Bio

Clinical Focus


  • Neurology
  • Stroke
  • Traumatic Brain Injury
  • Concussion
  • Cerebrovascular Circulation

Academic Appointments


Professional Education


  • Fellowship:UCSF Dept of Neurology (2012) CA
  • Medical Education:Stanford University School of Medicine Registrar (2012) CA
  • Residency:Johns Hopkins Neurology Residency (2010) MD
  • Internship:Stanford University Internal Medicine Residency Training (2007) 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)

Research & Scholarship

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.

Clinical Trials


  • Computed Tomography Perfusion (CTP) to Predict Response to Recanalization in Ischemic Stroke Project (CRISP) Not Recruiting

    The overall goal of the CTP to predict Response to recanalization in Ischemic Stroke Project (CRISP) is to develop a practical tool to identify acute stroke patients who are likely to benefit from endovascular therapy. The project has two main parts. During the first part, the investigators propose to develop a fully automated system (RAPID) for processing of CT Perfusion (CTP) images that will generate brain maps of the ischemic core and penumbra. There will be no patient enrollment in part one of this project. During the second part, the investigators aim to demonstrate that physicians in the emergency setting, with the aid of a fully automated CTP analysis program (RAPID), can accurately predict response to recanalization in stroke patients undergoing revascularization. To achieve this aim the investigators will conduct a prospective cohort study of 240 consecutive stroke patients who will undergo a CTP scan prior to endovascular therapy. The study will be conducted at four sites (Stanford University, St Luke's Hospital, University of Pittsburgh Medical Center, and Emory University/Grady Hospital). Patients will have an early follow-up MRI scan within 12+/-6 hours to assess reperfusion and a late follow-up MRI scan at day 5 to determine the final infarct.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stephanie M Kemp, BS, 650-723-4481.

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  • Imaging Collaterals in Acute Stroke (iCAS) Recruiting

    Stroke is caused by a sudden blockage of a blood vessel that delivers blood to the brain. Unblocking the blood vessel with a blood clot removal device restores blood flow and if done quickly may prevent the disability that can be caused by a stroke. However, not all stroke patients benefit from having their blood vessel unblocked. The aim of this study is to determine if special brain imaging, called MRI, can be used to identify which stroke patients are most likely to benefit from attempts to unblock their blood vessel with a special blood clot removal device. In particular, we will assess in this trial whether a noncontrast MR imaging sequence, arterial spin labeling (ASL), can demonstrate the presence of collateral blood flow (compared with a gold standard of the angiogram) and whether it is useful to predict who will benefit from treatment.

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  • Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial Not Recruiting

    The Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial is a multicenter, randomized, controlled clinical trial of 1400 patients that will include approximately 60 enrolling sites. The study hypotheses are that treatment of hyperglycemic acute ischemic stroke patients with targeted glucose concentration (80mg/dL - 130 mg/dL) will be safe and result in improved 3 month outcome after stroke. Eligible subjects must be randomized within 12 hours of stroke symptom onset and either have type 2 diabetes and glucose concentrations of over 110 mg/dL or no history of diabetes and glucose concentrations of 150 mg/dL or higher on initial evaluation. The enrolling sites will include the Neurological Emergencies Treatment Trials (NETT) sites as well as non NETT sites from all over the United States. The study will evaluate the safety and efficacy of targeted glucose control (treatment group - IV insulin with target 80-130 mg/dl) verses control therapy of sub q insulin plus basal insulin with target glucose less than 180 mg/ dL. The primary outcome will be functional outcome at 3 months as measured by the modified Rankin Scale (mRS) Score. The primary safety outcome will be severe hypoglycemia defined as <40 mg/dL. Enrollment will occur over 5-7 years.

    Stanford is currently not accepting patients for this trial. For more information, please contact Rosen Mann, (650) 721-2645.

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  • Established Status Epilepticus Treatment Trial Recruiting

    The primary objective is to determine the most effective and/or the least effective treatment of benzodiazepine-refractory status epilepticus (SE) among patients older than 2 years. There are three active treatment arms being compared: fosphenytoin (FOS),levetiracetam (LEV), and valproic acid (VPA). The second objective is comparison of three drugs with respect to secondary outcomes. The final objective is to ensure that the trial is informative for treatment of established SE in children by describing the effectiveness, safety, and rate of adverse reactions of these drugs in children.

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  • Transient Ischemic Attack (TIA) Triage and Evaluation of Stroke Risk Not Recruiting

    Transient ischemic attack (TIA) is a transient neurological deficit (speech disturbance, weakness…), caused by temporary occlusion of a brain vessel by a blood clot that leaves no lasting effect. TIA diagnosis can be challenging and an expert stroke evaluation combined with magnetic resonance imaging (MRI) could improve the diagnosis accuracy. The risk of a debilitating stroke can be as high as 5% during the first 72 hrs after TIA. TIA characteristics (duration, type of symptoms, age of the patient), the presence of a significant narrowing of the neck vessels responsible for the patient's symptoms (symptomatic stenosis), and an abnormal MRI are associated with an increased risk of stroke. An emergent evaluation and treatment of TIA patients by a stroke specialist could reduce the risk of stroke to 2%. Stanford has implemented an expedited triage pathway for TIA patients combining a clinical evaluation by a stroke neurologist, an acute MRI of the brain and the vessels and a sampling of biomarkers (Lp-PLA2). The investigators are investigating the yield of this unique approach to improve TIA diagnosis, prognosis and secondary stroke prevention. The objective of this prospective cohort study is to determine which factors will help the physician to confirm the diagnosis of TIA and to define the risk of stroke after a TIA.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stephanie Kemp, BS, 650-723-4481.

