Sayona John

Transfer Delay Is a Major Factor Limiting the Use of Intra-Arterial Treatment in Acute Ischemic Stroke

Background and Purpose— The development of comprehensive stroke centers within hub-and-spoke stroke networks offers the opportunity to increase the proportion of acute ischemic stroke patients treated with intra-arterial therapies (IAT). Interhospital transfer delays will be critical in evaluating the success of this strategy. Methods— We collected data on consecutive patients who were transferred to our institution for possible IAT. We defined transfer time as time elapsed from initial transfer call to arrival at our hospital and assessed whether transfer time was a predictor of emergent angiography using multivariable logistic regression. Results— Among 132 patients referred for IAT, 53 (40.2%) were excluded on clinical grounds. The remaining 79 (59.8%) patients (mean age, 61 years; median National Institutes of Health Stroke Scale score, 18; 49.4% male) were analyzed. Sixty-one of 79 (77%) patients underwent emergent angiography for IAT. The median hospital-to-hospital distance was 14.7 (interquartile range, 8.5–21.9) miles and median transfer time was 104 (interquartile range, 80–135) minutes. Transfer time was 33% lower among those who underwent emergent angiography (100.6 versus 149.0 minutes; P<0.001). Adjusting for relevant covariates, transfer time remained an independent predictor of emergent angiography (OR, 0.975; 95% CI, 0.956–0.995; P=0.014). The odds of treatment decrease by 2.5% for every minute of transfer time. Conclusions— Delay in hospital-to-hospital transfer is a common reason that acute ischemic stroke patients are excluded from interventional therapy. The likelihood of receiving IAT decreases rapidly by increasing transfer time. Specific goals for transfer time should be considered in future quality standards for hub-and-spoke–organized stroke networks.

Acute Brain Infarcts After Spontaneous Intracerebral Hemorrhage A Diffusion-Weighted Imaging Study

Background and Purpose— We aimed to determine the prevalence of acute brain infarcts using diffusion-weighted imaging (DWI) in patients with spontaneous intracerebral hemorrhage (ICH). Methods— We collected data on consecutive patients with spontaneous ICH admitted to our institution between August 1, 2006 and December 31, 2008 and in whom DWI was performed within 28 days of admission. Patients with hemorrhage attributable to trauma, tumor, aneurysm, vascular malformation, and hemorrhagic conversion of arterial or venous infarction were excluded. Restricted diffusion within, contiguous with, or immediately neighboring the hematoma or chronic infarcts was not considered abnormal. Using multivariable logistic regression, we evaluated potential predictors of DWI abnormality including clinical and radiographic characteristics and treatments. A probability value <0.05 was considered significant in the final model. Results— Among 118 spontaneous ICH patients (mean 59.6 years, 47.5% male, and 31.4% white) who also underwent MRI, DWI abnormality was observed in 22.9%. The majority of infarcts were small (median volume 0.25 mL), subcortical (70.4%), and subclinical (88.9%). Factors independently associated with DWI abnormality were prior ischemic stroke (P=0.002), MAP lowering by ≥40% (P=0.004), and craniotomy for ICH evacuation (P=0.001). Conclusion— We found that acute brain infarction is relatively common after acute spontaneous ICH. Several factors, including aggressive blood pressure lowering, may be associated with acute ischemic infarcts after ICH. These preliminary findings require further prospective study.

A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Phase III Study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III)

Background In adults, intraventricular thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) facilitates resolution of intraventricular haemorrhage (IVH), reduces intracranial pressure, decreases duration of cerebrospinal fluid diversion, and may ameliorate direct neural injury. We hypothesize that patients with small parenchymal haematoma volumes (<30 cc) and relatively large IVH causing acute obstructive hydrocephalus would have improved clinical outcomes when given injections of low-dose rtPA to accelerate lysis and evacuation of IVH compared with placebo. Methods The Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III trial is an investigator-initiated, phase III, randomized, multicenter, double-blind, placebo-controlled study comparing the use of external ventricular drainage (EVD) combined with intraventricular injection of rtPA to EVD plus intraventricular injection of normal saline (placebo) for the treatment of IVH. Patients with known symptom onset within 24 h of the computed tomography scan confirmed IVH and third or fourth ventricle obstruction, with or without supratentorial intracerebral haemorrhage volume <30 cc, who require EVD are screened with a computed tomography scan at least six hours after EVD placement and, if necessary, at consecutive 12-h intervals until stabilization of any intracranial bleeding has been established. Patients who meet clinical and imaging criteria (no ongoing coagulopathy and no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly) will be randomized to either intraventricular rtPA or placebo. Results The primary outcome measure is dichotomized modified Rankin Scale 0–3 vs. 4–6 at 180 days. Clinical secondary outcomes include additional modified Rankin Scale dichotomizations at 180 days (0–4 vs. 5–6), ordinal modified Rankin Scale (0–6), mortality and safety events at 30 days, mortality at 180 days, functional status measures, type and intensity of intensive care unit management, rate and extent of ventricular blood clot removal, and quality of life measures.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

BACKGROUND Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING National Institute of Neurological Disorders and Stroke.

Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III

Background and Purpose— The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography–based planimetry (CTP). Methods— In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. Results— In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r2=0.93) than with site-ABC (r2=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm3; CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (&kgr;=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. Conclusions— ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

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.

CSF inflammatory response after intraventricular hemorrhage

Objective: To investigate the temporal pattern and relevant associations of CSF inflammatory measures after intraventricular hemorrhage (IVH). Methods: We analyzed prospectively collected CSF cell counts and protein and glucose levels from participants in the Clot Lysis Evaluation of Accelerated Resolution of IVH phase III (CLEAR III) trial. Corrected leukocyte count and cell index were calculated to adjust for CSF leukocytes attributable to circulating blood. Data were chronologically plotted. CSF inflammatory measures (daily, mean, median, maximum, and cases with highest quartile response) were correlated with initial IVH volume, IVH clearance rate, thrombolytic treatment, bacterial infection, and adjudicated clinical outcome at 30 and 180 days. Results: A total of 11,376 data points of CSF results from 464 trial participants were analyzed. Measures of CSF inflammatory response evolved during the resolution of IVH. This was significantly more pronounced with initial IVH volume exceeding 20 mL. Intraventricular alteplase was associated with a significantly augmented inflammatory response compared to saline, even after correcting for initial IVH volume. There was an association but nonpredictive correlation of CSF inflammation measures with culture-positive CSF bacterial infection. None of the CSF inflammatory measures, including cases with upper quartile inflammatory response, was associated with a significant detrimental effect on 30 or 180 days functional outcome or mortality after multivariate adjustment for measures of disease severity. Conclusions: Aseptic CSF inflammation after IVH is primarily dependent on the volume of initial bleed. Thrombolysis intensifies the inflammatory response, with no apparent detrimental effect on clinical outcome. Clinicaltrials.gov identifier: NCT00784134.

Factors Associated with Fever in Intracerebral Hemorrhage

BACKGROUND Fever is common in patients with intracerebral hemorrhage (ICH). We sought to identify predictors of fever in patients hospitalized with ICH, and compare infectious fever with noninfectious fever. METHODS A retrospective review on consecutive spontaneous ICH patients from April 2009 to March 2010 was performed. Fever was defined as temperature 100.9°F or higher and attributed to infectious versus noninfectious etiology, based upon the National Healthcare Safety Network criteria. Univariate analysis and multivariable logistic regression model were used to determine factors associated with fever and with infection. RESULTS Among the 351 ICH patients, 136 (39%) developed fever. Factors associated with fever included mean ICH volume, intraventricular hemorrhage (IVH), external ventricular drain (EVD) placement or surgical evacuation, positive microbial cultures, longer length of stay (LOS), and higher in-hospital mortality. Among patients with fever, 96 (71%) were noninfectious and 40 (29%) were infectious. Infectious fever was associated with higher LOS. Noninfectious fever was associated with higher in-hospital mortality. In multivariable analysis, ICH volume (OR = 1.01, P = .04), IVH (OR = 2.0, P = .03), EVD (OR = 3.7, P < .0001), and surgical evacuation (OR = 6.78, P < .0001) were significant predictors of fever. Infectious fever (OR = 5.26, P = .004), EVD (OR = 4.86, P = .01), and surgical evacuation (OR = 4.77, P = .04) correlated with prolonged LOS when dichotomized using a median of 15 days. CONCLUSIONS Fever is common in ICH patients and is not associated with a clear infectious etiology in the majority of patients. Patients with noninfectious fever have higher in-hospital mortality, but survivors have shorter LOS. Further studies are warranted to better understand fevers in ICH.

Extrapontine myelinolysis effects in intracranial langerhans cell histiocytosis: Case report

Langerhans cell histiocytosis (LCH) is an uncommon disease with an incidence of 0.2–2.0 cases per 100,000 children under 15 years of age [1]. The frequency in adults is not known. The hypothalamic-pituitary manifestations of LCH (often diabetes insipidus) are well known. Thus, complications with sodium level shifts may be present. Rapid changes of sodium concentrations are associated with osmotic demyelination syndromes including pontine and extrapontine demyelination. Here we present a case of a woman with intracranial LCH and subsequent diabetes insipidus who developed extrapontine myelinolysis after she missed doses of desmopressin and subsequent rapid correction of hypernatremia.