- Traumatic Brain Injury
- Cerebrovascular Circulation
Fellowship: UCSF Dept of Neurology (2012) CA
Residency, Johns Hopkins University, Neurology (2010)
Internship, Stanford University, Internal Medicine (2007)
MD, Stanford University (2006)
Board Certification: Neurocritical Care, United Council for Neurologic Subspecialties (2013)
Board Certification: Neurology, American Board of Psychiatry and Neurology (2010)
Current Research and Scholarly Interests
Dr. Karen G. Hirsch cares for critically ill patients with neurologic disorders in the intensive care unit and for patients with cerebrovascular disease in the inpatient stroke unit. Dr. Hirsch's research focuses on novel imaging techniques such as functional brain imaging in patients with cardiac arrest and traumatic brain injury. She also studies methods of non-invasive measurement of cerebral blood flow, oxygenation, and cerebrovascular autoregulation and how these parameters might be targeted to improve outcome in patients with neurologic injury. In the outpatient clinic, she sees patients with head injury, stroke and other neurovascular diseases in addition to patients who have been discharged from the neurological intensive care unit.
Prognostic value of diffusion-weighted MRI for post-cardiac arrest coma.
OBJECTIVE: To validate quantitative diffusion-weighted imaging (DWI) MRI thresholds that correlate with poor outcome in comatose cardiac arrest survivors, we conducted a clinician-blinded study and prospectively obtained MRIs from comatose patients after cardiac arrest.METHODS: Consecutive comatose post-cardiac arrest adult patients were prospectively enrolled. MRIs obtained within 7 days after arrest were evaluated. The clinical team was blinded to the DWI MRI results and followed a prescribed prognostication algorithm. Apparent diffusion coefficient (ADC) values and thresholds differentiating good and poor outcome were analyzed. Poor outcome was defined as a Glasgow Outcome Scale score of ≤2 at 6 months after arrest.RESULTS: Ninety-seven patients were included, and 75 patients (77%) had MRIs. In 51 patients with MRI completed by postarrest day 7, the prespecified threshold of >10% of brain tissue with an ADC <650 *10-6 mm2/s was highly predictive for poor outcome with a sensitivity of 0.63 (95% confidence interval [CI] 0.42-0.80), a specificity of 0.96 (95% CI 0.77-0.998), and a positive predictive value (PPV) of 0.94 (95% CI 0.71-0.997). The mean whole-brain ADC was higher among patients with good outcomes. Receiver operating characteristic curve analysis showed that ADC <650 *10-6 mm2/s had an area under the curve of 0.79 (95% CI 0.65-0.93, p < 0.001). Quantitative DWI MRI data improved prognostication of both good and poor outcomes.CONCLUSIONS: This prospective, clinician-blinded study validates previous research showing that an ADC <650 *10-6 mm2/s in >10% of brain tissue in an MRI obtained by postarrest day 7 is highly specific for poor outcome in comatose patients after cardiac arrest.
View details for DOI 10.1212/WNL.0000000000009289
View details for PubMedID 32269116
- A Standardized Checklist Improves the Transfer of Stroke Patients from the Neurocritical Care Unit to Hospital Ward NEUROHOSPITALIST 2020; 10 (2): 100–108
Global Survey of Outcomes of Neurocritical Care Patients: Analysis of the PRINCE Study Part 2
2020; 32 (1): 88–103
Neurocritical care is devoted to the care of critically ill patients with acute neurological or neurosurgical emergencies. There is limited information regarding epidemiological data, disease characteristics, variability of clinical care, and in-hospital mortality of neurocritically ill patients worldwide. We addressed these issues in the Point PRevalence In Neurocritical CarE (PRINCE) study, a prospective, cross-sectional, observational study.We recruited patients from various intensive care units (ICUs) admitted on a pre-specified date, and the investigators recorded specific clinical care activities they performed on the subjects during their first 7 days of admission or discharge (whichever came first) from their ICUs and at hospital discharge. In this manuscript, we analyzed the final data set of the study that included patient admission characteristics, disease type and severity, ICU resources, ICU and hospital length of stay, and in-hospital mortality. We present descriptive statistics to summarize data from the case report form. We tested differences between geographically grouped data using parametric and nonparametric testing as appropriate. We used a multivariable logistic regression model to evaluate factors associated with in-hospital mortality.We analyzed data from 1545 patients admitted to 147 participating sites from 31 countries of which most were from North America (69%, N = 1063). Globally, there was variability in patient characteristics, admission diagnosis, ICU treatment team and resource allocation, and in-hospital mortality. Seventy-three percent of the participating centers were academic, and the most common admitting diagnosis was subarachnoid hemorrhage (13%). The majority of patients were male (59%), a half of whom had at least two comorbidities, and median Glasgow Coma Scale (GCS) of 13. Factors associated with in-hospital mortality included age (OR 1.03; 95% CI, 1.02 to 1.04); lower GCS (OR 1.20; 95% CI, 1.14 to 1.16 for every point reduction in GCS); pupillary reactivity (OR 1.8; 95% CI, 1.09 to 3.23 for bilateral unreactive pupils); admission source (emergency room versus direct admission [OR 2.2; 95% CI, 1.3 to 3.75]; admission from a general ward versus direct admission [OR 5.85; 95% CI, 2.75 to 12.45; and admission from another ICU versus direct admission [OR 3.34; 95% CI, 1.27 to 8.8]); and the absence of a dedicated neurocritical care unit (NCCU) (OR 1.7; 95% CI, 1.04 to 2.47).PRINCE is the first study to evaluate care patterns of neurocritical patients worldwide. The data suggest that there is a wide variability in clinical care resources and patient characteristics. Neurological severity of illness and the absence of a dedicated NCCU are independent predictors of in-patient mortality.
View details for DOI 10.1007/s12028-019-00835-z
View details for Web of Science ID 000512861100004
View details for PubMedID 31486027
- Will We Ever Make Headway in Severe Traumatic Brain Injury Treatment Trials? JAMA neurology 2020
Unsupervised learning of early post-arrest brain injury phenotypes.
