardiac life support. This case underscores the importance of high-quality cardiopulmonary resuscitation and raises questions about the appropriate duration of resuscitation efforts in otherwise healthy young mothers with a potentially reversible cause of arrest.

    View details for DOI 10.1213/XAA.0000000000000163

    View details for PubMedID 26125692

  • Clinical chorioamnionitis and uterine contractility Zackler, A., Dajao, R., Flood, P., Goetzl, L. MOSBY-ELSEVIER. 2015: S78
  • Genetic Variability in the Activity of Monoamines: A Window into the Complexity of Pain ANESTHESIA AND ANALGESIA Flood, P., Clark, D. 2014; 119 (5): 1032-1038

    View details for DOI 10.1213/ANE.0000000000000447

    View details for PubMedID 25329022

  • Impact of Cervical Effacement and Fetal Station on Progress during the First Stage of Labor: A Biexponential Model AMERICAN JOURNAL OF PERINATOLOGY Quincy, M. M., Weng, C., Shafer, S. L., Smiley, R. M., Flood, P. D., Mirza, F. G. 2014; 31 (9): 745-751


    To develop a model that uses cervical effacement, fetal station, and parity to predict progress during the first stage of labor.This was a secondary analysis of a cohort of 1,128 parturients delivering after 34 weeks. Timed cervical exams from each patient were fit with a biexponential model. Methods for consideration of fetal station, cervical effacement and parity were developed and validated.The biexponential model fit the data in an unbiased manner with a median absolute prediction error of 1.1 cm. Although nulliparous women had slower active labor, they did not differ from multiparous women in their rate of latent labor or the cervical dilation at which they transitioned to active labor. In addition, nulliparous women began laboring with a more effaced cervix (45 vs. 31%) and lower fetal station (-2.8 vs. -3.2).We validated a biexponential model for labor progress using a large mixed parity cohort. We demonstrated that parity and initial fetal station add important clinical information that can be used to make a labor model more accurate. As such, parity and fetal station can be utilized in such structural models to predict normal labor progress and potentially identify abnormalities in labor progress.

    View details for DOI 10.1055/s-0033-1359721

    View details for Web of Science ID 000340901000005

    View details for PubMedID 24338118

  • Nicotine is out: nicotinic agonists may have utility as analgesics. Anesthesia and analgesia Flood, P., Damaj, M. I. 2014; 119 (2): 232-233

    View details for DOI 10.1213/ANE.0000000000000304

    View details for PubMedID 25046780

  • Polymorphism in the ADRB2 Gene Explains a Small Portion of Intersubject Variability in Pain Relative to Cervical Dilation in the First Stage of Labor ANESTHESIOLOGY Terkawi, A. S., Jackson, W. M., Hansoti, S., Tabassum, R., Flood, P. 2014; 121 (1): 140-148


    Variability in labor pain has been associated with demographic, clinical, and psychological factors. Polymorphisms of the β2-adrenergic receptor gene (ADRB2) influence sensitivity to experimental pain in humans and are a risk factor for chronic pain. The authors hypothesized that polymorphisms in ADRB2 may influence labor pain.After Institutional Review Board approval and written informed consent, the authors prospectively obtained hourly pain reports from 233 nulliparous parturients during the first stage of labor, of which 199 were included in the current analysis. DNA from blood samples was genotyped at polymorphisms in the genes for the β2-adrenergic receptor, the μ opioid receptor subtype 1, catechol-O-methyltransferase, fatty acid amide hydrolase, and the oxytocin receptor. Labor pain as a function of cervical dilation was modeled with previously described methods. Patient covariates, ADRB2 genotype, and obstetrical and anesthesia treatment were evaluated as covariates in the model.Labor pain more rapidly became severe in parturients heterozygous or homozygous for the G allele at rs1042714 in the ADRB2 gene. Labor pain increased more rapidly after artificial rupture of membranes, augmentation with oxytocin, and in younger women. Inclusion of covariates explained approximately 10% of the variability between subjects. ADRB2 genotype explained less than 1% of the intersubject variability.ADRB2 genotype correlates with labor pain but explained less than 1% of the intersubject variance in the model.

    View details for DOI 10.1097/ALN.0000000000000258

    View details for Web of Science ID 000337758500018

  • Polymorphism in the ADRB2 gene explains a small portion of intersubject variability in pain relative to cervical dilation in the first stage of labor. Anesthesiology Terkawi, A. S., Jackson, W. M., Hansoti, S., Tabassum, R., Flood, P. 2014; 121 (1): 140-148


    Variability in labor pain has been associated with demographic, clinical, and psychological factors. Polymorphisms of the β2-adrenergic receptor gene (ADRB2) influence sensitivity to experimental pain in humans and are a risk factor for chronic pain. The authors hypothesized that polymorphisms in ADRB2 may influence labor pain.After Institutional Review Board approval and written informed consent, the authors prospectively obtained hourly pain reports from 233 nulliparous parturients during the first stage of labor, of which 199 were included in the current analysis. DNA from blood samples was genotyped at polymorphisms in the genes for the β2-adrenergic receptor, the μ opioid receptor subtype 1, catechol-O-methyltransferase, fatty acid amide hydrolase, and the oxytocin receptor. Labor pain as a function of cervical dilation was modeled with previously described methods. Patient covariates, ADRB2 genotype, and obstetrical and anesthesia treatment were evaluated as covariates in the model.Labor pain more rapidly became severe in parturients heterozygous or homozygous for the G allele at rs1042714 in the ADRB2 gene. Labor pain increased more rapidly after artificial rupture of membranes, augmentation with oxytocin, and in younger women. Inclusion of covariates explained approximately 10% of the variability between subjects. ADRB2 genotype explained less than 1% of the intersubject variability.ADRB2 genotype correlates with labor pain but explained less than 1% of the intersubject variance in the model.

    View details for DOI 10.1097/ALN.0000000000000258

    View details for PubMedID 24714117

  • Balance in opioid prescription during pregnancy. Anesthesiology Flood, P., Raja, S. N. 2014; 120 (5): 1063-1064

    View details for DOI 10.1097/ALN.0000000000000173

    View details for PubMedID 24525629

    View details for PubMedCentralID PMC3999615

  • Maternal inflammatory markers and term labor performance AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Cierny, J. T., Unal, E. R., Flood, P., Rhee, K. Y., Praktish, A., Olson, T. H., Goetzl, L. 2014; 210 (5)


    We sought to examine the relationship between maternal markers of inflammation and labor performance.A nested cohort study was performed utilizing an established cohort of term nulliparous patients. Maternal blood was collected at the onset of regular, painful contractions in patients undergoing labor induction or at admission in patients with spontaneous labor. Levels of cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor-α were determined using standard multiplex methodology. Maternal demographic data were collected prospectively. Detailed retrospective chart review was performed to extract data on cervical dilation, effacement, and station during labor. Subjects were excluded if they failed to achieve complete dilation. Mixed effects modeling was used to examine the association between serum cytokine quartiles and labor progress in the latent and active phases.In all, 334 women were included in our analysis. The lowest quartile of IL-6 was associated with slower latent labor (P = .001). In contrast, the highest quartiles of IL-1 and tumor necrosis factor-α were associated with slower active labor (P = .03 and .0002, respectively).Proinflammatory activation is important in labor initiation. However, once active labor is established, excess inflammation can be detrimental to efficient labor progress. These data may explain, in part, the known associations among clinical chorioamnionitis, cesarean delivery, and postpartum hemorrhage.

    View details for DOI 10.1016/j.ajog.2013.11.038

    View details for Web of Science ID 000335510700016

    View details for PubMedID 24295921

  • Editorial commentary: "progressive encephalomyelitis with rigidity and myoclonus: anesthesia and glycine receptor antibodies". A & A case reports Flood, P. 2014; 2 (7): 86-87

    View details for DOI 10.1097/ACC.0b013e3182a6d86e

    View details for PubMedID 25611648

  • Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept NEUROPSYCHOPHARMACOLOGY Rodriguez, C. I., Kegeles, L. S., Levinson, A., Feng, T., Marcus, S. M., Vermes, D., Flood, P., Simpson, H. B. 2013; 38 (12): 2475-2483


    Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine's effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (≥35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

    View details for DOI 10.1038/npp.2013.150

    View details for Web of Science ID 000325710200016

    View details for PubMedID 23783065

    View details for PubMedCentralID PMC3799067

  • Oral choline supplementation for postoperative pain BRITISH JOURNAL OF ANAESTHESIA Sidhu, N., Davies, S., Nadarajah, A., Rivera, J., Whittington, R., Mercier, R. J., Virag, L., Wang, S., Flood, P. 2013; 111 (2): 249-255


    Activation of nicotinic receptors with nicotine has been shown to reduce post-surgical pain in clinical and preclinical studies. Choline is a selective agonist at α7-type nicotinic receptors that does not have addictive or sympathetic activating properties. It is anti-nociceptive in animal studies. We conducted a double-blind randomized trial of oral choline supplementation with lecithin to aid in the treatment of pain after gynaecological surgery.Sixty women having open gynaecological surgery were randomly assigned to receive 20 g of lecithin before surgery or placebo. Plasma choline concentration and tumour necrosis factor (TNF) were measured. Pain report was the primary outcome measure.We achieved a small but statistically significant increase in choline after surgery with oral supplementation. Plasma TNF was not decreased and pain report was not different between groups at rest or with movement. There were no adverse effects of treatment.Oral supplementation with lecithin during the perioperative period resulted in very slow absorption and thus only a small increase in plasma choline was achieved. This concentration was inadequate to reduce TNF as has been shown in other studies. The absence of an anti-inflammatory effect was likely related to our failure to demonstrate efficacy in pain reduction.

    View details for DOI 10.1093/bja/aet031

    View details for Web of Science ID 000322337900018

    View details for PubMedID 23568851

  • Magnesium Is There a Signal in the Noise? ANESTHESIOLOGY Naidu, R., Flood, P. 2013; 119 (1): 13-15

    View details for DOI 10.1097/ALN.0b013e3182976508

    View details for Web of Science ID 000320579300007

    View details for PubMedID 23665913

  • HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Tibbs, G. R., Rowley, T. J., Sanford, R. L., Herold, K. F., Proekt, A., Hemmings, H. C., Andersen, O. S., Goldstein, P. A., Flood, P. D. 2013; 345 (3): 363-373


    Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarization-activated, cyclic nucleotide-regulated (HCN)-mediated IH pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-di-iso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA(A) receptor (GABA(A)-R) potentiation, and general anesthesia. Thus, 2,6- and 2,4-di-tertbutylphenol (2,6- and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6- and 2,4-di-sec-butylphenol (2,6- and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA(A)-R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA(A)-R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

    View details for DOI 10.1124/jpet.113.203620

    View details for Web of Science ID 000319201500004

    View details for PubMedID 23549867

    View details for PubMedCentralID PMC3657108

  • Role of Capsaicin in a Murine Model of Labor and Delivery ANESTHESIOLOGY Mirza, F. G., Fakhoury, A. A., Rowley, T. J., Flood, P. D. 2013; 118 (2): 430-435


    The objectives of this study were to develop a murine model of labor and delivery and to use this model to examine whether capsaicin diminishes labor pain and expedites delivery.To develop a murine model of labor pain, the authors identified and compared the incidence of four proposed pain behaviors in 46 mice: (1) No analgesia in labor and the postpartum period, and (2) increasing doses of an analgesic, morphine. The model was then used to examine the impact of topical cervical capsaicin on: (1) labor pain behaviors and (2) labor progress by examining its impact on the time from treatment to delivery of the first pup and on the duration of delivery per pup. The treatment was randomly allocated and the behavioral observation was blinded.In the absence of analgesia, there was a statistically significant decrease in all four proposed pain behaviors in the postpartum period compared with labor (cumulative 55.0 ± 16.1/h vs. 16.1 ± 8.7/h; P < 0.0001). Additionally, morphine reduced their incidence during labor in a dose-dependent manner (cumulative 55.0 ± 16.1.7/h control, 46.4 ± 15.8 morphine 0.1 mg/kg/h, 34.6 ± 5.6/h, morphine 0.5 mg/kg/h; P = 0.1988, 0.0014). In addition, the incidence of identified pain behaviors was reduced by pericervical capsaicin (cumulative 55.0 ± 16.1.7/h control, 38.9 ± 15.4 capsaicin, P = 0.02).In this pilot study, the authors developed a novel mouse model of labor and delivery. Pericervical capsaicin applied days before delivery reduces labor pain behaviors.

