Rajeev Garg

Reduced Platelet Activity Is Associated With Early Clot Growth and Worse 3-Month Outcome After Intracerebral Hemorrhage

Background and Purpose— Antiplatelet medication use and reduced platelet activity may be associated with mortality after intracerebral hemorrhage (ICH). We tested the hypothesis that reduced platelet activity is associated with early ICH clot growth and worse outcomes. Methods— We prospectively identified patients with spontaneous ICH, measured platelet activity (VerifyNow-ASA, Accumetrics) on admission, and recorded antiplatelet medication use. ICH volume was calculated using computerized volumetric analysis. Data were analyzed with nonparametric statistics and repeated measures ANOVA as appropriate. Patients were prospectively followed for functional outcomes. Data are presented as mean±SD or median [Q1 to Q3]. Results— Reduced platelet activity (≤550 aspirin reaction units [ARU]) was associated with increased ICH volume growth (P<0.05) for patients with the diagnostic CT within 12 hours. In the subset of patients not known to take aspirin, 24% had reduced platelet activity. Sixteen (24%) patients received a platelet transfusion 21.2±11.4 hours after symptom onset with an increase in platelet activity (448 [414-479] to 586 [530-639] ARU, P=0.001), but without impact on outcomes. Reduced platelet activity was associated with worse modified Rankin Scores at 3 months (P=0.02). Conclusions— Reduced platelet activity was associated with early ICH volume growth and worse functional outcome. Because platelet activity can be increased with platelet transfusion, increasing platelet activity is a potential method to reduce ICH volume growth and improve functional outcomes.

Anticonvulsant Use and Outcomes After Intracerebral Hemorrhage

Background and Purpose— There are few data on the effectiveness and side effects of antiepileptic drug therapy after intracerebral hemorrhage. We tested the hypothesis that antiepileptic drug use is associated with more complications and worse outcome after intracerebral hemorrhage. Methods— We prospectively enrolled 98 patients with intracerebral hemorrhage and recorded antiepileptic drug use as either prophylactic or therapeutic along with clinical characteristics. Antiepileptic drug administration and free phenytoin serum levels were retrieved from the electronic medical records. Patients with depressed mental status underwent continuous electroencephalographic monitoring. Outcomes were measured with the National Institutes of Health Stroke Scale and modified Rankin Scale at 14 days or discharge and the modified Rankin Scale at 28 days and 3 months. We constructed logistic regression models for poor outcome at 3 months with a forward conditional model. Results— Seven (7%) patients had a clinical seizure, 5 on the day of intracerebral hemorrhage. Phenytoin was associated with more fever (P=0.03), worse National Institutes of Health Stroke Scale at 14 days (23 [9 to 42] versus 11 [4 to 23], P=0.003), and worse modified Rankin Scale at 14 days, 28 days, and 3 months. In a forward conditional logistic regression model, phenytoin prophylaxis was associated with an increased risk of poor outcome (OR, 9.8; 1.4 to 68.6; P=0.02), entering after admission National Institutes of Health Stroke Scale and age. Excluding patients with a seizure did not change the results. Levetiracetam was not associated with demographics, seizures, complications, or outcomes. Conclusions— Phenytoin was associated with more fever and worse outcomes after intracerebral hemorrhage.

Blood Pressure Reduction, Decreased Diffusion on MRI, and Outcomes After Intracerebral Hemorrhage

Background and Purpose— Decreased diffusion (DD) consistent with acute ischemia may be detected on MRI after acute intracerebral hemorrhage (ICH), but its risk factors and impact on functional outcomes are not well-defined. We tested the hypotheses that DD after ICH is related to acute blood pressure (BP) reduction and lower hemoglobin and presages worse functional outcomes. Methods— Patients who underwent MRI were prospectively evaluated for DD by certified neuroradiologists blinded to outcomes. Hemoglobin and BP data were obtained via electronic queries. Outcomes were obtained at 14 days and 3 months with the modified Rankin Scale, a functional scale scored from 0 (no symptoms) to 6 (dead). We used logistic regression for dependence or death (modified Rankin Scale score 4–6). Results— DD distinct from the hematoma was found on MRI in 39 of 95 patients (41%). DD was associated with greater BP reductions from baseline and a higher risk of dependence or death at 3 months (odds ratio, 4.8; 95% confidence interval, 1.7–13.9; P=0.004) after correction for ICH score (1.8 per point; 95% confidence interval, 1.2–3.1; P=0.01). Lower hemoglobin was associated with worse ICH score, larger hematoma volume, and worse outcomes, but not DD. Conclusions— DD is common after ICH, associated with greater acute BP reductions, and associated with disability and death at 3 months in multivariate analysis. The potential benefits of acute BP reduction to reduce hematoma growth may be limited by DD. The prevention and treatment of cerebral ischemia manifested as DD are potential methods to improve outcomes.