Trials may be neutral when they do not appropriately target the experimental intervention. We speculated multimodality assessment of early hypoxic-ischemic brain injury would identify phenotypes likely to benefit from therapeutic interventions.We performed a retrospective study including comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) by one of 126 emergency medical services or in-hospital arrest at one of 26 hospitals from 2011 to 2019. All patients were ultimately transported to a single tertiary center for care including standardized initial neurological examination, brain imaging and electroencephalography; targeted temperature management (TTM); hemodynamic optimization targeting mean arterial pressure (MAP) >80mmHg; and, coronary angiography for clinical suspicion for acute coronary syndrome. We used unsupervised learning to identify brain injury phenotypes defined by admission neurodiagnostics. We tested for interactions between phenotype and TTM, hemodynamic management and cardiac catheterization in models predicting recovery.We included 1,086 patients with mean (SD) age 58 (17) years of whom 955 (88%) were resuscitated from OHCA. Survival to hospital discharge was 27%, and 248 (23%) were discharged with Cerebral Performance Category (CPC) 1-3. We identified 5 clusters defining distinct brain injury phenotypes, each comprising 14% to 30% of the cohort with discharge CPC 1-3 in 59% to<1%. We found significant interactions between cluster and TTM strategy (P=0.01), MAP (P<0.001) and coronary angiography (P=0.04) in models predicting outcomes.We identified patterns of early hypoxic-ischemic injury based on multiple diagnostic modalities that predict responsiveness to several therapeutic interventions recently tested in neutral clinical trials.
View details for DOI 10.1016/j.resuscitation.2020.05.051
View details for PubMedID 32531403
Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients.
Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety.The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy.The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy.The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema.
View details for DOI 10.1007/s12028-020-00959-7
View details for PubMedID 32227294
A Standardized Checklist Improves the Transfer of Stroke Patients from the Neurocritical Care Unit to Hospital Ward.
2020; 10 (2): 100–108
The transfer of patients with ischemic stroke from the intensive care unit (ICU) to noncritical care inpatient wards involves detailed information sharing between care teams. Our local transfer process was not standardized, leading to potential patient risk. We developed and evaluated an "ICU Transfer Checklist" to standardize communication between the neurocritical care team and the stroke ward team.Retrospective review of consecutive patients with ischemic stroke admitted to the neurocritical care unit who were transferred to the stroke ward was used to characterize transfer documentation. A multidisciplinary team developed and implemented an ICU Transfer Checklist that contained a synthesis of the patient's clinical course, immediate "to-do" action items, and a system-based review of active medical problems. Postintervention checklist utilization was recorded for 8 months, and quality metrics for the postintervention cohort were compared to the preintervention cohort. Providers were surveyed pre- and postintervention to characterize perceived workflow and quality of care.Patients before (n = 52) and after (n = 81) ICU Transfer Checklist implementation had similar demographic and clinical characteristics. In the postchecklist implementation period, the ICU Transfer Checklist was used in over 85% of patients and median hospital length of stay (LOS) decreased (8.6 days vs 5.4 days, P = .003), while ICU readmission rate remained low. The checklist was associated with improved perceptions of safety and decreased time needed to transfer patients.Use of the standardized ICU Transfer Checklist was associated with decreased hospital LOS and with improvements in providers' perceptions of patient safety.
View details for DOI 10.1177/1941874419873810
View details for PubMedID 32373272
View details for PubMedCentralID PMC7191660
2019 American Heart Association Focused Update on Systems of Care: Dispatcher-Assisted Cardiopulmonary Resuscitation and Cardiac Arrest Centers An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
2019; 140 (24): E895–E903
Survival after out-of-hospital cardiac arrest requires an integrated system of care (chain of survival) between the community elements responding to an event and the healthcare professionals who continue to care for and transport the patient for appropriate interventions. As a result of the dynamic nature of the prehospital setting, coordination and communication can be challenging, and identification of methods to optimize care is essential. This 2019 focused update to the American Heart Association systems of care guidelines summarizes the most recent published evidence for and recommendations on the use of dispatcher-assisted cardiopulmonary resuscitation and cardiac arrest centers. This article includes the revised recommendations that emergency dispatch centers should offer and instruct bystanders in cardiopulmonary resuscitation during out-of-hospital cardiac arrest and that a regionalized approach to post-cardiac arrest care may be reasonable when comprehensive postarrest care is not available at local facilities.
View details for DOI 10.1161/CIR.0000000000000733
View details for Web of Science ID 000508367200005
View details for PubMedID 31722563
2019 American Heart Association Focused Update on Advanced Cardiovascular Life Support Use of Advanced Airways, Vasopressors, and Extracorporeal Cardiopulmonary Resuscitation During Cardiac Arrest An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
2019; 140 (24): E881–E894
The fundamentals of cardiac resuscitation include the immediate provision of high-quality cardiopulmonary resuscitation combined with rapid defibrillation (as appropriate). These mainstays of therapy set the groundwork for other possible interventions such as medications, advanced airways, extracorporeal cardiopulmonary resuscitation, and post-cardiac arrest care, including targeted temperature management, cardiorespiratory support, and percutaneous coronary intervention. Since 2015, an increased number of studies have been published evaluating some of these interventions, requiring a reassessment of their use and impact on survival from cardiac arrest. This 2019 focused update to the American Heart Association advanced cardiovascular life support guidelines summarizes the most recent published evidence for and recommendations on the use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest. It includes revised recommendations for all 3 areas, including the choice of advanced airway devices and strategies during cardiac arrest (eg, bag-mask ventilation, supraglottic airway, or endotracheal intubation), the training and retraining required, the administration of standard-dose epinephrine, and the decisions involved in the application of extracorporeal cardiopulmonary resuscitation and its potential impact on cardiac arrest survival.