    View details for Web of Science ID 000313977700021

    View details for PubMedID 23340354

  • Chronic Pain Secondary to Childbirth Does It Exist? ANESTHESIOLOGY Flood, P., Wong, C. A. 2013; 118 (1): 16-18

    View details for DOI 10.1097/ALN.0b013e318278cbfd

    View details for Web of Science ID 000312536800006

    View details for PubMedID 23249926

  • Oxytocin and catechol-O-methyltransferase receptor genotype predict the length of the first stage of labor AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Terkawi, A. S., Jackson, W. M., Thiet, M., Hansoti, S., Tabassum, R., Flood, P. 2012; 207 (3)


    We aimed to identify genetic factors that influence the rate of the first stage of labor.We prospectively enrolled 233 laboring nulliparous parturients. Demographic, clinical, and genetic data were collected. We evaluated the influence of population and individual variability using a nonlinear mixed effects model.Parturients who were homozygous for "G" at oxytocin receptor gene rs53576 transitioned to active labor later and thus had slower labor. Catechol-O-methyltransferase rs4633 genotype TT was associated with slower latent phase labor. Labor induction with prostaglandin was associated with faster labor, and request for meperidine was associated with slower labor. Birthweight was related inversely to the rate of the active phase.There are demographic, clinical, and genetic factors that influence an individual's rate of labor progress. This information could be used in automated form to improve the prediction of the length of the first stage of labor.

    View details for DOI 10.1016/j.ajog.2012.06.079

    View details for Web of Science ID 000308583100019

    View details for PubMedID 22939719

  • Unintentional Dural Puncture with a Tuohy Needle Increases Risk of Chronic Headache ANESTHESIA AND ANALGESIA Webb, C. A., Weyker, P. D., Zhang, L., Stanley, S., Coyle, D. T., Tang, T., Smiley, R. M., Flood, P. 2012; 115 (1): 124-132


    Neuraxial analgesia is chosen by almost half of women who give birth in the United States. Unintentional dural puncture is the most common complication of this pain management technique, occurring in 0.4% to 6% of parturients. Severe positional headaches develop acutely in 70% to 80% of these parturients. Acute postdural puncture headaches are well known, but few studies have investigated long-term sequelae. We investigated the incidence of and risk factors for chronic headache and chronic back pain in parturients who experienced unintentional dural puncture with a 17-gauge Tuohy needle compared with matched controls.In a case control design, 40 parturients who sustained unintentional dural puncture with a 17-gauge Tuohy needle over an 18-month period and 40 controls matched for age, weight, and time of delivery were recruited by telephone and 2 validated questionnaires were administered assessing headache and back pain symptoms 12 to 24 months after delivery.The incidence of chronic headaches in the study group (28%) was significantly higher than in the matched controls (5%) (OR = 7, P = 0.0129). Subjects who experienced dural punctures were more likely than controls to report chronic back pain (OR = 4, P = 0.0250), but treatment with an epidural blood patch was not a risk factor for chronic back pain.Patients who incur unintentional dural punctures with large-gauge needles are surprisingly likely to continue to suffer chronic headaches. Treatment with an epidural blood patch does not enhance the risk of chronic back pain. The pathophysiology underlying these symptoms and the best treatment for this syndrome are not known.

    View details for DOI 10.1213/ANE.0b013e3182501c06

    View details for Web of Science ID 000305600800022

    View details for PubMedID 22467897

  • Imaging Intracranial Pressure An Introduction to Ultrasonography of the Optic Nerve Sheath ANESTHESIOLOGY Rollins, M., Flood, P. 2012; 116 (5): 983-984

    View details for DOI 10.1097/ALN.0b013e31824c16e4

    View details for Web of Science ID 000303199600004

    View details for PubMedID 22337164

  • A Terrible Headache in Obstetric Anesthesia ANESTHESIOLOGY Flood, P., Li, G. 2012; 116 (2): 242-243

    View details for DOI 10.1097/ALN.0b013e3182410cf5

    View details for Web of Science ID 000299666200004

    View details for PubMedID 22166949

  • Cesarean Hysterectomy Requiring Emergent Thoracotomy A Case Report of a Complication of Placenta Percreta Requiring a Multidisciplinary Effort JOURNAL OF REPRODUCTIVE MEDICINE Pri-Paz, S., Devine, P. C., Miller, R. S., Flood, P. D., Laifer-Narin, S. L., Wright, J. D. 2012; 57 (1-2): 58-60


    Currently a leading indication for cesarean hysterectomy among multiparous women, placenta accreta is associated with significant maternal morbidity and mortality.A 34-year-old woman with a pregnancy complicated by placenta previa and previous cesarean deliveries was transferred to our institution following late diagnosis of placenta percreta. She underwent cesarean hysterectomy complicated by substantial hemorrhage. Massive blood product replacement precipitated severe hyperkaIemia and hypocalcemia with resultant asystole. Cardiac bypass with concomitant obligate anticoagulation was temporarily required while normalizing the patient's electrolytes. Numerous surgical and medical interventions were required to achieve hemostasis, and the patient survived to hospital discharge with moderate residual morbidity.Optimal management of placenta accreta requires a multidisciplinary approach within a tertiary center possessing extensive resources necessary for managing the most severe complications.

    View details for Web of Science ID 000299801900012

    View details for PubMedID 22324270

  • Anaesthetic considerations for non-obstetric surgery during pregnancy BRITISH JOURNAL OF ANAESTHESIA Reitman, E., Flood, P. 2011; 107: 72-78

    View details for DOI 10.1093/bja/aer343

    View details for Web of Science ID 000297857500007

  • Anaesthetic considerations for non-obstetric surgery during pregnancy. British journal of anaesthesia Reitman, E., Flood, P. 2011; 107: i72-8


    Surgery during pregnancy is complicated by the need to balance the requirements of two patients. Under usual circumstances, surgery is only conducted during pregnancy when it is absolutely necessary for the wellbeing of the mother, fetus, or both. Even so, the outcome is generally favourable for both the mother and the fetus. All general anaesthetic drugs cross the placenta and there is no optimal general anaesthetic technique. Neither is there convincing evidence that any particular anaesthetic drug is toxic in humans. There is weak evidence that nitrous oxide should be avoided in early pregnancy due to a potential association with pregnancy loss with high exposure. There is evidence in animal models that many general anaesthetic techniques cause inappropriate neuronal apoptosis and behavioural deficits in later life. It is not known whether these considerations affect the human fetus but studies are underway. Given the general considerations of avoiding fetal exposure to unnecessary medication and potential protection of the maternal airway, regional anaesthesia is usually preferred in pregnancy when it is practical for the medical and surgical condition. When surgery is indicated during pregnancy maintenance of maternal oxygenation, perfusion and homeostasis with the least extensive anaesthetic that is practical will assure the best outcome for the fetus.

    View details for DOI 10.1093/bja/aer343

    View details for PubMedID 22156272

  • Case Scenario: Perioperative Management of a Multigravida at 34-week Gestation Diagnosed with Abnormal Placentation ANESTHESIOLOGY Reitman, E., Devine, P. C., Laifer-Narin, S. L., Flood, P. 2011; 115 (4): 852-857

    View details for DOI 10.1097/ALN.0b013e31822ea436

    View details for Web of Science ID 000295079500027

    View details for PubMedID 21844796

  • Beta-2 adrenoceptor genotype and progress in term and late preterm active labor AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Miller, R. S., Smiley, R. M., Daniel, D., Weng, C., Emala, C. W., Blouin, J., Flood, P. D. 2011; 205 (2)


    We sought to evaluate whether beta-2 adrenoceptor (β2AR) genotype at a functional polymorphic site encoding for amino acid residue 16 influences rate of cervical dilatation in term and late preterm active labor.Subjects who underwent vaginal delivery at ≥34 weeks' gestational age from May 2006 through August 2007 were identified. Each subject had provided venous blood from which DNA was extracted for β2AR genotyping. Digital cervical examinations with paired examination times were collected from intrapartum records. Rate of cervical dilatation in active labor was determined using linear regression. Rates were compared between genotype groups.Among 401 subjects with satisfactory genotype and intrapartum data, overall rate of active labor was 0.76±0.01 cm/h. When labor was compared by genotype, homozygous Arg/Arg16 subjects progressed at a slower rate (0.64±0.03 cm/h) than all other pooled genotypes (0.8±0.02 cm/h, P<.001).Homozygous β2AR genotype encoding for Arg/Arg16 was associated with slower progress in active labor.

    View details for DOI 10.1016/j.ajog.2011.03.045

    View details for Web of Science ID 000293219400028

    View details for PubMedID 21600547

    View details for PubMedCentralID PMC3192244

  • Nicotine Nasal Spray as an Adjuvant Analgesic for Third Molar Surgery JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY Yagoubian, B., Akkara, J., Afzali, P., Alfi, D. M., Olson, L., Conell-Price, J., Yeh, J., Eisig, S. B., Flood, P. 2011; 69 (5): 1316-1319


    To determine the efficacy of preoperatively administered nicotine nasal spray (3 mg) for analgesia after third molar (TM) surgery.A single-center, prospective, randomized, double-blind, crossover trial was conducted. The study population consisted of 20 nonsmoking patients referred to the Department of Oral and Maxillofacial Surgery of Columbia University College of Dental Medicine for extraction of all 4 TMs. Each patient received nicotine nasal spray or placebo spray before TM surgery. At a subsequent visit the contralateral TMs were removed with prior administration of the alternate treatment. For an hour postoperatively, subjects reported information on pain and nausea, and hemodynamic variables were recorded at 15-minute intervals. Telephone follow-up was recorded for 5 days postoperatively, where patients reported information on pain, nausea, and use of hydrocodone/acetaminophen as rescue analgesia.Nicotine treatment was associated with a highly significant decrease in pain reported during the 5 days after TM surgery. There was no difference in the amount of hydrocodone/acetaminophen used or amount of nausea reported. There was a small but significant increase in heart rate after nicotine treatment compared with placebo during the first hour after surgery. There was no difference in blood pressure between groups.Pain is well controlled by hydrocodone/acetaminophen in most patients after TM surgery. However, there is significant variability in pain reported. Nicotinic agonists represent a new class of analgesic that can be considered for patients who are expected to have significant opioid-resistant pain after TM surgery. Caution should be used with patients in whom a small increase in heart rate would be deleterious.

    View details for DOI 10.1016/j.joms.2010.07.025

    View details for Web of Science ID 000290242300022

    View details for PubMedID 21256649

  • beta 2-Adrenergic Receptor Genotype and Other Variables that Contribute to Labor Pain and Progress ANESTHESIOLOGY Reitman, E., Conell-Price, J., Evansmith, J., Olson, L., Drosinos, S., Jasper, N., Randolph, P., Smiley, R. M., Shafer, S., Flood, P. 2011; 114 (4): 927-939


    β2-Adrenergic receptor (β2AR) activity influences labor. Its genotype affects the incidence of preterm delivery. We determined the effect of β2AR genotype on term labor progress and maternal pain.We prospectively enrolled 150 nulliparous parturients in the third trimester and obtained sensory thresholds, demographic information, and DNA. Cervical dilation, pain scores, and labor management data were extracted with associated times. The association of genetic and demographic factors with labor was tested using mixed effects models.Parturients who express Gln at the 27 position of the β2AR had slower labor (P < 0.03). They progressed from 1-10 cm dilation in approximately 21 h compared with 14 h among other patients. Asian ethnicity, previously associated with slower labor, is highly associated with this polymorphism (P < 0.0001). Heavier and black patients had slower latent labor (P < 0.01, 0.01). Neuraxial analgesia was associated with slower labor progress (P < 0.0001). It could take up to 36 h for parturients who were black and/or more than median weight (165 lb) to transition from 1 cm cervical dilation to active labor. However, after this active phase began, labor rates among these patients were similar to that of other parturients.We detected a strong association between β2AR genotype and slower labor. Asian ethnicity may be a proxy for β2AR genotype. Black women and those of higher than average weight have slower latent labor. These results confirm many of the associations found when this mathematical model was applied to a large retrospective cohort, further validating this approach to description and analysis of labor progress.