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Publications

All Publications


  • 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 Panchal, A. R., Berg, K. M., Kudenchuk, P. J., Del Rios, M., Hirsch, K. G., Link, M. S., Kurz, M. C., Chan, P. S., Cabanas, J. G., Morley, P. T., Hazinski, M., Donnino, M. W. 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 Chung-Esaki, H. M., Mui, G., Mlynash, M., Eyngorn, I., Catabay, K., Hirsch, K. G. 2018; 57: 99–104

    Abstract

    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 DOI 10.1016/j.jocn.2018.08.020

    View details for Web of Science ID 000448494000018

    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 May, T. L., Riker, R. R., Fraser, G. L., Hirsch, K. G., Agarwal, S., Duarte, C., Friberg, H., Soreide, E., McPherson, J., Hand, R., Kent, D., Nielsen, N., Seder, D. B. 2018; 46 (10): E975–E980

    Abstract

    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 DOI 10.1097/CCM.0000000000003301

    View details for Web of Science ID 000444480100002

    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 NEUROCRITICAL CARE Wiley, S., Razavi, B., Krishnamohan, P., Mlynash, M., Eyngorn, I., Meador, K. J., Hirsch, K. G. 2018; 28 (1): 51–59

    Abstract

    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 DOI 10.1007/s12028-017-0419-2

    View details for Web of Science ID 000425631100008

    View details for PubMedID 28646267

  • Practical Pearl: Use of MRI to Differentiate Pseudo-subarachnoid Hemorrhage from True Subarachnoid Hemorrhage. Neurocritical care Ho, A. L., Sussman, E. S., Pendharkar, A. V., Iv, M., Hirsch, K. G., Fischbein, N. J., Dodd, R. L. 2018

    View details for DOI 10.1007/s12028-018-0547-3

    View details for PubMedID 29948997

  • QUANTITATIVE DIFFUSION-WEIGHTED MRI PREDICTS OUTCOMES IN SURVIVORS OF PEDIATRIC CARDIAC ARREST Yacoub, M., Birchansky, B., Mlynash, M., Berg, M., Knight, L., Hirsch, K., Su, F. LIPPINCOTT WILLIAMS & WILKINS. 2018: 149
  • The author replies. Critical care medicine Hirsch, K. G. 2017; 45 (3): e339-e340

    View details for DOI 10.1097/CCM.0000000000002222

    View details for PubMedID 28212244

  • Functional Neurologic Outcomes Change Over the First 6 Months After Cardiac Arrest. Critical care medicine Tong, J. T., Eyngorn, I., Mlynash, M., Albers, G. W., Hirsch, K. G. 2016; 44 (12): e1202-e1207

    Abstract

    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

    View details for PubMedCentralID PMC5115936

  • Development of a Mobile Tool That Semiautomatically Screens Patients for Stroke Clinical Trials. Stroke; a journal of cerebral circulation Spokoyny, I., Lansberg, M., Thiessen, R., Kemp, S. M., Aksoy, D., Lee, Y., Mlynash, M., Hirsch, K. G. 2016; 47 (10): 2652-2655

    Abstract

    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. Neurocritical care Hirsch, K. G., Mlynash, M., Eyngorn, I., Pirsaheli, R., Okada, A., Komshian, S., Chen, C., Mayer, S. A., Meschia, J. F., Bernstein, R. A., Wu, O., Greer, D. M., Wijman, C. A., Albers, G. W. 2016; 24 (1): 82-89

    Abstract

    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 Shakir, A., Aksoy, D., Mlynash, M., Harris, O. A., Albers, G. W., Hirsch, K. G. 2016; 26 (1): 103-108

    Abstract

    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 Hirsch, K. G., Mlynash, M., Jansen, S., Persoon, S., Eyngorn, I., Krasnokutsky, M. V., Wijman, C. A., Fischbein, N. J. 2015; 25 (3): 430-437

    Abstract

    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 Wright, D. W., Yeatts, S. D., Silbergleit, R., Palesch, Y. Y., Hertzberg, V. S., Frankel, M., Goldstein, F. C., Caveney, A. F., Howlett-Smith, H., Bengelink, E. M., Manley, G. T., Merck, L. H., Janis, L. S., Barsan, W. G. 2014; 371 (26): 2457-2466

    Abstract

    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 Hirsch, K. G., Josephson, S. A. 2013; 20 (1): 39-44

    Abstract

    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 NEUROCRITICAL CARE Hirsch, K. G., Spock, T., Koenig, M. A., Geocadin, R. G. 2012; 17 (3): 388-394

    Abstract

    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 NEUROCRITICAL CARE Hirsch, K. G., Hoesch, R. E. 2012; 16 (3): 450-451

    Abstract

    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 Lee, J. K., Brady, K. M., Mytar, J. O., Kibler, K. K., Carter, E. L., Hirsch, K. G., Hogue, C. W., Easley, R. B., Jordan, L. C., Smielewski, P., Czosnyka, M., Shaffner, D. H., Koehler, R. C. 2011; 39 (10): 2337-2345

    Abstract

    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 Schwartz, N. E., Vertinsky, A. T., Hirsch, K. G., Albers, G. W. 2009; 18 (6): 416-423

    Abstract

    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 NEUROCRITICAL CARE Hirsch, K. G., Froehler, M. T., Huang, J., Ziai, W. C. 2009; 10 (3): 339-343

    Abstract

    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 ONCOGENE Rahmani, M., Yu, C. R., Reese, E., Ahmed, W., Hirsch, K., Dent, P., Grant, S. 2003; 22 (40): 6231-6242

    Abstract

    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 CANCER RESEARCH Cartee, L., Wang, Z. L., Decker, R. H., Chellappan, S. P., Fusaro, G., Hirsch, K. G., Sankala, H. M., Dent, P., Grant, S. 2001; 61 (6): 2583-2591

    Abstract

    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