View details for DOI 10.1161/CIR.0000000000000732
View details for Web of Science ID 000508367200004
View details for PubMedID 31722552
Functional outcomes associated with varying levels of targeted temperature management after out-of-hospital cardiac arrest - An INTCAR2 registry analysis.
INTRODUCTION: Targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) has been recommended in international guidelines since 2005. The TTM-trial published in 2013 showed no difference in survival or neurological outcome for patients randomised to 33°C or 36°C, and many hospitals have changed practice. The optimal utilization of TTM is still debated. This study aimed to analyse if a difference in temperature goal was associated with outcome in an unselected international registry population.METHODS: This is a retrospective observational study based on a prospective registry - the International Cardiac Arrest Registry 2. Patients were categorized as receiving TTM in the lower range at 32-34°C (TTM-low) or at 35-37°C (TTM-high). Primary outcome was good functional status defined as cerebral performance category (CPC) of 1-2 at hospital discharge and secondary outcome was adverse events related to TTM. A logistic regression model was created to evaluate the independent effect of temperature by correcting for clinical and demographic factors associated with outcome.RESULTS: Of 1710 patients included, 1242 (72,6%) received TTM-low and 468 (27,4%) TTM-high. In patients receiving TTM-low, 31.3% survived with good outcome compared to 28.8% in the TTM-high group. There was no significant association between temperature and outcome (p=0.352). In analyses adjusted for baseline differences the OR for a good outcome with TTM-low was 1.27, 95% CI (0.94-1.73). Haemodynamic instability leading to discontinuation of TTM was more common in TTM-low.CONCLUSIONS: No significant difference in functional outcome at hospital discharge was found in patients receiving lower- versus higher targeted temperature management.
View details for DOI 10.1016/j.resuscitation.2019.10.020
View details for PubMedID 31706964
- Correction to: Variability in functional outcome and treatment practices by treatment center after out-of-hospital cardiac arrest: analysis of International Cardiac Arrest Registry. Intensive care medicine 2019
- Early withdrawal of life support after resuscitation from cardiac arrest is common and may result in additional deaths RESUSCITATION 2019; 139: 308–13
- Translating Protective Hypothermia During Cardiac Arrest Into Clinical Practice JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 2019; 321 (17): 1673–75
- Variability in functional outcome and treatment practices by treatment center after out-of-hospital cardiac arrest: analysis of International Cardiac Arrest Registry INTENSIVE CARE MEDICINE 2019; 45 (5): 637–46
Variability in functional outcome and treatment practices by treatment center after out-of-hospital cardiac arrest: analysis of International Cardiac Arrest Registry.
Intensive care medicine
PURPOSE: Functional outcomes vary between centers after out-of-hospital cardiac arrest (OHCA) and are partially explained by pre-existing health status and arrest characteristics, while the effects of in-hospital treatments on functional outcome are less understood. We examined variation in functional outcomes by center after adjusting for patient- and arrest-specific characteristics and evaluated how in-hospital management differs between high- and low-performing centers.METHODS: Analysis of observational registry data within the International Cardiac Arrest Registry was used to perform a hierarchical model of center-specific risk standardized rates for good outcome, adjusted for demographics, pre-existing functional status, and arrest-related factors with treatment center as a random effect variable. We described the variability in treatments and diagnostic tests that may influence outcome at centers with adjusted rates significantly above and below registry average.RESULTS: A total of 3855 patients were admitted to an ICU following cardiac arrest with return of spontaneous circulation. The overall prevalence of good outcome was 11-63% among centers. After adjustment, center-specific risk standardized rates for good functional outcome ranged from 0.47 (0.37-0.58) to 0.20 (0.12-0.26). High-performing centers had faster time to goal temperature, were more likely to have goal temperature of 33°C, more likely to perform unconscious cardiac catheterization and percutaneous coronary intervention, and had differing prognostication practices than low-performing centers.CONCLUSIONS: Center-specific differences in outcomes after OHCA after adjusting for patient-specific factors exist. This variation could partially be explained by in-hospital management differences. Future research should address the contribution of these factors to the differences in outcomes after resuscitation.
View details for PubMedID 30848327
Early withdrawal of life support after resuscitation from cardiac arrest is common and may result in additional deaths.
AIM: "Early" withdrawal of life support therapies (eWLST) within the first 3 calendar days after resuscitation from cardiac arrest (CA) is discouraged. We evaluated a prospective multicenter registry of patients admitted to hospitals after resuscitation from CA to determine predictors of eWLST and estimate its impact on outcomes.METHODS: CA survivors enrolled from 2012-2017 in the International Cardiac Arrest Registry (INTCAR) were included. We developed a propensity score for eWLST and matched a cohort with similar probabilities of eWLST who received ongoing care. The incidence of good outcome (Cerebral Performance Category of 1 or 2) was measured across deciles of eWLST in the matched cohort.RESULTS: 2688 patients from 24 hospitals were included. Median ischemic time was 20 (IQR 11, 30) minutes, and 1148 (43%) had an initial shockable rhythm. Withdrawal of life support occurred in 1162 (43%) cases, with 459 (17%) classified as eWLST. Older age, initial non-shockable rhythm, increased ischemic time, shock on admission, out-of-hospital arrest, and admission in the United States were each independently associated with eWLST. All patients with eWLST died, while the matched cohort, good outcome occurred in 21% of patients. 19% of patients within the eWLST group were predicted to have a good outcome, had eWLST not occurred.CONCLUSIONS: Early withdrawal of life support occurs frequently after cardiac arrest. Although the mortality of patients matched to those with eWLST was high, these data showed excess mortality with eWLST.
View details for PubMedID 30836171
Translating Protective Hypothermia During Cardiac Arrest Into Clinical Practice.
2019; 321 (17): 1673–75
View details for PubMedID 31063554
The Prognostic Value of Quantitative Diffusion-Weighted MRI after Pediatric Cardiopulmonary Arrest.