    View details for Web of Science ID 000288694400024

    View details for PubMedID 21394004

  • Rapid Resolution of Obsessions After an Infusion of Intravenous Ketamine in a Patient With Treatment-Resistant Obsessive-Compulsive Disorder JOURNAL OF CLINICAL PSYCHIATRY Rodriguez, C. I., Kegeles, L. S., Flood, P., Simpson, H. B. 2011; 72 (4): 567-569

    View details for DOI 10.4088/JCP.10l06653

    View details for Web of Science ID 000290012500020

    View details for PubMedID 21527129

    View details for PubMedCentralID PMC3727240

  • Fetal Anesthesia and Brain Development ANESTHESIOLOGY Flood, P. 2011; 114 (3): 479-480

    View details for DOI 10.1097/ALN.0b013e318209aa8c

    View details for Web of Science ID 000287660300002

    View details for PubMedID 21278569

  • Impact of topical capsaicin on labor in a novel mouse model Mirza, F., Fakhoury, A., Rowley, T., Flood, P. MOSBY-ELSEVIER. 2011: S124-S125
  • Validation of a bi-exponential model for labor progress in a cohort of mixed parity with quantification of the impact of cervical effacement and fetal station Smiley, R., Quincy, M., Mirza, F., Weng, C., Flood, P. MOSBY-ELSEVIER. 2011: S130-S131
  • Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain BRITISH JOURNAL OF ANAESTHESIA Rowley, T. J., McKinstry, A., GREENIDGE, E., Smith, W., Flood, P. 2010; 105 (2): 201-207


    Choline is a dietary supplement that activates alpha7 nicotinic receptors. alpha7 nicotinic activation reduces cytokine production by macrophages and has antinociceptive activity in inflammatory pain models. We hypothesized that systemic administration of choline would reduce the inflammatory response from macrophages and have antinociceptive efficacy in a murine model of postoperative pain.We studied the response of wild-type and alpha7 nicotinic knockout mice to heat and punctate pressure after a model surgical procedure. We investigated the effect of genotype and choline treatment on alpha-bungarotoxin binding to, and their production of tumour necrosis factor (TNF) from, macrophages.Choline provided moderate antinociception. The ED(50) for choline inhibition of heat-induced allodynia was 1.7 mg kg(-1) h(-1). The ED(50) for punctate pressure threshold was 4.7 mg kg(-1) h(-1) choline. alpha7 nicotinic knockout mice had no change in hypersensitivity to heat or pressure and were significantly different from littermate controls when treated with choline 5 mg kg(-1) h(-1) (P<0.05, 0.01). Choline 100 mM reduced binding of alpha-bungarotoxin to macrophages by 72% and decreased their release of TNF by up to 51 (sd 11)%. There was no difference by genotype in the inhibition of TNF release by choline.Systemic choline is a moderately effective analgesic via activation of alpha7 nicotinic acetylcholine receptors. The antinocicepive effect may not be mediated by a reduction of TNF pathway cytokine release from macrophages. Although choline at millimolar concentrations clearly inhibits the release of TNF, this effect is not alpha7 subunit-dependent and occurs at concentrations likely higher than reached systemically in vivo.

    View details for DOI 10.1093/bja/aeq113

    View details for Web of Science ID 000280013800016

    View details for PubMedID 20511332

  • PRO: Accumulating Evidence for an Outrageous Claim ANESTHESIA AND ANALGESIA Flood, P. 2010; 111 (1): 86-87

    View details for DOI 10.1213/ANE.0b013e3181dde32e

    View details for Web of Science ID 000279281500019

    View details for PubMedID 20576965

  • Wasabi and a Volatile Anesthetic ANESTHESIOLOGY Gallos, G., Flood, P. 2010; 112 (6): 1309-1310

    View details for DOI 10.1097/ALN.0b013e3181d94e1b

    View details for Web of Science ID 000278339200004

    View details for PubMedID 20502113

  • Personalized intravenous regional anesthesia. Saudi journal of anaesthesia Flood, P. 2010; 4 (2): 46-?

    View details for DOI 10.4103/1658-354X.65117

    View details for PubMedID 20927261

    View details for PubMedCentralID PMC2945513

  • Additional References on the Epidemiology of Anesthesia Complications in Labor and Delivery Response ANESTHESIA AND ANALGESIA Li, G., Brady, J. E., Cheesman, K., Flood, P. 2010; 110 (5): 1512
  • A Transdermal Nicotine Patch Is Not Effective for Postoperative Pain Management in Smokers: A Pilot Dose-Ranging Study ANESTHESIA AND ANALGESIA Olson, L. C., Hong, D., Conell-Price, J. S., Cheng, S., Flood, P. 2009; 109 (6): 1987-1991


    Nicotine has an antinociceptive effect in animal models. The analgesic effect in humans has been examined, but studies have had mixed results. A proposed etiology is variability in chronic nicotine exposure because of differences in tobacco smoking rates and second-hand smoke exposure. In this study, we examined the postoperative analgesic effect of a transdermal nicotine patch in smokers in a parallel design to a previous study in nonsmokers.We conducted a randomized, double-blind, prospective, placebo-controlled trial of 28 patients undergoing abdominal or pelvic surgery who required patient-controlled analgesia and an overnight hospital stay. Before anesthetic induction, a transdermal nicotine patch was applied (0, 5, 10, or 15 mg). The primary outcome variable was postoperative pain reported over the first hour and over the next 5 days using a standard numerical rating scale. Secondary outcome variables were pain medication use, hemodynamic values, nausea, and sedation.Patients treated with nicotine reported higher pain scores than those treated with placebo over the first hour after surgery (P < 0.01, average numerical rating scale increase = 0.67) and there was no difference between groups in the subsequent 5 days (P > 0.05). There was no significant dose effect. Diastolic blood pressure in the first hour was higher in the placebo group compared with the nicotine-treated group (P < 0.01, average increase = 11 mm Hg). There was no difference in nausea or sedation.Transdermal nicotine, 5-15 mg, failed to relieve postoperative pain or reduce opioid use in smokers.

    View details for DOI 10.1213/ANE.0b013e3181bd1612

    View details for Web of Science ID 000272000100040

    View details for PubMedID 19923530

  • Impact of analgesia on maternal activities in a novel murine model of labor and delivery Mirza, F., Fakhoury, A., Rowley, T., Flood, P. MOSBY-ELSEVIER. 2009: S122
  • Mathematical Modeling of the Pain and Progress of the First Stage of Nulliparous Labor Annual Meeting of the American-Society-of-Anesthesiologist Debiec, J., Conell-Price, J., Evansmith, J., Shafer, S. L., Flood, P. LIPPINCOTT WILLIAMS & WILKINS. 2009: 1093–1110


    Patient characteristics may contribute to the progress and pain of labor. Quantitative evaluation of the effects of patient characteristics requires robust mathematical models of labor progress and labor pain.The authors retrospectively studied 100 sequential deliveries from each of five self-reported ethnic groups (Asian, Black, Hispanic, Other, and White). Demographic variables, cervical dilation, and numerical rating scores for pain before analgesia and cervical dilation were abstracted from the automated medical record. Labor progress was modeled with a biexponential function describing the latent and active phases of labor. Labor pain was modeled as a sigmoid function of cervical dilation by using a previously validated mathematical model. The covariates, including self-described ethnicity, were analyzed with NONMEM.The biexponential function described the time course of labor progress better than several alternative functions, including the sigmoidal function introduced by Friedman. The sigmoidal function of labor pain described its dynamic nature well, with substantial intersubject variability. Asian women had slower active labor than other ethnicities (P < 0.01). Asian women also reported less pain during their labor compared to all other patients (P < 0.001). Slower labor progress was associated with less rapid progression of pain, but this did not obviate the effect of Asian ethnicity on pain. Neuraxial analgesia is strongly associated with slower labor (P < 0.0001). Greater maternal weight was associated with slower active labor (P < 0.0001).Mathematical models can be used to detect subtle effects of patient covariates on the progress and pain of the first stage of labor. Asian women and heavier women had slower labor and slower onset of labor pain than others. These effects were modest compared with the substantial remaining unexplained subject-to-subject variability in labor progress and labor pain.

    View details for Web of Science ID 000271172500021

    View details for PubMedID 19858874

  • Primary versus Secondary Outcomes in Gargantuan Studies ANESTHESIOLOGY Flood, P. 2009; 111 (4): 704-705

    View details for Web of Science ID 000270210100008

    View details for PubMedID 19707120

  • Epidemiology of Anesthesia-Related Complications in Labor and Delivery, New York State, 2002-2005 ANESTHESIA AND ANALGESIA Cheesman, K., Brady, J. E., Flood, P., Li, G. 2009; 109 (4): 1174-1181


    Epidemiologic data on anesthesia-related complications occurring during labor and delivery are essential for measuring and evaluating the safety and quality of obstetric anesthesia care but are lacking. We aimed to fill this research gap by exploring the epidemiologic patterns and risk factors of anesthesia-related complications in a large sample of women giving birth in New York hospitals.Using the Healthcare Cost and Utilization Project State Inpatient Databases files, we identified all discharge records for labor and delivery from New York hospitals between 2002 and 2005. We then identified women who experienced any recorded anesthesia-related complication during labor and delivery as determined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. The incidence of anesthesia-related complications was calculated by demographic and clinical characteristics. Multivariate logistic regression was performed to assess risk factors of anesthesia-related complications.Of the 957,471 deliveries studied, 4438 (0.46%) had at least one anesthesia-related complication. The majority (55%) of anesthesia-related events occurring during labor and delivery were spinal complications, followed by systemic complications (43%) and overdose or adverse effects (2%). Multivariate logistic regression revealed five risk factors of anesthesia-related complications: cesarean delivery (odds ratio [OR] 2.51, 95% confidence interval [CI] 2.36-2.68), rural area (OR 1.33, 95% CI 1.21-1.46), Charlson-Deyo Comorbidity Index >or=1 (OR 1.47, 95% CI 1.28-1.69), Caucasian race (OR 1.37, 95% CI 1.24-1.52), and scheduled admission (OR 1.10, 95% CI 1.03-1.18). Anesthesia-related complications were associated with about a one-day increase in the average length of stay (3.89 +/- 3.69 [mean +/- SD] days vs 2.92 +/- 2.38 days for deliveries without anesthesia-related complications, P < 0.0001) and a 22-fold increased risk of maternal mortality (OR 22.26, 95% CI 11.20-44.24).The incidence of anesthesia-related complications during labor and delivery seems to be low but remains a cause of concern, particularly in women undergoing cesarean delivery, living in rural areas, or having preexisting medical conditions.

    View details for DOI 10.1213/ane.0b013e3181b2ef75

    View details for Web of Science ID 000270209100029

    View details for PubMedID 19762746

    View details for PubMedCentralID PMC3391736

  • The Stressed-out Rat A Model for Anesthetic Prevention of Post-Traumatic Stress Disorder ANESTHESIOLOGY Flood, P. D. 2009; 110 (3): 447-448

    View details for Web of Science ID 000263734900003

    View details for PubMedID 19204563

  • The side effects of morphine and hydromorphone patient-controlled analgesia ANESTHESIA AND ANALGESIA Hong, D., Flood, P., Diaz, G. 2008; 107 (4): 1384-1389


    Despite "clinical lore" among health care providers that treatment with hydromorphone results in improved pain control and fewer adverse side effects, morphine continues to be the first-line medication for postoperative patient-controlled analgesia (PCA). In this study, we compared the efficacy and side-effect profiles of morphine and hydromorphone at concentrations producing equivalent drug effect measured by pain score and miosis.We conducted a prospective, randomized, double-blind trial of 50 general and gynecological surgery patients. Subjects were randomly assigned to receive either morphine (1 mg/mL) or hydromorphone (0.2 mg/mL) via PCA after surgery and were followed for a period of 8 h. The primary outcome was nausea. Secondary outcome variables were pruritus, vomiting, sedation, pain report, pupillary miosis, and patient satisfaction.The side effect profile was not different between drugs. The incidence of nausea did not differ between morphine and hydromorphone-treated patients (1 h: 44% vs 52%, 8 h: 68% vs 64%), vomiting (1 h: 4% vs 0%, 8 h: 0% vs 4%), or pruritus (1 h: 4% vs 16%, 8 h: 40% vs 40%). There was no difference in the amount of medication required to treat side effects or patient satisfaction. The average ratio of morphine to hydromorphone use was about 7:1. The patients used 10.9+/-6.0 mg morphine versus 1.57+/-1.0 mg hydromorphone after 1 h and 29.0+/-18.0 mg morphine versus 3.9+/-2.5 mg hydromorphone after 8 h. There was no difference between the morphine and hydromorphone groups with respect to postoperative pain scores with movement at 1 h (7.9+/-2.3 vs 7.1+/-2.4) or 8 h (5.7+/-2.8 vs 5.9+/-2.7). There was also no difference in pain at rest or miosis between groups.We found no systematic difference between morphine and hydromorphone in opioid-related side effects. Neither was there any difference in efficacy of pain control or patient satisfaction when patients self-titrated to equal drug effect as measured by equianalgesia and pupillary miosis. The choice between morphine and hydromorphone for use in PCA should be guided by patient history, as there may be idiosyncratic reactions to either drug.