Reduced platelet activity is associated with more intraventricular hemorrhage

OBJECTIVEIntraventricular hemorrhage (IVH) is a serious complication of intracerebral hemorrhage (ICH). We hypothesized that antiplatelet medication use and platelet activity would be associated with more IVH. METHODSWe prospectively identified patients with spontaneous ICH and measured platelet activity on admission with the VerifyNow-Aspirin assay (Accumetrics, San Diego, CA). IVH volume was quantified with the Graeb scale, divided into categories of 0 (no IVH), 1 to 2 (minimal IVH), 3 to 5 (moderate IVH), and 6 and above (severe IVH). Antiplatelet medications were prospectively recorded. We used ordinal regression to measure the effect of platelet activity after correcting for ICH location and ICH volume. Outcomes were measured at 14 days or discharge with the National Institutes of Health Stroke Scale and modified Rankin Scale (mRS) and at 28 days and 3 months with the mRS. RESULTSIn our cohort of 73 patients, 36 had no IVH, 11 had minimal IVH, 10 had moderate IVH, and 16 had severe IVH. Aspirin and clopidogrel (P = 0.03 for both) were associated with less platelet activity. More IVH was related to reduced platelet activity (P = 0.01) after correction for ICH volume and location without contribution from aspirin or clopidogrel use. IVH was associated with worse National Institutes of Health Stroke Scale score (P = 0.002) and mRS score (P = 0.001) at 14 days and with mRS scores at 28 days (P = 0.02) and 3 months (P = 0.008). CONCLUSIONReduced platelet activity was related to more IVH as a complication of ICH. The relationship of platelet activity to IVH deserves further study.

Warfarin-Associated Intracerebral Hemorrhage Is Inadequately Treated at Community Emergency Departments

Background and Purpose— The purpose of this study was to investigate time delays, adherence to guidelines, and their impact on outcomes in patients with warfarin-associated intracerebral hemorrhage transferred from community emergency departments to a comprehensive stroke center. Methods— We collected demographic, clinical, transfer time, treatment, and outcome data for patients transferred to our institution with warfarin-associated intracerebral hemorrhage from community emergency departments. Results— Among 928 patients with intracerebral hemorrhage, 56 (6%) with warfarin-associated intracerebral hemorrhage (median international normalized ratio, 2.55) were transferred to the comprehensive stroke center. Twenty patients received no acute reversal therapy before transfer, only 4 of whom had international normalized ratios ⩽1.4 in the community emergency department. Median time of emergency department stay was 3.66 hours and median time to initiation of acute reversal therapy was 4.48 hours. Those who received ≥3 U of fresh–frozen plasma or recombinant activated Factor VIIa (11 patients) before transfer had lower repeat international normalized ratios and better discharge dispositions than those treated less aggressively. Conclusions— Treatment of warfarin-associated intracerebral hemorrhage in community emergency departments is often suboptimal and does not adhere to published guidelines. Treating coagulopathy aggressively before interhospital transfer may improve outcomes and warrants further investigation.

Therapeutic Hypothermia After Cardiac Arrest is Underutilized in the United States

Little is known about the frequency of therapeutic hypothermia use after cardiac arrest in the United States. We, therefore, analyzed the Nationwide Inpatient Sample (NIS) to determine the prevalence of hypothermia use after cardiac arrest and patient and hospital factors associated with its use. Using 2007 NIS data, we identified adult patients with cardiac arrest using the ICD-9 diagnosis code, 427.5, while the use of therapeutic hypothermia was based on the ICD-9 procedure code, 99.81. Among 26,519 adult patients with cardiac arrest, only 92 (0.35%) were coded as having received therapeutic hypothermia. In a multivariable logistic regression model, independent factors associated with the use of therapeutic hypothermia included age as a continuous variable ([odds ratios] OR 0.97, 95% CI 0.963-0.989, p<0.001), comorbidity adjusted mortality score (OR 1.06, 95% CI 1.04-1.08, p<0.001), admission from the emergency room (OR 2.17, 95% CI 1.191-3.949, p=0.011), teaching hospital status (OR 2.68, 95% CI 1.36-5.29, p=0.005), acute myocardial infarction (OR 1.96, 95% CI 1.14-3.36, p=0.015), hospital location in the western United States (OR 2.21, 95% CI 1.16-3.14, p=0.011), and >97% registered nurse hospital staffing (OR 2.64, 95% CI 1.62-4.30, p<0.001). Therapeutic hypothermia may be utilized in <1% of cardiac arrest patients in U.S. hospitals. We identified important patient and hospital factors associated with therapeutic hypothermia utilization. Efforts to increase generalized utilization of this effective resuscitation strategy are warranted.