OBJECTIVES: The prognostic value of quantitative diffusion-weighted magnetic resonance imaging (DWI MRI) in predicting neurologic outcomes after pediatric cardiopulmonary arrest (CPA) has not been determined. The aim of this study was to identify a DWI MRI threshold for brain volume percent that correlates with neurologic outcome in children who remain comatose or display significant neurologic deficits immediately after resuscitation from CPA.METHODS: This single-center retrospective study analyzed DWI MRIs of pediatric patients who remained neurologically impaired after CPA. Any MRI obtained within 2 weeks after CPA was analyzed. The apparent diffusion coefficient (ADC) value of each voxel within the brain was determined. Percentage brain volume with voxels below each ADC threshold between 300-1200 * 10-6 mm2/s with a step of 50 were calculated. Area under the receiver operating characteristics curve (AUC) was used to identify optimal DWI MRI thresholds for brain volume percent most predictive of poor neurologic outcome. The primary outcome measure was neurologic outcome 6-months after CPA based on Pediatric Cerebral Performance Category (PCPC) score. Poor neurologic outcome was defined as PCPC score of 3-6, or a worsening from baseline score ≥ 1 if baseline PCPC score was ≥ 3.RESULTS: Twenty-six patients were included in this study. The median age was 8.5 years (2.2-14) and median time from CPA to MRI was 4 days (2-7). Two ADC thresholds for brain volume percent had the largest AUC for predicting poor neurologic outcome. An ADC threshold of < 600 * 10-6 mm2/s in ≥ 7% of brain volume; and < 650 * 10-6 mm2/s in ≥ 11% of brain volume both demonstrated a specificity of 1.0 (0.76-1.0, 95% CI) and a sensitivity of 0.8 (0.44- 0.96, 95% CI) for poor outcome.CONCLUSIONS: In pediatric patients who remain comatose or have significant neurologic deficits after CPA, quantitative DWI MRI correlates with neurologic outcome. Both an ADC threshold of < 600 * 10-6 mm2/s in ≥ 7% of brain volume and < 650 * 10-6 mm2/s in ≥ 11% of brain volume are highly specific for predicting poor neurologic outcome. A prospective trial to validate these thresholds is needed.
View details for PubMedID 30576784
- 2018 American Heart Association Focused Update on Advanced Cardiovascular Life Support Use of Antiarrhythmic Drugs During and Immediately After Cardiac Arrest: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care CIRCULATION 2018; 138 (23): E740–E749
The neuron specific enolase (NSE) ratio offers benefits over absolute value thresholds in post-cardiac arrest coma prognosis
JOURNAL OF CLINICAL NEUROSCIENCE
2018; 57: 99–104
Serum neuron-specific enolase (NSE) levels have been shown to correlate with neurologic outcome in comatose survivors of cardiac arrest but use of absolute NSE thresholds is limited. This study describes and evaluates a novel approach to analyzing NSE, the NSE ratio, and evaluates the prognostic utility of NSE absolute value thresholds and trends over time.100 consecutive adult comatose cardiac arrest survivors were prospectively enrolled. NSE levels were assessed at 24, 48, and 72 h post-arrest. Primary outcome was the Glasgow Outcome Score (GOS) at 6 months post-arrest; good outcome was defined as GOS 3-5. Absolute and relative NSE values (i.e. the NSE ratio), peak values, and the trend in NSE over 72 h were analyzed.98 patients were included. 42 (43%) had a good outcome. Five good outcome patients had peak NSE >33 µg/L (34.9-46.4 µg/L). NSE trends between 24 and 48 h differed between outcome groups (decrease by 3.0 µg/L (0.9-7.0 µg/L) vs. increase by 13.4 µg/L (-3.7 to 69.4 µg/L), good vs. poor, p = 0.004). The 48:24 h NSE ratio differed between the good and poor outcome groups (0.8 (0.6-0.9) vs. 1.4 (0.8-2.5), p = 0.001), and a 48:24 h ratio of ≥1.7 was 100% specific for poor outcome.The NSE ratio is a unique method to quantify NSE changes over time. Values greater than 1.0 indicate increasing NSE and may be reflective of ongoing neuronal injury. The NSE ratio obviates the need for an absolute value cut-off.
View details for PubMedID 30145080
View details for PubMedCentralID PMC6191328
Variation in Sedation and Neuromuscular Blockade Regimens on Outcome After Cardiac Arrest
CRITICAL CARE MEDICINE
2018; 46 (10): E975–E980
Sedation and neuromuscular blockade protocols in patients undergoing targeted temperature management after cardiac arrest address patient discomfort and manage shivering. These protocols vary widely between centers and may affect outcomes.Consecutive patients admitted to 20 centers after resuscitation from cardiac arrest were prospectively entered into the International Cardiac Arrest Registry between 2006 and 2016. Additional data about each center's sedation and shivering management practice were obtained via survey. Sedation and shivering practices were categorized as escalating doses of sedation and minimal or no neuromuscular blockade (sedation and shivering practice 1), sedation with continuous or scheduled neuromuscular blockade (sedation and shivering practice 2), or sedation with as-needed neuromuscular blockade (sedation and shivering practice 3). Good outcome was defined as Cerebral Performance Category score of 1 or 2. A logistic regression hierarchical model was created with two levels (patient-level data with standard confounders at level 1 and hospitals at level 2) and sedation and shivering practices as a fixed effect at the hospital level. The primary outcome was dichotomized Cerebral Performance Category at 6 months.Cardiac arrest receiving centers in Europe and the United states from 2006 to 2016 PATIENTS:: Four-thousand two-hundred sixty-seven cardiac arrest patients 18 years old or older enrolled in the International Cardiac Arrest Registry.None.The mean age was 62 ± 15 years, 36% were female, 77% out-of-hospital arrests, and mean ischemic time was 24 (± 18) minutes. Adjusted odds ratio (for age, return of spontaneous circulation, location of arrest, witnessed, initial rhythm, bystander cardiopulmonary resuscitation, defibrillation, medical history, country, and size of hospital) was 1.13 (0.74-1.73; p = 0.56) and 1.45 (1.00-2.13; p = 0.046) for sedation and shivering practice 2 and sedation and shivering practice 3, respectively, referenced to sedation and shivering practice 1.Cardiac arrest patients treated at centers using as-needed neuromuscular blockade had increased odds of good outcomes compared with centers using escalating sedation doses and avoidance of neuromuscular blockade, after adjusting for potential confounders. These findings should be further investigated in prospective studies.