    View details for DOI 10.1213/ane.0b013e3181823efb

    View details for Web of Science ID 000259522100051

    View details for PubMedID 18806056

  • Isoflurane prevents nicotine-evoked norepinephrine release from the mouse spinal cord at low clinical concentrations ANESTHESIA AND ANALGESIA Rowley, T. J., Flood, P. 2008; 107 (3): 885-889


    Volatile anesthetics inhibit nicotinic acetylcholine receptors at subanesthetic concentrations. In both animal and human studies, similar concentrations of volatile anesthetics have been associated with increased sensitivity to pain. Nicotinic analgesia is thought to involve the enhanced release of norepinephrine. These studies are intended as a "proof of concept" that alteration of the nicotinic facilitation of norepinephrine release is a potential mechanism for isoflurane-induced pronociception.We conducted our study using a murine lumbar spinal cord slice model. We evoked norepinephrine release with nicotine in the presence and absence of isoflurane. To identify the type of nicotinic receptor involved, we studied the effect of receptor and subtype-specific ligands and genetically engineered mice, which lacked the gene expression for the nicotinic beta2 subunit. The amount of [(3)H]-norepinephrine released was measured under the different conditions.Nicotine-facilitated norepinephrine release was significantly and maximally inhibited by isoflurane at concentrations that enhance pain sensitivity in vivo (0.38%). Facilitation of norepinephrine release was mimicked by the alpha 7 selective agonist choline and inhibited in the presence of alpha-bungarotoxin, an alpha 7-nicotinic selective antagonist. Facilitation of norepinephrine release was not different in animals lacking beta2 subunits compared with matched controls.Nicotinic facilitation of norepinephrine release in the spinal cord is inhibited by isoflurane at low clinically relevant concentrations. Because the net effect of noradrenergic tone in the spinal cord is inhibitory, the removal of this mechanism might be responsible for the enhanced pain sensitivity seen at these concentrations of isoflurane.

    View details for DOI 10.1213/01.ane.0000287646.85834.1a

    View details for Web of Science ID 000258702500029

    View details for PubMedID 18713901

  • The antinociceptive response to nicotinic agonists in a mouse model of postoperative pain ANESTHESIA AND ANALGESIA Rowley, T. J., Payappilly, J., Lu, J., Flood, P. 2008; 107 (3): 1052-1057


    Nicotine, the prototypical broad spectrum agonist at central nicotinic receptors, has analgesic action after surgery. Various subtype-specific nicotinic agonists have antinociceptive effects in animal models, but the response is highly dependent on the model tested. In an effort to determine what nicotinic subtypes might be targeted in future clinical studies, we tested agonists selective for alpha 4 beta 2 and alpha 7 containing nicotinic receptors in a mouse model of postoperative pain.After paw incision, mice were tested for heat latency and pressure threshold before and after treatment with a dose range of ligands selective for alpha 4 beta 2 and alpha 7 containing nicotinic receptors. To demonstrate that nicotine reduced nociceptive input in this model, the lumbar spinal cords of a subgroup of these mice were stained for the phosphorylated form if CREB.Nicotine and metanicotine (alpha 4 beta 2 selective) were fully effective as an analgesic in heat and pressure testing. The alpha 7 partial agonist GTS-21 significantly increased the heat latency after surgery, but did not alter pressure threshold. The alpha 7 selective antagonist methyllicaconitine decreased the efficacy of nicotine to increase heat latency but did not affect pressure threshold. The number of cells in the superficial dorsal horn with nuclei that stained for pCREB was double on the surgical side and the ratio was reduced by nicotine in a dose-dependent manner.Our findings suggest that nicotine reduced nociceptive input to the superficial and deep dorsal horn. It also provides support for alpha 4 beta 2 and alpha 7 nicotinic-mediated antinociceptive actions.

    View details for DOI 10.1213/ane.0b013e318165e0c0

    View details for Web of Science ID 000258702500055

    View details for PubMedID 18713928

  • Transdermal nicotine patch for postoperative pain management: A pilot dose-ranging study ANESTHESIA AND ANALGESIA Hong, D., Conell-Price, J., Cheng, S., Flood, P. 2008; 107 (3): 1005-1010


    Nicotine has been shown to be antinociceptive in the postoperative period in animal studies. Human studies with nasal nicotine sprays have had mixed results, possibly due to variability in pharmacokinetics and potential patient variables such as exposure to nicotine in tobacco smokers. In this pilot study, we examined the analgesic effect of a transdermal nicotine patch applied before surgery in nonsmokers.We conducted a randomized, double-blind, prospective placebo-controlled trial of 40 subjects, undergoing general surgery that required postoperative patient-controlled analgesia and an overnight hospital admission. Immediately before surgery, a transdermal nicotine patch containing 0, 5, 10, or 15 mg was applied. The primary outcome variable was pain report using a numerical rating scale (NRS) in the first hour after surgery and over the next 5 days. Secondary outcomes were pain medication use, hemodynamic values, nausea, and sedation.Patients treated with nicotine reported lower pain scores when compared with those treated with placebo during the first hour after surgery (P = 0.003, average NRS decrease = 1.4, 95% CI = 0.3-2.6) and for 5 days after surgery (P = 0.03, average NRS decrease = 1.0, 95% CI = 0.1-1.9). There was no increased benefit of nicotine with doses larger than 5 mg. There was a trend suggesting decreased pain medicine use, increased nausea, decreased tachycardia, and slightly decreased systolic blood pressure in the nicotine groups, but these values did not reach significance.Transdermal nicotine, 5-15 mg, reduced postoperative pain scores but failed to decrease the need for opioid analgesics or opioid-related side effects after general surgical procedures.

    View details for DOI 10.1213/ane.0b013e318163204f

    View details for Web of Science ID 000258702500049

    View details for PubMedID 18713921

  • Additivity versus synergy: A theoretical analysis of implications for anesthetic mechanisms ANESTHESIA AND ANALGESIA Shafer, S. L., Hendrickx, J. F., Flood, P., Sonner, J., Eger, E. I. 2008; 107 (2): 507-524


    Inhaled anesthetics have been postulated to act at multiple receptors, with modest action at each site summing to produce immobility to noxious stimulation. Recent experimental results affirm prior findings that inhaled anesthetics interact additively. Synergy implies multiple sites of action by definition. In this essay, we explore the converse: does additivity imply a single site of action?The interaction of one versus two ligands competing for the same binding site at a receptor was explored using the law of mass action. Circuits were then constructed to investigate how the potency of drugs and the steepness of the concentration versus response relationship is amplified by the arrangement of suppressors into serial circuits, and enhancers into parallel circuits. Assemblies of suppressor and enhancer circuits into signal processing units were then explored to investigate the constraints signal processing units impose on additive interactions. Lastly, the relationship between synergy, additivity, and fractional receptor occupancy was explored to understand the constraints imposed by additivity.Drugs that compete for a single receptor, and that similarly affect the receptor, must be additive in their effects. Receptors that bind suppressors in serial circuits, or enhancers in parallel circuits, increase the apparent potency of the drugs and the steepness of the concentration versus response relationship. When assemblies of suppressor and enhancer circuits are arranged into signal processing units, the interactions may be additive or synergistic. The primary determinant is the relationship between the concentration of drug associated with the effect of interest and the concentration associated with 50% receptor occupancy, k(d). Effects mediated by very low concentrations are more likely to be additive. Similarly, inhaled anesthetics that act at separate sites are unlikely to exhibit additive interactions if anesthetic drug effect occurs at concentrations at or above 50% receptor occupancy. However, if anesthetic drug effect occurs at very low levels of receptor occupancy, then additivity is expected even among anesthetics acting on different receptors.Additivity among drugs acting on different receptors is only likely if the concentrations responsible for the drug effect of interest are well below the concentration associated with 50% receptor occupancy.

    View details for DOI 10.1213/ane.0b013e31817b7140

    View details for Web of Science ID 000258168300025

    View details for PubMedID 18633029

  • Inhaled anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats ANESTHESIA AND ANALGESIA Eger, E. J., Tang, M., Liao, M., Laster, M. J., Solt, K., Flood, P., Jenkins, A., Raines, D., Hendrickx, J. F., Shafer, S. L., Yasumasa, T., Sonner, J. M. 2008; 107 (2): 479-485


    We hypothesized that pairs of inhaled anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that anesthetics act on multiple sites to produce anesthesia.Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By "divergently," we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and gamma-aminobutyric acid type A, glycine, N-methyl-D-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-D-aspartic acid blocker MK-801 had divergent effects on the MACs of these anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane.All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found.Such results are consistent with the notion that inhaled anesthetics act on a single site to produce immobility in the face of noxious stimulation.

    View details for DOI 10.1213/01.ane.0000295805.70887.65

    View details for Web of Science ID 000258168300022

    View details for PubMedID 18633026

  • Galloping in full pursuit of the mechanism of anesthetic immobility ANESTHESIOLOGY Hemmings, H. C., Flood, P. 2008; 108 (6): 975-976

    View details for Web of Science ID 000256203200002

    View details for PubMedID 18497595

  • The development and validation of a dynamic model to account for the progress of labor in the assessment of pain ANESTHESIA AND ANALGESIA Conell-Price, J., Evans, J. B., Hong, D., Shafer, S., Flood, P. 2008; 106 (5): 1509-1515


    Labor pain is often described as the worst pain in a woman's life, but the experience is highly variable. Although many factors have been linked to labor pain, it has been difficult to assess the individual effects of these factors because labor is a dynamic process and pain intensity changes over the course of labor. Previous studies have used average pain scores. The aim of this study was to develop and validate a model that would allow for the statistical analysis of factors that affect pain throughout labor.We conducted this study with a retrospective database drawn from the medical records of 200 consecutive nulliparous parturients who delivered at New York Presbyterian Hospital between October 2006 and January 2007. Numerical rating scale scores for pain with contractions (0-10 scale), cervical dilation, and oxytocin use before analgesia request were recorded. Nonlinear effects modeling with a sigmoid equation was used to describe the relationship between reported pain and cervical dilation. The modeling technique was developed with data from 91 parturients and validated with an independent set of 95 parturients (all parturients with pain scores more than zero). The resulting model was used to analyze the effect of a sample covariate, oxytocin administration, on reported pain in the entire data set.The model derived from our training set was predictive of the data from our validation set (P < 0.001). Predicted pain scores were on average two numerical rating scale points above or below measured pain scores. Analyzing oxytocin as a covariant showed that women treated with oxytocin reported 48% more pain at the start of labor but did not have a significantly more rapid increase in pain or higher maximal pain when compared with women not treated with oxytocin. Women treated with oxytocin had slower early labor and more rapid late labor.We have developed and validated a model for describing pain over the course of labor. Our model is suited to the statistical analysis of covariance and could potentially be used to compare the effects of covariants on labor pain and the rate of change of pain.