Re: Confounding by Indication in Retrospective Studies of Intracerebral Hemorrhage: Antiepileptic Treatment and Mortality

To the Editor, We were interested to read the article by Battey and colleagues [1] regarding the analysis of datasets of patients with intracerebral hemorrhage (ICH). It is asserted that patients who survive at least 5 days are more suitable for analysis for the effect of seizure medications (now the preferred term [2]). This technique, however, is itself likely to lead to a biased dataset, and such a selection criterion is particularly inappropriate to evaluate seizure medications. The analysis does not take the duration of treatment or dose of seizure medications given into account, but it is likely to be important. One day of phenytoin (while a comatose patient undergoes EEG monitoring) is not likely to be the same as 14 days of phenytoin, which is why we took care to show that longer duration of treatment is associated with more complications in patients with ICH [2], and subsequent worse functional outcomes. More intense therapy is also associated with more complications and worse outcome in patients with subarachnoid hemorrhage [3]. Similar to the metric of pack-years for smoking exposure instead of a dichotomous one, analysis utilizing total dose exposure is important and fundamental to investigations of adverse drug effects. Furthermore, in this manuscript, seizure medications are grouped together, but each medication is likely to have a different safety profile and each may have a different effect on complications and outcomes. Five days after ICH symptom onset seems to be an arbitrary time to assess the impact of seizure medications. We [2] and others [4] have found that seizures after ICH usually occur within 24 h of symptom onset. Restricting the analysis to those who have survived at least 5 days will introduce bias by excluding patients most likely to have a seizure as a marker of disease, or who die as a consequence of seizures [5]. Mortality after ICH usually has a nonneurologic cause after a few days [6], so it is unclear why seizure medications should affect mortality. If one were to wait until 5 days after ICH symptom onset to randomize patients in a clinical trial of seizure medications, there would be relatively few events to study. The authors emphasize that their initial results suggested that seizure medications are lifesaving after ICH, and that only by selecting the subset of patients who had survived 5 days could they see that this was false. The initial results are a feint, however, since there is no established mechanism by which seizure medications would reduce mortality. Early clinical seizures are not independently associated with outcomes [4]. Seizure medications probably reduce mortality vs. placebo in patients with status epilepticus, but it is not clear from these data why such treatment should reduce mortality in an unselected cohort. We agree that patients who are prescribed seizure medications are likely to have more severe neurologic disease, but the authors neither present data on how the excluded patients might have differed from the overall dataset (i.e., might bias it) nor cite statistical literature that calls for excluding patients in this manner. The usual technique is to adjust the whole eligible cohort for A. M. Naidech (&) M. B. Maas E. M. Liotta J. C. Guth S. U. Schuele Departments of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA e-mail: a-naidech@northwestern.edu

Response to Letter to the Editor by Dr. Witsch et al.

We thank Dr. Witsch et al. for their kind interest in our recent article on ‘‘Risk Stratification for the In-Hospital mortality in Subarachnoid Hemorrhage: The HAIR score’’. We acknowledge that between score 6 and 7, mortality was essentially the same (in our data, 82.1 vs. 83.3 %), and Dr. Witsch reports similar numbers, albeit with a slightly decreased mortality (79.7 vs. 78.4 %). This small reversal is likely due to low power as the number of patients in the moribund subgroups (score 6, 7, 8) were likely relatively small compared to the overall cohort. In our data, there were only 6 patients with a score of 7 and no patients with a score of 8. Recognizing this, we chose to validate the HAIR score in our second cohort using a simplified risk stratification with low (score 0–2), moderate (score 3–5), and high (score 6–8), and clinically, it may be more meaningful to categorize patients this way. Of interest, Dr. Witsch’s findings included patients with the maximum HAIR score of 8, which was associated with 100 % mortality. Inclusion of patients in the highest subgroup is important and appears to be consistent with the HAIR score prediction. Dr. Witsch’s findings of an area under the ROC-curve of 0.9 indicates robust performance in discrimination overall, and we are pleased that the HAIR score has been externally validated in a separate cohort of over 1,600 subarachnoid hemorrhage patients.