View details for PubMedID 29979225
View details for PubMedCentralID PMC6138551
Quantitative EEG Metrics Differ Between Outcome Groups and Change Over the First 72 h in Comatose Cardiac Arrest Patients
2018; 28 (1): 51–59
Forty to sixty-six percent of patients resuscitated from cardiac arrest remain comatose, and historic outcome predictors are unreliable. Quantitative spectral analysis of continuous electroencephalography (cEEG) may differ between patients with good and poor outcomes.Consecutive patients with post-cardiac arrest hypoxic-ischemic coma undergoing cEEG were enrolled. Spectral analysis was conducted on artifact-free contiguous 5-min cEEG epochs from each hour. Whole band (1-30 Hz), delta (δ, 1-4 Hz), theta (θ, 4-8 Hz), alpha (α, 8-13 Hz), beta (β, 13-30 Hz), α/δ power ratio, percent suppression, and variability were calculated and correlated with outcome. Graphical patterns of quantitative EEG (qEEG) were described and categorized as correlating with outcome. Clinical outcome was dichotomized, with good neurologic outcome being consciousness recovery.Ten subjects with a mean age = 50 yrs (range = 18-65) were analyzed. There were significant differences in total power (3.50 [3.30-4.06] vs. 0.68 [0.52-1.02], p = 0.01), alpha power (1.39 [0.66-1.79] vs 0.27 [0.17-0.48], p < 0.05), delta power (2.78 [2.21-3.01] vs 0.55 [0.38-0.83], p = 0.01), percent suppression (0.66 [0.02-2.42] vs 73.4 [48.0-97.5], p = 0.01), and multiple measures of variability between good and poor outcome patients (all values median [IQR], good vs. poor). qEEG patterns with high or increasing power or large power variability were associated with good outcome (n = 6). Patterns with consistently low or decreasing power or minimal power variability were associated with poor outcome (n = 4).These preliminary results suggest qEEG metrics correlate with outcome. In some patients, qEEG patterns change over the first three days post-arrest.
View details for PubMedID 28646267
- QUANTITATIVE DIFFUSION-WEIGHTED MRI PREDICTS OUTCOMES IN SURVIVORS OF PEDIATRIC CARDIAC ARREST LIPPINCOTT WILLIAMS & WILKINS. 2018: 149
Practical Pearl: Use of MRI to Differentiate Pseudo-subarachnoid Hemorrhage from True Subarachnoid Hemorrhage.
View details for PubMedID 29948997
- The author replies. Critical care medicine 2017; 45 (3): e339-e340
Functional Neurologic Outcomes Change Over the First 6 Months After Cardiac Arrest.
Critical care medicine
2016; 44 (12): e1202-e1207
To determine the longitudinal changes in functional outcome and compare ordinal outcome scale assessments in comatose cardiac arrest survivors.Prospective observational study of comatose cardiac arrest survivors. Subjects who survived to 1 month were included.Academic medical center ICU.Ninety-eight consecutive patients who remained comatose after resuscitation from cardiac arrest; 45 patients survived to 1 month.None.Patients' functional neurologic outcomes were assessed by phone call or in-person clinic visit at 1, 3, 6, and 12 months postcardiac arrest using the modified Rankin Scale, Glasgow Outcome Scale, and Barthel Index. A "good" outcome was defined as modified Rankin Scale 0-3, Barthel Index 70-100, and Glasgow Outcome Scale 4-5. Changes in dichotomized outcomes and shifts on each outcome scale were analyzed. The mean age of survivors was 51 ± 19 years and 18 (40%) were women. Five (19%) out of 26 patients with data available at all timepoints improved to good modified Rankin Scale outcome and none worsened to poor outcome between postarrest months 1 and 6 (p = 0.06). Thirteen patients (50%) improved on the modified Rankin Scale by 1-3 points and four (15%) worsened by 1-2 points between months 1 and 6 (overall improvement by 0.5 points; 95% CI, 0-1; p = 0.04). From postarrest months 6 to 12, there was no change in the number of patients with good versus poor outcomes. The modified Rankin Scale and Barthel Index were more sensitive to detecting changes in outcome than the Glasgow Outcome Scale.In initially comatose cardiac arrest survivors, improvements in functional status occur over the first 6 months after the event. There was no significant change in outcome between postarrest months 6 and 12. The modified Rankin Scale is a sensitive outcome scale in this population.
View details for PubMedID 27495816
Development of a Mobile Tool That Semiautomatically Screens Patients for Stroke Clinical Trials.
Stroke; a journal of cerebral circulation
2016; 47 (10): 2652-2655
Despite several national coordinated research networks, enrollment in many cerebrovascular trials remains challenging. An electronic tool was needed that would improve the efficiency and efficacy of screening for multiple simultaneous acute clinical stroke trials by automating the evaluation of inclusion and exclusion criteria, improving screening procedures and streamlining the communication process between the stroke research coordinators and the stroke clinicians.A multidisciplinary group consisting of physicians, study coordinators, and biostatisticians designed and developed an electronic clinical trial screening tool on a HIPAA (Health Insurance Portability and Accountability Act)-compliant platform.A web-based tool was developed that uses branch logic to determine eligibility for simultaneously enrolling clinical trials and automatically notifies the study coordinator teams about eligible patients. After 12 weeks of use, 225 surveys were completed, and 51 patients were enrolled in acute stroke clinical trials. Compared with the 12 weeks before implementation of the tool, there was an increase in enrollment from 16.5% of patients screened to 23.4% of patients screened (P<0.05). Clinicians and coordinators reported increased satisfaction with the process and improved ease of screening.We created a semiautomated electronic screening tool that uses branch logic to screen patients for stroke clinical trials. The tool has improved efficiency and efficacy of screening, and it could be adapted for use at other sites and in other medical fields.