    View details for DOI 10.1213/ane.0b013e31816d14f3

    View details for Web of Science ID 000255222700031

    View details for PubMedID 18420869

  • Anesthesia matters: Patients anesthetized with propofol have less postoperative pain than those anesthetized with isoflurane ANESTHESIA AND ANALGESIA Cheng, S. S., Yeh, J., Flood, P. 2008; 106 (1): 264-269


    Preclinical studies have suggested that some volatile anesthetics induce a hyperalgesic state that may be secondary to nicotinic inhibition. A previous trial of treatment with nicotine nasal spray demonstrated postoperative analgesia in women anesthetized with isoflurane. To determine whether the effect of nicotine was reversing hyperalgesia induced by isoflurane, or simply acting as an analgesic, we studied the effect of nicotine on postoperative pain in women anesthetized with isoflurane or propofol, with fentanyl.In a randomized, prospective, double-blind trial, we assigned 80 women having open uterine surgery to be anesthetized with isoflurane or propofol. Within each anesthetic group, the subjects were further randomly assigned to receive nicotine 3 mg or placebo. Pain reported with a numerical analog scale was the primary outcome variable.The patient demographics were similar. Women who were anesthetized with propofol reported less pain and used less morphine during the first day after surgery than women who were anesthetized with isoflurane (P < 0.01, P < 0.01). Nicotine treatment did not change pain report or morphine use in either anesthetic group (P > 0.05).General anesthesia with propofol and is associated with less postoperative pain and morphine use than general anesthesia with isoflurane. Nicotine was not analgesic in this trial. If these results are repeated in other populations, reduced postoperative pain can be added to the previously described improvement in nausea and vomiting as a potential benefit of anesthesia with propofol.

    View details for DOI 10.1213/01.ane.0000287653.77372.d9

    View details for Web of Science ID 000251824300047

    View details for PubMedID 18165589

  • A new treatment for hypoxic brain injury? ANESTHESIA AND ANALGESIA Flood, P. 2007; 105 (3): 559-560
  • Aerobic exercise attenuates inducible TNF production in humans JOURNAL OF APPLIED PHYSIOLOGY Sloan, R. P., Shapiro, P. A., DeMeersman, R. E., McKinley, P. S., Tracey, K. J., Slavov, I., Fang, Y., Flood, P. D. 2007; 103 (3): 1007-1011


    Aerobic exercise reduces coronary heart disease risk, but the mechanisms of this protection are not fully understood. Atherosclerosis is an inflammatory disease mediated by monocyte-derived macrophages, which accumulate in arterial plaques and become activated to release factors, including cytokines, that cause damage. Here we studied the effects of aerobic training on monocyte production of tumor necrosis factor (TNF) in whole blood ex vivo. Healthy young sedentary adults (n = 61, age 20-45 yr) were randomized to a moderate- (M) or a high- (H) intensity 12-wk training program. Whole blood was extracted before and after training, and then it was stimulated by addition of lipopolysaccharide (LPS); inducible TNF was measured in the plasma. Data were analyzed according to intention to treat principles using a random-effect model to determine the impact of training group on maximal aerobic capacity and LPS-stimulated TNF after correcting for covariates. Analyses revealed improvement in aerobic capacity in both the H (9%) and the M (7%) groups. However, aerobic training led to significant (P < 0.001) decreases in TNF release only in the H group. These data suggest that in healthy young adults, a 12-wk high-intensity aerobic training program downregulates blood monocyte production of stimulated cytokine release.

    View details for DOI 10.1152/japplphysiol.00147.2007

    View details for Web of Science ID 000249054700038

    View details for PubMedID 17626836

  • The pronociceptive effect of ondansetron in the setting of P-glycoprotein inhibition ANESTHESIA AND ANALGESIA Scott, J. A., Wood, M., Flood, P. 2006; 103 (3): 742-746


    Ondansetron is a potent antiemetic drug that acts through inhibition of the 5HT3 receptors for serotonin. Minimum alveolar concentration (MAC) for isoflurane is not affected by systemic ondansetron; however ondansetron is a substrate of P-glycoprotein, a transport pump expressed in the blood-brain barrier. Thus, we hypothesized that central nervous system concentrations of ondansetron might be reduced by the P-gp protein. As potent inhibitors of P-gp are in clinical trials to improve access of desirable chemotherapeutic and antibiotic drugs to the central nervous system, we studied the effect of ondansetron in the absence of extrusion by P-gp. Normal rats were given lumbar intrathecal ondansetron or vehicle. P-gp knockout mice and wild-type controls were treated with systemic ondansetron in the presence and absence of clinically used P-gp inhibitors. Nociception was assessed as thermal hindpaw withdrawal latency and immobility was assessed as isoflurane MAC. In rats, intrathecal ondansetron (20 g) increased thermal pain sensitivity by 20.0% +/- 5.8% (P < 0.01). Systemic ondansetron (2 mg/kg) increased pain sensitivity in P-gp knockout mice but had no effect in wild-type mice (P < 0.01). Systemic ondansetron had a small but statistically significant pronociceptive effect after treatment of wild-type mice with the P-gp inhibitor quinidine but not with cyclosporine or verapamil. Isoflurane MAC was not changed by intrathecal ondansetron in rats or systemically administered ondansetron in P-gp knockout mice. Intrathecal ondansetron can enhance thermal pain sensitivity. In the absence of P-gp protein, ondansetron can reach concentrations sufficient to increase pain sensitivity. Even with direct spinal application, ondansetron does not alter isoflurane MAC, supporting the idea that 5HT3 modulation does not play a role in general anesthetic immobility.

    View details for DOI 10.1213/01.ane.0000228861.80314.22

    View details for Web of Science ID 000240049800037

    View details for PubMedID 16931690

  • Strategies for effective postoperative pain management MINERVA ANESTESIOLOGICA Diaz, G., Flood, P. 2006; 72 (3): 145-150


    Postoperative pain management an important clinical issue. The clinicians tool-bag remains incomplete. Improvements in the management of postoperative pain will ultimately translate into the broader, safer application of surgical procedures upon a wider patient population. The application of multimodal therapy that includes non-pharmacologic therapies, preemptive therapies, and new medications for the treatment of postoperative pain is an emerging concept that provides significant immediate as well as potential future advantages.

    View details for Web of Science ID 000241884100006

    View details for PubMedID 16493390

  • Report of the 13th annual meeting of the International Society for Anaesthetic Pharmacology. Anesthesia and analgesia Keltner, J. R., Flood, P. 2005; 101 (5): 1556-1557

    View details for PubMedID 16244032

  • Prophylactic ephedrine and combined spinal epidural - Maternal blood pressure and fetal heart rate patterns OBSTETRICS AND GYNECOLOGY Cleary-Goldman, J., Negron, M., Scott, J., Downing, R. A., Camann, W., Simpson, L., Flood, P. 2005; 106 (3): 466-472


    Labor analgesia with the combined spinal epidural approach has been associated with maternal hypotension and fetal heart rate (FHR) changes. The purpose of this study was to estimate whether prophylactic intramuscular ephedrine before combined spinal epidural prevents these complications.In a prospective double blind trial, 100 healthy patients with term singletons received intramuscular ephedrine 25 mg or placebo by random allocation before combined spinal epidural. During the first hour after analgesia, maternal heart rate, blood pressure, and need for treatment of significant hypotension were recorded. Fetal heart rate tracings for 1 hour before and for 1 hour after administration of anesthetic were evaluated. Categorical variables were compared with Fisher exact test. Continuous variables were compared with one way analysis of variance for repeated measures. P < .05 was considered significant.Prophylactic ephedrine reduced the incidence of maternal hypotension after combined spinal epidural (P < .007). In controls, there was a significant increase in the incidence and frequency of late decelerations in the hour following combined spinal epidural compared with the previous hour (P < .005 and P < .01). Compared with controls, there was an increased incidence of fetal tachycardia in patients who received prophylactic ephedrine (P < .006), which was associated with increased FHR reactivity (P < .03).Although prophylactic ephedrine prevents maternal hypotension and fetal late decelerations, it is associated with fetal tachycardia. The value of prophylactic ephedrine at combined spinal epidural should be weighed against potential changes in fetal heart rate patterns.I.

    View details for Web of Science ID 000231492900005

    View details for PubMedID 16135575

  • The role of nicotinic inhibition in ketamine-induced behavior ANESTHESIA AND ANALGESIA Udesky, J. O., Spence, N. Z., Achiel, R., Lee, C., Flood, P. 2005; 101 (2): 407-411


    Several anesthetic drugs are nicotinic antagonists at or below levels used for anesthesia, including ketamine and volatile anesthetics. In contrast, propofol does not inhibit nicotinic receptors. To determine the potential behavioral ramifications of nicotinic inhibition by ketamine, we determined the doses of ketamine required to induce immobility, impair the righting reflex, and cause analgesia in the absence and presence of several nicotinic ligands. Propofol was used as a control in similar experiments. When used as a sole anesthetic drug, 383 +/- 22 mg/kg ketamine intraperitoneally (IP) was required for immobility and 180 +/- 17 mg/kg IP impaired righting reflex. Propofol, 371 +/- 34 mg/kg IP, induced immobility whereas 199 mg/kg IP inhibited the righting reflex. Nicotinic antagonists had no effect on the dose of propofol or ketamine required for either end-point. When nociceptive responses were tested at subhypnotic doses, no pronociceptive or antinociceptive phase was identified for propofol, whereas analgesia was induced at ketamine doses larger than 60 mg/kg IP. The broad-spectrum nicotinic antagonist mecamylamine enhanced the analgesic action of ketamine. These findings are different than those seen with volatile anesthetics, where nicotinic inhibition is thought to be responsible for a pronociceptive action. Such a phase is possibly obscured by analgesia induced as a result of N-methyl-d-aspartic acid antagonism by ketamine.Ketamine and volatile anesthetics, but not propofol, inhibit neuronal nicotinic acetylcholine receptors in clinically relevant concentration ranges. Nicotinic inhibition by ketamine is not related to its immobilizing or sedating effects but may play a role in ketamine's analgesic action.

    View details for DOI 10.1213/01.ANE.0000155291.81338.90

    View details for Web of Science ID 000230739100021

    View details for PubMedID 16037153

  • The importance of myorelaxants in anesthesia CURRENT OPINION IN PHARMACOLOGY Flood, P. 2005; 5 (3): 322-327


    Neuromuscular blocking drugs were introduced into clinical practice in 1942. Although these drugs made new surgical techniques possible, they also led to morbidity and mortality owing to respiratory muscle paralysis and paralysis in the face of inadequate anesthesia. Newer competitive antagonists at the neuromuscular junction have been developed that have a more rapid onset of action, including rocuronium and mivacurium, making them suitable for use at the onset of anesthesia. Rapid titratable offset of action has been more difficult to achieve, but has been attempted with the inclusion of ester bonds (mivacurium) and binding agents that are in clinical trials. These novel approaches to pharmaceuticals, along with improved understanding of the physiology of the neuromuscular junction in health and disease, have made surgical treatment possible in a wide breadth of clinical situations.

    View details for DOI 10.1016/j.coph.2004.12.009

    View details for Web of Science ID 000229620300017

    View details for PubMedID 15907920

  • The role of adrenergic and cholinergic transmission in volatile anesthetic-induced pain enhancement ANESTHESIA AND ANALGESIA Rowley, T. J., Daniel, D., Flood, P. 2005; 100 (4): 991-995


    Volatile anesthetic drugs have a biphasic effect on pain transmission. At very small concentrations they enhance pain sensitivity whereas at larger subanesthetic concentrations they have an analgesic effect. Previous work has suggested that nicotinic inhibition could mediate the pronociceptive action of isoflurane. Furthermore, activation of nicotinic receptors facilitates the release of norepinephrine in the spinal cord. We hypothesize that nicotinic modulation of norepinephrine release in the spinal cord mediates isoflurane's pronociceptive action. We used hindpaw withdrawal latency as a measure of pain sensitivity after inhibition of adrenergic activity or treatment with nicotine in mice. Isoflurane's effect on pain is separable by concentration. The 50% effective concentration for pain enhancement is 0.16% isoflurane whereas the 50% effective concentration for the antinociceptive action of isoflurane is 0.8%. Depletion of systemic norepinephrine with the neurotoxin DSP-4 caused a reduction in baseline withdrawal latencies and prevented isoflurane pronociception. Baseline latency was also reduced by intrathecal yohimbine. After treatment with yohimbine, isoflurane had no additional pronociceptive effect. Nicotine administered through intracerebroventricular injection increased baseline latency but did not prevent isoflurane pronociception. Conversely, intrathecal applications of nicotine caused a slight reduction in baseline latency and prevented isoflurane's pronociceptive effect. We conclude that spinal noradrenergic transmission seems to be necessary for isoflurane pronociception to occur. Isoflurane may act by inhibiting tonically active nicotinic receptors that modulate the release of norepinephrine in the spinal cord.