View details for DOI 10.1161/STROKEAHA.116.013456
View details for PubMedID 27608822
View details for PubMedCentralID PMC5039105
Multi-Center Study of Diffusion-Weighted Imaging in Coma After Cardiac Arrest.
2016; 24 (1): 82-89
The ability to predict outcomes in acutely comatose cardiac arrest survivors is limited. Brain diffusion-weighted magnetic resonance imaging (DWI MRI) has been shown in initial studies to be a simple and effective prognostic tool. This study aimed to determine the predictive value of previously defined DWI MRI thresholds in a multi-center cohort.DWI MRIs of comatose post-cardiac arrest patients were analyzed in this multi-center retrospective observational study. Poor outcome was defined as failure to regain consciousness within 14 days and/or death during the hospitalization. The apparent diffusion coefficient (ADC) value of each brain voxel was determined. ADC thresholds and brain volumes below each threshold were analyzed for their correlation with outcome.125 patients were included in the analysis. 33 patients (26 %) had a good outcome. An ADC value of less than 650 × 10(-6) mm(2)/s in ≥10 % of brain volume was highly specific [91 % (95 % CI 75-98)] and had a good sensitivity [72 % (95 % CI 61-80)] for predicting poor outcome. This threshold remained an independent predictor of poor outcome in multivariable analysis (p = 0.002). An ADC value of less than 650 × 10(-6) mm(2)/s in >22 % of brain volume was needed to achieve 100 % specificity for poor outcome.In patients who remain comatose after cardiac arrest, quantitative DWI MRI findings correlate with early recovery of consciousness. A DWI MRI threshold of 650 × 10(-6) mm(2)/s in ≥10 % of brain volume can differentiate patients with good versus poor outcome, though in this patient population the threshold was not 100 % specific for poor outcome.
View details for DOI 10.1007/s12028-015-0179-9
View details for PubMedID 26156112
Prognostic Value of Quantitative Diffusion-Weighted MRI in Patients with Traumatic Brain Injury.
Journal of neuroimaging
2016; 26 (1): 103-108
Data about the predictive value of quantitative diffusion-weighted MRI in traumatic brain injury (TBI) patients is lacking. This study aimed to determine if specific apparent diffusion coefficient (ADC) thresholds could be determined that correlate with outcome in moderate-severe TBI.This retrospective observational study investigated patients with moderate-severe TBI. MRIs obtained post-injury days 1-13 were analyzed. MRIs were obtained on a 1.5T scanner; 20-23 contiguous diffusion-weighted imaging (DWI) sections with a spin-echo echo planar imaging DWI 256×256 reconstructed matrix; field of view 24×24 cm; slice thickness/gap of 5/1.5 or 5/2.5 mm. The ADC value of each brain tissue voxel was determined. The percentage of voxels below different ADC thresholds was calculated and correlated with outcome. A good outcome was defined as discharge to home or a rehabilitation facility.Seventy-six patients were analyzed. Thirty-five patients (46%) had a good outcome. The timing of MRI scans did not differ between groups, but the mean age did (42±18 years vs. 56±19 years, p<.01, good vs. poor outcome). Patients with poor outcome had significantly higher percentage of brain volume with ADC < 400×10(-6) mm2 /second (.85±.67% vs. .60±.29%, poor vs. good outcome, p<.05). Using a ROC curve analysis and Youden's index, an ADC <400×10(-6) mm2 /second in ≥.49% of brain was 85% sensitive and 46% specific for poor outcome (p<.05).Quantitative MRI offers additional prognostic information in acute TBI. A whole brain tissue ADC threshold of <400×10(-6) mm2 /second in ≥.49% of brain may be a novel prognostic biomarker.
View details for DOI 10.1111/jon.12286
View details for PubMedID 26296810
Prognostic Value of A Qualitative Brain MRI Scoring System After Cardiac Arrest
JOURNAL OF NEUROIMAGING
2015; 25 (3): 430-437
To develop a qualitative brain magnetic resonance imaging (MRI) scoring system for comatose cardiac arrest patients that can be used in clinical practice.Consecutive comatose postcardiac arrest patients were prospectively enrolled. Routine MR brain sequences were scored by two independent blinded experts. Predefined brain regions were qualitatively scored on the fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences according to the severity of the abnormality on a scale from 0 to 4. The mean score of the raters was used. Poor outcome was defined as death or vegetative state at 6 months.Sixty-eight patients with 88 brain MRI scans were included. Median time from the arrest to the initial MRI was 77 hours (IQR 58-144 hours). At 100% specificity, the "cortex score" performed best in predicting unfavorable outcome with a sensitivity of 55%-60% (95% CI 41-74) depending on time window selection. When comparing the "cortex score" with historically used predictors for poor outcome, MRI improved the sensitivity for poor outcome over conventional predictors by 27% at 100% specificity.A qualitative MRI scoring system helps assess hypoxic-ischemic brain injury severity following cardiac arrest and may provide useful prognostic information in comatose cardiac arrest patients.
View details for DOI 10.1111/jon.12143
View details for Web of Science ID 000354129000014
View details for PubMedID 25040353
Very Early Administration of Progesterone for Acute Traumatic Brain Injury
NEW ENGLAND JOURNAL OF MEDICINE
2014; 371 (26): 2457-2466
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI.We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score.A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes.This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).
View details for DOI 10.1056/NEJMoa1404304
View details for Web of Science ID 000346920300005
View details for PubMedID 25493974
An Update on Neurocritical Care for the Patient With Kidney Disease
ADVANCES IN CHRONIC KIDNEY DISEASE
2013; 20 (1): 39-44
Patients with kidney disease have increased rates of neurologic illness such as intracerebral hemorrhage and ischemic stroke. The acute care of patients with critical neurologic illness and concomitant kidney disease requires unique management considerations including attention to hyponatremia, renal replacement modalities in the setting of high intracranial pressure, reversal of coagulopathy, and seizure management to achieve good neurologic outcomes.