    View details for DOI 10.1213/01.ANE.0000147708.73945.B3

    View details for Web of Science ID 000227792400015

    View details for PubMedID 15781512

  • Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: In vitro and in vivo selectivity JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Damaj, M. I., Flood, P., Ho, K. K., May, E. L., Martin, B. R. 2005; 312 (2): 780-785


    The effects of dextrometorphan and its metabolite dextrorphan on nicotine-induced antinociception in two acute thermal pain assays after systematic administration were evaluated in mice and compared with that of mecamylamine. Dextrometorphan and dextrorphan were found to block nicotine's antinociception in the tail-flick and hot-plate tests with different potencies (dextrometorphan is 10 times more potent than its metabolite). This blockade was not due to antagonism of N-methyl-d-aspartate receptors and/or interaction with opiate receptors, since selective drugs of these receptors failed to block nicotine's analgesic effects. Our results with the tail-flick and hot-plate tests showed an interesting in vivo functional selectivity for dextrometorphan over dextrorphan. In oocytes expressing various neuronal acetylcholine nicotinic receptors (nAChR), dextrometorphan and dextrorphan blocked nicotine activation of expressed alpha(3)beta(4), alpha(4)beta(2), and alpha(7) subtypes with a small degree of selectivity. However, the in vivo antagonistic potency of dextrometorphan and dextrorphan in the pain tests does not correlate well with their in vitro blockade potency at expressed nAChR subtypes. Furthermore, the apparent in vivo selectivity of dextrometorphan over dextrorphan is not related to its in vitro potency and does suggest the involvement of other mechanisms. In that respect, dextrometorphan seems to behave as another mecamylamine, a noncompetitive nicotinic receptor antagonist with a preferential activity to alpha(3)beta(4)(*) neuronal nAChR subtypes.

    View details for DOI 10.1124/jpet.104.075093

    View details for Web of Science ID 000226367100043

    View details for PubMedID 15356218

  • Intranasal nicotine for postoperative pain treatment ANESTHESIOLOGY Flood, P., Daniel, D. 2004; 101 (6): 1417-1421


    Despite pharmacological treatment, 70-80% of patients report moderate to severe pain after surgery. Because nicotine has been reported to have analgesic properties in animal and human volunteer studies, the authors assessed the analgesic efficacy of a single 3 mg dose of nicotine nasal spray administered before emergence from general anesthesia.The authors conducted a randomized, double blind, placebo controlled trial of 20 healthy women (mean age 45 (SD 8) yr) who were to undergo uterine surgery through a low transverse incision. After the conclusion of surgery but before emergence from general anesthesia, the anesthesiologist administered either nicotine nasal spray or a placebo. Numerical analog pain score and morphine utilization and hemodynamic values were measured for 24 h.The patients treated with nicotine reported lower pain scores during the first hour after surgery (peak numerical analog score, 7.6 (SD 1.4) versus 5.3 (SD 1.6); P < 0.001) and used half the amount of morphine as the control group (12 (SD 6) versus 6 (SD 5) mg; P < 0.05). Patients who received nicotine still reported less pain than those in the control group 24 h after surgery (1.5 (SD 0.5) versus 4.9 (SD 1.4); P < 0.01). Systolic blood pressure was lower in the group that received nicotine (105 (SD 3) versus 122 (SD 3); P < 0.001), but there was no difference in diastolic blood pressure or heart rate.Treatment with a single dose of nicotine immediately before emergence from anesthesia was associated with significantly lower reported pain scores during the first day after surgery. The decreased pain was associated with a reduction in morphine utilization and the analgesic effect of nicotine was not associated with hypertension or tachycardia.

    View details for Web of Science ID 000225380200022

    View details for PubMedID 15564950

  • Single amino acid residue in the extracellular portion of transmembrane segment 2 in the nicotinic alpha 7 acetylcholine receptor modulates sensitivity to ketamine ANESTHESIOLOGY Ho, K. K., Flood, P. 2004; 100 (3): 657-662


    Ketamine inhibits the activation of both heteromeric and homomeric nicotinic acetylcholine receptors. The site of molecular interaction is unknown.The inhibition of alpha7 nicotinic acetylcholine receptors by ketamine was compared to that of 5-hydroxytryptamine-3A (5HT3A) receptors that are resistant to ketamine inhibition in Xenopus laevis oocytes. To determine whether the region of transmembrane segments 2 and 3 is relevant for ketamine inhibition of nicotinic receptors, the authors identified single amino acid residues that differ in the sequence alignment of the two proteins. They created 22 mutant alpha7 nicotinic receptors that contain the single homologous amino acid residue in the 5HT3A sequence.Of the 22 mutant alpha7 nicotinic receptors tested, only one (alpha7 A258S) was significantly resistant to 20 microM ketamine. The ketamine concentration response relationship for the alpha7 A258S mutant was shifted to the right with the IC50 for ketamine increased from 17 +/- 2 for wild type to 30 +/- 3 microM in the mutant (P < 0.001). Agonist activation was unchanged by the mutation. The homologous amino acid residue in the 5HT3A receptor was mutated to the alanine that occurs in the wild-type nicotinic receptor. This mutation made the previously insensitive 5HT3A receptor sensitive to ketamine (P < 0.001).Conservative mutation of a single amino acid in the extracellular transmembrane segment 2 domain induces resistance to ketamine inhibition in the alpha7 nicotinic receptor and sensitivity to inhibition in the 5HT3A receptor. This region may represent a ketamine binding site in the alpha7 nicotinic receptor, or it may be an important transduction site for ketamine action.

    View details for Web of Science ID 000189251700027

    View details for PubMedID 15108982

  • Inhaled anesthetics and immobility: Mechanisms, mysteries, and minimum alveolar anesthetic concentration ANESTHESIA AND ANALGESIA Sonner, J. M., Antognini, J. F., Dutton, R. C., Flood, P., Gray, A. T., Harris, R. A., Homanics, G. E., Kendig, J., Orser, B., Raines, D. E., Trudell, J., Vissel, B., Eger, E. I. 2003; 97 (3): 718-740


    Studies using molecular modeling, genetic engineering, neurophysiology/pharmacology, and whole animals have advanced our understanding of where and how inhaled anesthetics act to produce immobility (minimum alveolar anesthetic concentration; MAC) by actions on the spinal cord. Numerous ligand- and voltage-gated channels might plausibly mediate MAC, and specific amino acid sites in certain receptors present likely candidates for mediation. However, in vivo studies to date suggest that several channels or receptors may not be mediators (e.g., gamma-aminobutyric acid A, acetylcholine, potassium, 5-hydroxytryptamine-3, opioids, and alpha(2)-adrenergic), whereas other receptors/channels (e.g., glycine, N-methyl-D-aspartate, and sodium) remain credible candidates.

    View details for DOI 10.1213/01.ANE.0000081063.76651.33

    View details for Web of Science ID 000184890300025

    View details for PubMedID 12933393

  • Pronociceptive actions of isoflurane - A protective role for estrogen ANESTHESIOLOGY Flood, P., Daniel, D. 2003; 99 (2): 476-479


    Low concentrations of inhaled anesthetics present in the early postoperative period can increase pain sensitivity. Changes in pain threshold associated with inhaled anesthetics have been reported in male mice, rats, and humans.The authors compared the pain-enhancing effects of isoflurane in male and female mice in response to a thermal stimulus and studied the consequences of hormonal manipulation.Isoflurane produced a larger increase in pain sensitivity in female mice. Both castration and oophorectomy resulted in an increase in baseline pain sensitivity and potentiated pain enhancement by isoflurane. At stages of the estrus cycle when estrogen was low, female mice showed greater pain enhancement from isoflurane than at high estrogen stages. Treatment with exogenous estrogen reduced isoflurane-induced pain sensitivity. Exogenous testosterone treatment had a similar effect, which did not occur when enzymatic conversion to estrogen was prevented.Because both estrogen and testosterone reduce the pronociceptive action of isoflurane, intact females may exhibit a larger increase in pain sensitivity because of their cyclical estrogen levels. Testosterone is effective in the male because of conversion to estrogen. Enhanced pain sensitivity is clearly undesirable in the postoperative setting. If these findings also apply to humans, the menstrual cycle may be an important factor in determining pain levels after emergence from general anesthesia.

    View details for Web of Science ID 000184352400030

    View details for PubMedID 12883422

  • Volatile anesthetics reduce agonist affinity at nicotinic acetylcholine receptors in the brain ANESTHESIA AND ANALGESIA Rada, E. M., Tharakan, E. C., Flood, P. 2003; 96 (1): 108-111


    In previous studies we and others have demonstrated that the activation of nicotinic acetylcholine receptors (nAChRs) is inhibited by subanesthetic concentrations of volatile anesthetics. The mechanism by which activation is inhibited is unknown. Studies of the evolutionarily related nAChRs from the electric fish Torpedo have suggested that volatile anesthetics alter the affinity of the agonist for the receptor. We studied the effect of two volatile anesthetics, isoflurane and sevoflurane, on equilibrium binding of the high-affinity nicotinic agonist epibatidine to nicotinic receptors from mouse brain. We studied binding to male and female brain separately, because sex differences in nicotine responses have been reported. Male and female brains have equal epibatidine binding without anesthetic. Isoflurane and sevoflurane reduce the binding of [(3)H]epibatidine to male and female nicotinic receptors, but only at concentrations at and above those required for anesthesia. The 50% inhibitory concentration for isoflurane inhibition of [(3)H]epibatidine binding to male brain was 0.58 +/- 0.07 mM and to female brain was 1.62 +/- 0.30 mM. The 50% inhibitory concentration for sevoflurane inhibition of [(3)H]epibatidine binding to male brain was 0.77 +/- 0.05 mM and to female brain was 0.77 +/- 0.04 mM. There was no statistically significant difference in the effect of either drug between sexes (P > 0.05). Although there is a slight decrease in agonist affinity at anesthetic concentrations, the marked reductions in nAChR function at subanesthetic concentrations cannot be attributed to changes in agonist affinity.Volatile anesthetics reduce the activation of nicotinic acetylcholine receptors by an unknown mechanism. We have demonstrated that although isoflurane and sevoflurane inhibit agonist affinity, the concentrations required are too large to be responsible for the dynamic changes observed.

    View details for DOI 10.1213/01.ANE.0000041901.85266.92

    View details for Web of Science ID 000180169700023

    View details for PubMedID 12505934

  • Acetylcholine receptors and thresholds for convulsions from flurothyl and 1,2-dichlorohexafluorocyclobutane ANESTHESIA AND ANALGESIA Eger, E. I., Gong, D., Xing, Y. L., Raines, D. E., Flood, P. 2002; 95 (6): 1611-1615


    There are acetylcholine receptors throughout the central nervous system, and they may mediate some forms and aspects of convulsive activity. Most high-affinity binding sites on nicotinic acetylcholine receptors for nicotine, cytisine, and epibatidine in the brain contain the beta2 subunit of the receptor. Transitional inhaled compounds (compounds less potent than predicted from their lipophilicity and the Meyer-Overton hypothesis) and nonimmobilizers (compounds that do not produce immobility despite a lipophilicity that suggests anesthetic qualities as predicted from the Meyer-Overton hypothesis) can produce convulsions. The nonimmobilizer flurothyl [di-(2,2,2,-trifluoroethyl)ether] blocks the action of gamma-aminobutyric acid on gamma-aminobutyric acid(A) receptors, whereas the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N, also called F6) does not. 2N can block the action of acetylcholine on nicotinic acetylcholine receptors. We examined the relative capacities of these compounds to cause convulsions in mice having and lacking the beta2 subunit of the acetylcholine receptor. The partial pressure causing convulsions in half the mice (the 50% effective concentration [EC(50)]) was the same as in control mice. For the knockout mice, the EC(50) for flurothyl was 0.00170 +/- 0.00030 atm (mean +/- SD), and for 2N, it was 0.0345 +/- 0.0041 atm. For the control mice, the respective values were 0.00172 +/- 0.00057 atm and 0.0341 +/- 0.0048 atm. The ratio of the 2N to flurothyl EC(50) values was 20.8 +/- 3.5 for the knockout mice and 21.7 +/- 7.0 for the control mice. These results do not support the notion that acetylcholine receptors are important mediators of the capacity of 2N or flurothyl to cause convulsions. However, we also found that both nonimmobilizers inhibit rat alpha4beta2 neuronal nicotinic acetylcholine receptors at EC(50) partial pressures (0.00091 atm and 0.062 atm for flurothyl and 2N, respectively) that approximate those that produce convulsions (0.0015 atm and 0.04 atm).The results from the present study provide conflicting data concerning the notion that acetylcholine receptors mediate the capacity of nonimmobilizers to produce convulsions.

    View details for DOI 10.1213/01.ANE.0000033434.54946.87

    View details for Web of Science ID 000179646100026

    View details for PubMedID 12456426

  • Heteromeric nicotinic inhibition by isoflurane does not mediate MAC or loss of righting reflex ANESTHESIOLOGY Flood, P., Sonner, J. M., Gong, D., Coates, K. M. 2002; 97 (4): 902-905


    Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in the mechanism of action of isoflurane as they are inhibited at subanesthetic concentrations. Despite clear evidence for nicotinic inhibition at relevant isoflurane concentrations, it is unclear what behavioral result ensues, if any.The authors have modeled two behaviors common to all general anesthetics, immobility and hypnosis, as minimum alveolar concentration that prevents movement in response to a supramaximal stimulus (MAC) and loss of righting reflex (LORR). They have tested the ability of nicotinic pharmacologic modulators and congenital absence of most heteromeric nAChRs to affect concentration of isoflurane required for these behaviors.Neither mecamylamine, 5 mg/kg, nor chlorisondamine, 10 mg/kg, affected isoflurane MAC. Nicotine caused a small decrease in MAC. None of the above agents had any effect on the concentration of isoflurane required for LORR. Mice genetically engineered to lack the beta 2 nicotinic gene product were not different in MAC or LORR from controls.Nicotinic antagonists do not cause MAC or LORR. Inhibition of nicotinic acetylcholine receptors by isoflurane is not likely related to its ability to provide immobility and hypnosis in a surgical setting. This is perhaps not surprising as the inhibition of nAChRs in vitro is complete at an isoflurane concentration equal to one half of MAC. Nicotinic inhibition may, however, be involved in anesthetic behaviors such as amnesia and analgesia, which occur at lower anesthetic concentrations.

    View details for Web of Science ID 000178409800022

    View details for PubMedID 12357157

  • Sensitivity of the alpha 7 nicotinic acetylcholine receptor to isoflurane may depend on receptor inactivation ANESTHESIA AND ANALGESIA Flood, P., Coates, K. M. 2002; 95 (1): 83-87


    In previous studies, we demonstrated that nicotinic acetylcholine receptors (nAChRs) composed of the alpha7 subunit are unaffected by the co-application of isoflurane with agonists at concentrations up to 640 microM (two times the minimum alveolar anesthetic concentration). Modulation of alpha7-nAChR activity by isoflurane might have important behavioral ramifications because these receptors are expressed diffusely in the central and peripheral nervous systems and play pre- and postsynaptic roles in synaptic transmission. Here we have demonstrated that under some potentially physiologically relevant circumstances, the activation of alpha7 nAChRs may be inhibited by clinically relevant concentrations of isoflurane. We evaluated isoflurane inhibition of alpha7 nAChRs from chicks and humans expressed in Xenopus oocytes using two-electrode voltage clamp methodology. We determined the influence of time of preperfusion of isoflurane, agonist concentration, and membrane potential on inhibition by isoflurane. Both activation by a large concentration of agonist and isoflurane preperfusion increased inhibition. The half-maximal inhibitory concentration for isoflurane inhibition of chick alpha7 nAChR with isoflurane preperfusion and activation by 100 microM of acetylcholine was 938 +/- 26, and when activated by 1 mM of acetylcholine, it was 408 +/- 51 microM. The increase in inhibition with isoflurane preexposure and large agonist concentration raises the possibility that isoflurane interacts preferentially with a closed or closed-desensitized state of the channel.Nicotinic receptors expressed in the brain have been considered a possible target for the actions of isoflurane. We studied the effect of isoflurane on alpha7 type nicotinic receptors expressed in Xenopus oocytes. We find that when activated by large concentrations of acetylcholine, alpha7 nicotinic receptors are inhibited by isoflurane at concentrations near MAC.

    View details for DOI 10.1213/01.ANE.0000020692.65934.FE

    View details for Web of Science ID 000176634100015

    View details for PubMedID 12088948

  • Isofurane hyperalgesia is modulated by nicotinic inhibition ANESTHESIOLOGY Flood, P., Sonner, J. M., Gong, D., Coates, K. M. 2002; 97 (1): 192-198


    The inhaled anesthetic isoflurane inhibits neuronal nicotinic acetylcholine receptors (nAChRs) at concentrations lower than those used for anesthesia. Isoflurane produces biphasic nociceptive responses, with both hyperalgesia and analgesia within this concentration range. Because nicotinic agonists act as analgesics, the authors hypothesized that inhibition of nicotinic transmission by isoflurane causes hyperalgesia.The authors studied female mice at 6-8 weeks of age. They measured hind paw withdrawal latency at isoflurane concentrations from 0 to 0.98 vol% after the animals had received a nicotinic agonist (nicotine), a nicotinic antagonist (mecamylamine or chlorisondamine), or saline intraperitoneally. In addition, the authors tested the interactions between mecamylamine and isoflurane and nicotine and isoflurane in heterologously expressed alpha(4)beta(2) nAChRs.Female mice had significant hyperalgesia from isoflurane. Nicotine administration prevented isoflurane-induced hyperalgesia without altering the antinociception produced by higher isoflurane concentrations. Mecamylamine treatment caused a biphasic nociceptive response similar to that caused by isoflurane. Mecamylamine and isoflurane had an additive effect, both at heterologously expressed alpha(4)beta(2) nAChRs and on the production of hyperalgesia in vivo. Mecamylamine thus potentiated hyperalgesia but did not affect analgesia.Since hyperalgesia occurs in vivo at isoflurane doses that antagonize nAChRs in vitro, is prevented by a nicotinic agonist, and is mimicked and potentiated by nicotinic antagonists, the authors conclude that isoflurane inhibition of nAChRs activation is involved in the pathway that causes hyperalgesia. At subanesthetic doses, isoflurane can either enhance pain responses (produce hyperalgesia) or be analgesic (antinociceptive). In rats, low volatile anesthetic concentrations (0.1-0.2 minimum alveolar concentration [MAC]) elicit hyperalgesia, while 0.4-0.6 MAC elicits antinociception.

    View details for Web of Science ID 000176590800026

    View details for PubMedID 12131122

  • Acetylcholine receptors do not mediate the immobilization produced by inhaled anesthetics ANESTHESIA AND ANALGESIA Eger, E. I., Zhang, Y., Laster, M., Flood, P., Kendig, J. J., Sonner, J. M. 2002; 94 (6): 1500-1504


    Acetylcholine receptors transmit excitatory impulses, are broadly distributed throughout the central nervous system, and are particularly sensitive to the depressant effects of inhaled anesthetics. Thus these receptors are potential mediators of the immobility produced by inhaled anesthetics. We tested this potential in rats by giving intraperitoneal atropine, scopolamine, and mecamylamine to block muscarinic (atropine and scopolamine) and neuronal nicotinic (mecamylamine) acetylcholine receptors. Block with scopolamine (up to 100 mg/kg), atropine (10 mg/kg), mecamylamine (up to 4 mg/kg), or atropine (10 mg/kg) plus mecamylamine (up to 4 mg/kg) did not significantly decrease the isoflurane concentration required to suppress movement to noxious stimulation (minimum alveolar anesthetic concentration). We also gave atropine intrathecally, finding that the infusions that did not cause permanent paralysis produced slight or no decreases in the minimum alveolar anesthetic concentration. We conclude that acetylcholine receptors do not seem to play a role as mediators of immobilization by inhaled anesthetics.Inhaled anesthetics produce two crucial effects: amnesia and immobility in the face of noxious stimulation. Block of muscarinic and neuronal nicotinic acetylcholine receptors in rats does not significantly decrease the isoflurane concentration required to suppress movement to stimulation. Thus, acetylcholine receptors do not seem to play a major role as mediators of the immobilization produced by inhaled anesthetics. Their capacity to mediate other effects of inhaled anesthetics (e.g., amnesia) remains to be tested.

    View details for Web of Science ID 000175890900024

    View details for PubMedID 12032015

  • Postdural puncture headache in obstetrics SEMINARS IN PERINATOLOGY Flood, P. 2002; 26 (2): 146-153


    Postdural puncture headache (PDPH; or "spinal headache) is the most common significant complication from regional anesthesia or analgesia in obstetrics. Recent advances in spinal needle design have dramatically decreased the incidence of headache after spinal anesthesia, and now the most common cause of PDPH is inadvertent puncture of the dura with an epidural needle. The diagnosis and treatment of a PDPH should usually be the responsibility of the anesthesiologist, but it is important for the obstetrician to be familiar with the clinical course and options for therapy, and the usual treatment strategies. This article discusses the differential diagnosis of postdelivery headache, the current understanding of the pathophysiology of PDPH, options for medical treatment, and the controversial issue of whether and when to treat the headache with an epidural blood patch.

    View details for DOI 10.1053/sper.2002.32205

    View details for Web of Science ID 000175217000006

    View details for PubMedID 12005472

  • Droperidol inhibits GABA(A) and neuronal nicotinic receptor activation ANESTHESIOLOGY Flood, P., Coates, K. M. 2002; 96 (4): 987-993


    Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because gamma-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors.gamma-Aminobutyric acid type A alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 microm to modulate activation of these receptors by their native agonists.Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 microm) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant.Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.

    View details for Web of Science ID 000174716900028

    View details for PubMedID 11964609

  • Advances in neurobiology of the neuromuscular junction - Implications for the anesthesiologist ANESTHESIOLOGY Naguib, M., Flood, P., McArdle, J. J., Brenner, H. R. 2002; 96 (1): 202-231

    View details for Web of Science ID 000173086000031

    View details for PubMedID 11753022

  • Behavioral results of isoflurane inhibition of neuronal nicotinic acetylcholine receptors 6th International Conference on Molecular and Basic Mechanisms of Anesthesia Flood, P., Sonner, J. M. PABST SCIENCE PUBLISHERS. 2002: 88–93
  • Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant alpha 7 and alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes BRITISH JOURNAL OF PHARMACOLOGY Coates, K. M., Flood, P. 2001; 134 (4): 871-879


    1. Ketamine is a dissociative anaesthetic that is formulated as Ketalar, which contains the preservative benzethonium chloride (BCl). We have studied the effects of pure racemic ketamine, the preservative BCl and the Ketalar mixture on human neuronal nicotinic acetylcholine receptors (nAChRs) composed of the alpha7 subunit or alpha4 and beta2 subunits expressed in Xenopus laevis oocytes. 2. Ketamine inhibited responses to 1 mM acetylcholine (ACh) in both the human alpha7 and alpha4beta2 nAChRs, with IC(50) values of 20 and 50 microM respectively. Inhibition of the alpha7 nAChRs occurred within a clinically relevant concentration range, while inhibition of the alpha4beta2 nAChR was observed only at higher concentrations. The Ketalar formulation inhibited nAChR function more effectively than was expected given its ketamine concentration. The surprising increased inhibitory potency of Ketalar compared with pure ketamine appeared to be due to the activity of BCl, which inhibited both alpha7 (IC(50) value of 122 nM) and alpha4beta2 (IC(50) value of 49 nM) nAChRs at concentrations present in the clinical formulation of Ketalar. 3. Ketamine is a noncompetitive inhibitor at both the alpha7 and alpha4beta2 nAChR. In contrast, BCl causes a parallel shift in the ACh dose-response curve at the alpha7 nAChR suggesting competitive inhibition. Ketamine causes both voltage-dependent and use-dependent inhibition, only in the alpha4beta2 nAChR. 4. Since alpha7 nAChRs are likely to be inhibited during clinical use of Ketalar, the actions of ketamine and BCl on this receptor subtype may play a role in the profound analgesia, amnesia, immobility and/or autonomic modulation produced by this anaesthetic.