View details for DOI 10.1053/j.ackd.2012.09.003
View details for Web of Science ID 000313394500007
View details for PubMedID 23265595
Treatment of Elevated Intracranial Pressure with Hyperosmolar Therapy in Patients with Renal Failure
2012; 17 (3): 388-394
To evaluate the use of hyperosmolar therapy in the management of elevated intracranial pressure (ICP) and transtentorial herniation (TTH) in patients with renal failure and supratentorial lesions.Patients with renal failure undergoing renal replacement therapy treated with 23.4% saline (30-60 mL) and/or mannitol for high ICP or clinical evidence of TTH were analyzed in a retrospective cohort.The primary outcome measure was reversal of TTH or ICP crisis. Secondary outcome measures were modified Rankin scale on hospital discharge, survival to hospital discharge, and adverse effects. Of 254 subjects over 7 years, 6 patients with end-stage renal disease had 11 events. All patients received a 23.4% saline bolus, along with mannitol (91%), hypertonic saline (HS) maintenance fluids (82%), and surgical interventions (n = 2). Reversal occurred in 6/11 events (55%); 2 of 6 patients survived to discharge. ICP recording of 6 TTH events showed a reduction from ICP of 41 ± 3.8 mmHg (mean ± SEM) with TTH to 20.8 ± 3.9 mmHg (p = 0.05) 1 h after the 23.4% saline bolus. Serum sodium increased from 141.4 to 151.1 mmol/L 24 h after 23.4% saline bolus (p = 0.001). No patients were undergoing hemodialysis at the time of the event. There were no cases of pulmonary edema, clinical volume overload, or arrhythmia after HS.Treatment with hyperosmolar therapy, primarily 23.4% saline solution, was associated with clinical reversal of TTH and reduction in ICP and had few adverse effects in this cohort. Hyperosmolar therapy may be safe and effective in patients with renal failure and these initial findings should be validated in a prospective study.
View details for DOI 10.1007/s12028-012-9676-2
View details for Web of Science ID 000312069400012
View details for PubMedID 22328033
Boomerang Sign on MRI
2012; 16 (3): 450-451
Altered mental status and more subtle cognitive and personality changes after traumatic brain injury (TBI) are pervasive problems in patients who survive initial injury. MRI is not necessarily part of the diagnostic evaluation of these patients.Case report with relevant image and review of the literature.Injury to the corpus callosum is commonly described in traumatic brain injury; however, extensive lesions in the splenium are not well described. This image shows an important pattern of brain injury and demonstrates a common clinical syndrome seen in patients with corpus callosum pathology.Injury to the splenium of the corpus callosum due to trauma may be extensive and can cause significant neurologic deficits. MRI is important in the diagnostic evaluation of patients with cognitive changes after TBI.
View details for DOI 10.1007/s12028-012-9699-8
View details for Web of Science ID 000304619000016
View details for PubMedID 22565630
Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia
CRITICAL CARE MEDICINE
2011; 39 (10): 2337-2345
Knowledge remains limited regarding cerebral blood flow autoregulation after cardiac arrest and during postresuscitation hypothermia. We determined the relationship of cerebral blood flow to cerebral perfusion pressure in a swine model of pediatric hypoxic-asphyxic cardiac arrest during normothermia and hypothermia and tested novel measures of autoregulation derived from near-infrared spectroscopy.Prospective, balanced animal study.Basic physiology laboratory at an academic institution.Eighty-four neonatal swine.Piglets underwent hypoxic-asphyxic cardiac arrest or sham surgery and recovered for 2 hrs with normothermia followed by 4 hrs of either moderate hypothermia or normothermia. In half of the groups, blood pressure was slowly decreased through inflation of a balloon catheter in the inferior vena cava to identify the lower limit of cerebral autoregulation at 6 hrs postresuscitation. In the remaining groups, blood pressure was gradually increased by inflation of a balloon catheter in the aorta to determine the autoregulatory response to hypertension. Measures of autoregulation obtained from standard laser-Doppler flowmetry and indices derived from near-infrared spectroscopy were compared.Laser-Doppler flux was lower in postarrest animals compared to sham-operated controls during the 2-hr normothermic period after resuscitation. During the subsequent 4-hr recovery, hypothermia decreased laser-Doppler flux in both the sham surgery and postarrest groups. Autoregulation was intact during hypertension in all groups. With arterial hypotension, postarrest, hypothermic piglets had a significant decrease in the perfusion pressure lower limit of autoregulation compared to postarrest, normothermic piglets. The near-infrared spectroscopy-derived measures of autoregulation accurately detected loss of autoregulation during hypotension.In a pediatric model of cardiac arrest and resuscitation, delayed induction of hypothermia decreased cerebral perfusion and decreased the lower limit of autoregulation. Metrics derived from noninvasive near-infrared spectroscopy accurately identified the lower limit of autoregulation during normothermia and hypothermia in piglets resuscitated from arrest.
View details for DOI 10.1097/CCM.0b013e318223b910
View details for Web of Science ID 000294958500019
View details for PubMedID 21705904
Clinical and Radiographic Natural History of Cervical Artery Dissections
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES
2009; 18 (6): 416-423
Cervical artery dissection (CADsx) is a common cause of stroke in young patients, but long-term clinical and radiographic follow-up from a large population is lacking.Epidemiologic data, treatment, recurrence, and other features were extracted from the records of all patients seen at our stroke center with confirmed CAD during a 15-year period. A subset of cases was examined to provide detailed information about vessel status.In all, 177 patients (mean age 44.0 +/- 11.1 years) were identified, with the male patients being older than the female patients. Almost 60% of dissections were spontaneous, whereas the remainder involved some degree of head and/or neck trauma. More than 70% of patients were treated with anticoagulation. During follow-up (mean 18.2 months; 0-220 months) there were 15 cases (8.5%) of recurrent ischemic events, and two cases (1.1%) of a recurrent dissection. About half of recurrent stroke/transient ischemic attack events occurred within 2 weeks of presentation. There was no clear association between the choice of antithrombotic agent and recurrent ischemic events. Detailed analysis of imaging findings was performed in 51 cases. Some degree of recanalization was seen in 58.8% of patients overall, and was more frequent in women. The average time to total or near-total recanalization was 4.7 +/- 2.5 months. Patients with complete occlusions at presentation tended not to recanalize.This large series from a single institution highlights many of the features of CAD. A relatively benign course with low recurrence rate is supported, independent of the type and duration of antithrombotic therapy.