    View details for Web of Science ID 000171645100020

    View details for PubMedID 11606328

    View details for PubMedCentralID PMC1573008

  • General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Krasowski, M. D., Jenkins, A., Flood, P., Kung, A. Y., HOPFINGER, A. J., Harrison, N. L. 2001; 297 (1): 338-351


    A series of 27 analogs of the general anesthetic propofol (2,6-diisopropylphenol) were examined for general anesthetic activity in Xenopus laevis tadpoles and for the ability to produce enhancement of submaximal GABA responses and/or direct activation at recombinant GABA(A) receptors. Fourteen of the propofol analogs produced loss of righting reflex in the tadpoles, whereas 13 were inactive as anesthetics. The same pattern of activity was noted with the actions of the compounds at the GABA(A) alpha(1)beta(2)gamma(2s) receptor. The potencies of the analogs as general anesthetics in tadpoles correlated better with potentiation of GABA responses than direct activation at the GABA(A) alpha(1)beta(2)gamma(2s) receptor. The calculated octanol/water partition coefficients for the analogs did not explain the lack of activity exhibited by the 13 nonanesthetic analogs, although this physicochemical parameter did correlate modestly with in vivo anesthetic potency. The actions of one nonanesthetic analog, 2,6-di-tert-butylphenol, were examined in detail. 2,6-Di-tert-butylphenol was inactive at GABA(A) receptors, did not function as an anesthetic in the tadpoles, and did not antagonize any of the actions of propofol at GABA(A) receptors or in tadpoles. A key influence on the potency of propofol analogs appears to be the size and shape of the alkyl groups at positions 2 and 6 of the aromatic ring relative to the substituent at position 1. These data suggest steric constraints for the binding site for propofol on the GABA(A) receptor.

    View details for Web of Science ID 000167756700041

    View details for PubMedID 11259561

  • Thiopental is a competitive inhibitor at the human alpha 7 nicotinic acetylcholine receptor ANESTHESIA AND ANALGESIA Coates, K. M., Mather, L. E., Johnson, R., Flood, P. 2001; 92 (4): 930-933


    The nicotinic acetylcholine receptors (nAChRs) in the central nervous system may be a potential target for the anesthetic effects of thiopental. We evaluated the mechanism of action of thiopental on the human alpha7 nAChR by using 2-electrode voltage clamp methodology. Concentration response curves for agonist were prepared in the presence of 25-250 microM of thiopental. Inhibition by the S- and R-thiopental enantiomers was compared with inhibition by racemic thiopental. We found that thiopental acts as a competitive inhibitor at the human alpha7 nAChR. Inhibition is independent of membrane potential and the K(i(apparent)) is 13 microM of thiopental. The clinical 50% effective concentration for thiopental in humans is 25 microM. Thus, with a K(i(apparent)) of 13 microM, inhibition of the human alpha7 nAChR is within a clinically relevant range. The S- and R-enantiomers of thiopental cause inhibition indistinguishable from the inhibition caused by racemic thiopental. This discordance makes it unlikely that the alpha7 nAChR plays a role in loss of righting reflex induced by thiopental in mice, although nicotinic inhibition by thiopental may mediate other anesthetic effects and side effects.The receptors for nicotine in the brain may be involved in the mechanism of general anesthetics. We have shown that a human receptor for nicotine is inhibited by the anesthetic barbiturate thiopental, at concentrations used clinically. The nicotinic receptor thus may mediate some of the actions of this drug.

    View details for Web of Science ID 000167633200026

    View details for PubMedID 11273929

  • Intravenous anesthetics differentially modulate ligand-gated ion channels ANESTHESIOLOGY Flood, P., Krasowski, M. D. 2000; 92 (5): 1418-1425


    Heteromeric neuronal nicotinic acetylcholine receptors (nAChRs) are potently inhibited by volatile anesthetics, but it is not known whether they are affected by intravenous anesthetics. Ketamine potentiates gamma-aminobutyric acid type A (GABAA) receptors at high concentrations, but it is unknown whether there is potentiation at clinically relevant concentrations. Information about the effects of intravenous anesthetics with different behavioral profiles on specific ligand-gated ion channels may lead to hypotheses as to which ion channel effect produces a specific anesthetic behavior.A heteromeric nAChR composed of alpha4 and beta4 subunits was expressed heterologously in Xenopus laevis oocytes. Using the two-electrode voltage clamp technique, peak ACh-gated current was measured before and during application of ketamine, etomidate, or thiopental. The response to GABA of alpha1beta2gamma2s GABAA receptors expressed in human embryonic kidney cells and Xenopus oocytes was compared with and without coapplication of ketamine from 1 microm to 10 mm.Ketamine caused potent, concentration-dependent inhibition of the alpha4beta4 nAChR current with an IC50 of 0.24 microm. The inhibition by ketamine was use-dependent; the antagonist was more effective when the channel had been opened by agonist. Ketamine did not modulate the alpha1beta2gamma2s GABAA receptor response in the clinically relevant concentration range. Thiopental caused 27% inhibition of ACh response at its clinical EC50. Etomidate did not modulate the alpha4beta4 nAChR response in the clinically relevant concentration range, although there was inhibition at very high concentrations.The alpha4beta4 nAChR, which is predominantly found in the central nervous system (CNS), is differentially affected by clinically relevant concentrations of intravenous anesthetics. Ketamine, commonly known to be an inhibitor at the N-methyl-D-aspartate receptor, is also a potent inhibitor at a central nAChR. It has little effect on a common CNS GABAA receptor in a clinically relevant concentration range. Interaction between ketamine and specific subtypes of nAChRs in the CNS may result in anesthetic behaviors such as inattention to surgical stimulus and in analgesia. Thiopental causes minor inhibition at the alpha4beta4 nAChR. Modulation of the alpha4beta4 nAChR by etomidate is unlikely to be important in anesthesia practice based on the insensitivity of this receptor to clinically used concentrations.

    View details for Web of Science ID 000086867100029

    View details for PubMedID 10781289

  • Droperidol suppresses spontaneous electrical activity in neurons cultured from ventral midbrain - Implications for neuroleptanesthesia BRAIN RESEARCH Heyer, E. J., Flood, P. 2000; 863 (1-2): 20-24


    Droperidol is used in anesthesia as an antiemetic and as a component in neuroleptanalgesia. Its mechanism of action is thought to involve dopamine receptor blockade in the brain. The electrophysiological consequences associated with this action however, have not been elucidated. In this study we demonstrate a dose-dependent electrophysiological response to droperidol in central nervous system (CNS) neurons that express dopamine receptors that is absent in CNS neurons that do not express dopamine receptors. Primary dissociated cell (PDC) cultures were prepared from embryonal tissue dissected from ventral mesencephalon (VM) and spinal cord (SC). VM neurons were used to investigate the electrophysiological action of droperidol, a dopamine receptor antagonist, since these cultures contain neurons having dopamine receptors on their surface. SC neurons were used as a control as they do not express dopamine receptors. Some dopamine receptors are on dopaminergic neurons and therefore are called autoreceptors, while others are on nondopaminergic neurons, such as GABA producing (GABAergic) neurons. All neurons in both PDC cultures were spontaneously active. The percentage of neurons which spontaneously generated action potentials was reduced in a dose-dependent manner by droperidol (1 nM-10 microM) only in PDC cultures of VM. Exposure to droperidol had no effect on neurons from PDC cultures of SC which lack dopamine receptors. Our results suggest that droperidol modulates the electrophysiological properties of VM neurons with dopamine receptors possibly through facilitation of inhibitory interneurons. The reduced activity of VM neurons might contribute to the antiemetic and/or anesthetic activity of droperidol, since the concentrations of droperidol used in this study are at clinically relevant concentrations.

    View details for Web of Science ID 000086747800003

    View details for PubMedID 10773189

  • Neuronal nicotinic acetylcholine receptor modulation by general anesthetics. Toxicology letters Flood, P., Role, L. W. 1998; 100-101: 149-153


    1. General anesthetics have been shown to inhibit synaptic transmission in multiple areas of the central and peripheral nervous systems. 2. The mechanism of inhibition is not well understood. 3. It has become clear that general anesthetics modulate the function of members of the ligand gated ion channel superfamily, including receptors for GABA(A), glycine (Harrison et al., Mol. Pharmacol. 44(3), 1993, 628-632) and 5HT3 (Zhou and Lovinger, J. Pharmacol. Exp. Therap. 278(2), 1996, 732-740). 4. Studies of the activity of general anesthetics on recombinant neuronal nicotinic acetylcholine receptors have added this receptor family to those potently inhibited by general anesthetics (Flood et al., Anesthesiology 86(4), 1997, 859-865; Violet et al., Anesthesiology 86(4), 1997, 866-874). 5. Studies of neuronal nicotinic receptors in native neurons suggest that the inhibition of these receptors by general anesthetics at low clinical concentrations may be biologically significant (Nicoll, Science 199(4327), 1978, 451-452). 6. Recent work on neuronal nicotinic acetylcholine receptors in the central nervous system suggests that their primary role may be to modulate synaptic transmission (Role and Berg, Neuron 16(6), 1996, 1077-1085). 7. Thus, inhibition of nicotinic modulation in the central nervous system may result in inhibition of synaptic transmission and some of the behavioral consequences of general anesthesia.

    View details for PubMedID 10049135

  • Neuronal nicotinic acetylcholine receptor modulation by general anesthetics 5th International Conference on Molecular and Cellular Mechanisms of Anaesthesia Flood, P., Role, L. W. ELSEVIER IRELAND LTD. 1998: 149–153
  • alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected ANESTHESIOLOGY Flood, P., RamirezLatorre, J., Role, L. 1997; 86 (4): 859-865


    The mechanisms of action of general anesthetics are not completely understood. Many general anesthetics are reported to potentiate gamma-aminobutyric acid (GABAA) and glycine receptors in the central nervous system (CNS) and to inhibit the muscle-type nicotinic acetylcholine receptor (nAChR). The effects of general anesthetics on another family of ligand-gated ion channel in the CNS, the nAChRs, have not been defined.Two types of CNS acetylcholine receptor, the alpha 4 beta 2 receptor or the alpha 7 homomeric receptor, were expressed heterologously in Xenopus laevis oocytes. Using the standard two-microelectrode voltage-clamp technique, peak acetylcholinegated current was measured before and after coapplication of isoflurane or propofol.Coapplication of either isoflurane or propofol with acetylcholine resulted in potent, dose-dependent inhibition of the alpha 4 beta 2 receptor current with median inhibitory concentrations of 85 and 19 microM, respectively. The inhibition of the alpha 4 beta 2 receptor by both isoflurane and propofol appears to be competitive with respect to acetylcholine. The alpha 7 receptor current was not effected by either anesthetic.The CNS-type nAChRs are differentially affected by isoflurane and propofol. The alpha 4 beta 2 receptor is affected by isoflurane more potently than the most sensitive GABAA or glycine receptor that has been reported, whereas the alpha 7 homomeric receptor is not affected by either anesthetic. Inhibition of specific subtypes of nAChRs in the CNS, along with potentiation of GABAA and glycine receptors, may contribute to the effects and side effects of general anesthetics.

    View details for Web of Science ID A1997WT00800018

    View details for PubMedID 9105230



    To determine whether the risk factors for dementia in idiopathic Parkinson's disease (IPD) are similar to the risk factors for Alzheimer's disease, we conducted a case-control study of potential risk factors. A structured interview was administered to surrogates of 17 demented subjects with IPD and 54 nondemented subjects. Two factors emerged as possible risks for dementia. Demented patients were older than nondemented patients, although the duration of symptoms was similar. A family history of dementia was present in 30% of the demented group and 5.6% of the nondemented group. Dementia was most often reported among siblings. No difference was seen in toxic and occupational exposure, personal habits, or medical or surgical illnesses. We conclude that dementia in IPD shares some common risk factors with Alzheimer's disease. Efforts to assess the contribution of genetic susceptibility or shared environmental influences may clarify the relationship between these two diseases.

    View details for Web of Science ID A1990CV85100011

    View details for PubMedID 2325678