View details for DOI 10.1016/j.jstrokecerebrovasdis.2008.11.016
View details for Web of Science ID 000272114400002
View details for PubMedID 19900642
Occurrence of Perimesencephalic Subarachnoid Hemorrhage During Pregnancy
2009; 10 (3): 339-343
Perimesencephalic subarachnoid hemorrhage (P-SAH) is a benign subset of subarachnoid hemorrhage with a favorable prognosis and low rate of re-bleeding. Risk factors may include hypertension and tobacco use, but it has not previously been reported during pregnancy.We report two cases of P-SAH in pregnant women, a 40-year-old female, 8-weeks pregnant and a 37-year-old female at 35 weeks gestational age.CT scan confirmed P-SAH in both cases. CT angiography in one case and cerebral angiogram in the other did not reveal aneurysm or other potential bleeding source. The patients underwent transcranial Doppler ultrasound monitoring without evidence of vasospasm.P-SAH hemorrhage may occur during early or late pregnancy. We do not propose an increased risk of P-SAH during pregnancy. The clinical course appears favorable and CT angiography alone may be considered the preferred diagnostic test to assess for aneurysm in first trimester pregnancy.
View details for DOI 10.1007/s12028-009-9189-9
View details for Web of Science ID 000266328900013
View details for PubMedID 19184552
Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition
2003; 22 (40): 6231-6242
Effects of the PI-3 kinase inhibitor LY294002 (LY) have been examined in relation to responses of human leukemia cells to histone deacetylase inhibitors (HDIs). Coexposure of U937 cells for 24 h to marginally toxic concentrations of LY294002 (e.g., 30 microM) and sodium butyrate (SB; 1 mM) resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release, loss of DeltaPsi(m)), caspase activation, and apoptosis. Similar results were observed in Jurkat, HL-60, and K562 leukemic cells and with other HDIs (e.g., SAHA, MS-275). Exposure of cells to SB/LY was associated with Bcl-2 and Bid cleavage, XIAP and Mcl-1 downregulation, and diminished CD11b expression. While LY blocked SB-mediated Akt activation, enforced expression of a constitutively active (myristolated) Akt failed to attenuate SB/LY-mediated lethality. Unexpectedly, treatment of cells with SB+/-LY resulted in a marked reduction in phosphorylation (activation) of p44/42 mitogen-activated protein (MAP) kinase. Moreover, enforced expression of a constitutively active MEK1 construct partially but significantly attenuated SB/LY-induced apoptosis. Lastly, cotreatment with LY blocked SB-mediated induction of p21(CIP1/WAF1); moreover, enforced expression of p21(CIP1/WAF1) significantly reduced SB/LY-mediated apoptosis. Together, these findings indicate that LY promotes SB-mediated apoptosis through an AKT-independent process that involves MEK/MAP kinase inactivation and interference with p21(CIP1/WAF1) induction.
View details for DOI 10.1038/sj.onc.1206646
View details for Web of Science ID 000185506200013
View details for PubMedID 13679862
The cyclin-dependent kinase inhibitor (CDKI) flavopiridol disrupts phorbol 12-myristate 13-acetate-induced differentiation and CDKI expression while enhancing apoptosis in human myeloid leukemia cells
2001; 61 (6): 2583-2591
Interactions between the cyclin-dependent kinase inhibitor (CDKI) flavopiridol (FP) and phorbol 12-myristate 13-acetate (PMA) were examined in U937 human leukemia cells in relation to differentiation and apoptosis. Simultaneous, but not sequential, exposure of U937 cells to 100 nM FP and 10 nM PMA significantly increased apoptosis manifested by characteristic morphological features, mitochondrial dysfunction, caspase activation, and poly(ADP-ribose) polymerase cleavage while markedly inhibiting cellular differentiation, as reflected by diminished plastic adherence and CD11b expression. Enhanced apoptosis in U937 cells was associated with an early caspase-independent increase in cytochrome c release and accompanied by a substantial decline in leukemic cell clonogenicity. Moreover, PMA/FP cotreatment significantly increased apoptosis in HL-60 promyelocytic leukemia cells and in U937 cells ectopically expressing the Bcl-2 protein. In U937 cells, coadministration of FP blocked PMA-induced expression and reporter activity of the CDKI p21WAF/CIP1 and triggered caspase-mediated cleavage of the CDKI p27KIP1. Coexposure to FP also resulted in a more pronounced and sustained activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase cascade after PMA treatment, although disruption of this pathway by the mitogen-activated protein kinase kinase 1 inhibitor U0126 did not prevent potentiation of apoptosis. FP accelerated PMA-mediated dephosphorylation of the retinoblastoma protein (pRb), an event followed by pRb cleavage culminating in the complete loss of underphosphorylated pRb (approximately Mr 110,000) by 24 h. Finally, gel shift analysis revealed that coadministration of FP with PMA for 8 h led to diminished E2F/pRb binding compared to the effects of PMA alone. Collectively, these findings indicate that FP modulates the expression/activity of multiple signaling and cell cycle regulatory proteins in PMA-treated leukemia cells and that such alterations are associated with mitochondrial damage and apoptosis rather than maturation. These observations also raise the possibility that combining CDKIs and differentiation-inducing agents may represent a novel antileukemic strategy.
View details for Web of Science ID 000167697500042
View details for PubMedID 11289135