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1.  Influence of ATP-Binding Cassette Polymorphisms on Neurological Outcome After Traumatic Brain Injury 
Neurocritical care  2013;19(2):192-198.
Background
As important mediators of solute transport at the blood–brain and blood–cerebrospinal fluid barriers, ATP-binding cassette (ABC) transporters (including ABCB1, ABCC1, and ABCC2), impact the bioavailability of drugs and endogenous substrates in the brain. While several ABCB1, ABCC1, and ABCC2 single nucleotide polymorphisms (SNPs) have been identified, their impact on outcome after traumatic brain injury (TBI) is unknown.
Hypothesis
ABCB1, ABCC1, and ABCC2 SNPs are associated with Glasgow Outcome Scale (GOS) score after TBI.
Methods
DNA samples from 305 adult patients with severe TBI (Glasgow Coma Scale, GCS score ≤ 8) were genotyped for tagging SNPs of ABCB1 (rs1045642; rs1128503), ABCC1 (rs212093; rs35621; rs4148382), and ABCC2 (rs2273697). For each SNP, patients were dichotomized based on presence of variant allele for multivariate analysis to determine associations with GOS assigned at 6 months adjusting for GCS, Injury Severity score, age, and patient sex.
Results
For ABCB1 rs1045642, patients homozygous for the T allele were less likely to be assigned poor outcome versus those possessing the C allele [CT/CC; odds of unfavorable GOS = 0.71(0.55−0.92)]. For ABCC1 rs4148382, patients homozygous for the G allele were less likely to be assigned poor outcome versus those possessing the A allele [AG/AA; odds of unfavorable GOS = 0.73(0.55−0.98)].
Conclusions
In this single-center study, patients homozygous for the T allele of ABCB1 rs1045642 or the G allele of ABCC1 rs4148382 were found to have better outcome after severe TBI. Further study is necessary to replicate these very preliminary findings and to determine whether these associations are due to central nervous system bioavailability of ABC transporter drug substrates commonly used in the management of TBI, brain efflux of endogenous solutes, or both.
doi:10.1007/s12028-013-9881-7
PMCID: PMC4332629  PMID: 23896815
Blood-brain barrier; Head trauma; Membrane transporter; Multidrug resistance protein; Multidrug resistance-associated protein; P-Glycoprotein
2.  [No title available] 
PMCID: PMC4049542  PMID: 24233812
3.  Risk of Thromboembolism Following Acute Intracerebral Hemorrhage 
Neurocritical care  2008;10(1):28-34.
Introduction
Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulant therapy (OAT). While anticoagulated patients have increased severity of bleeding following ICH, they may also be at increased risk for thromboembolic events (TEs) given that they had been prescribed OAT prior to their ICH. We hypothesized that TEs are relatively common following ICH, and that anticoagulated patients are at higher risk for these complications.
Methods
Consecutive patients with primary ICH presenting to a tertiary care hospital from 1994 to 2006 were prospectively characterized and followed. Hospital records were retrospectively reviewed for clinically relevant inhospital TEs and patients were prospectively followed for 90 day mortality.
Results
For 988 patients of whom 218 (22%) were on OAT at presentation, median hospital length of stay was 7 (IQR 4–13) days and 90-day mortality was 36%. TEs were diagnosed in 71 patients (7.2%) including pulmonary embolism (1.8%), deep venous thrombosis (1.1%), myocardial ischemia (1.6%), and cerebrovascular ischemia (3.0%). Mean time to event was 8.4 ± 7.0 days. Rates of TE were 5% among those with OAT-related ICH and 8% among those with non-OAT ICH (P = 0.2). After multivariable Cox regression, the only independent risk factor for developing a TE was external ventricular drain placement (HR 2.1, 95% CI 1.1–4.1, P = 0.03). TEs had no effect on 90-day mortality (HR 0.7, 95% CI 0.5–1.1, P = 0.1).
Conclusions
The incidence of TEs in an unselected ICH population was 7.2%. Patients with OAT-related ICH were not at increased risk of TEs.
doi:10.1007/s12028-008-9134-3
PMCID: PMC4307935  PMID: 18810667
Cerebral hemorrhage; Warfarin; Venous thrombosis; Pulmonary embolism; Brain ischemia; Myocardial ischemia
4.  Unexpected Recovery of Function after Severe Traumatic Brain Injury: The Limits of Early Neuroimaging-Based Outcome Prediction 
Neurocritical care  2013;19(3):364-375.
Background
Prognostication in the early stage of traumatic coma is a common challenge in the neuro-intensive care unit. We report the unexpected recovery of functional milestones (i.e., consciousness, communication, and community reintegration) in a 19-year-old man who sustained a severe traumatic brain injury. The early magnetic resonance imaging (MRI) findings, at the time, suggested a poor prognosis.
Methods
During the first year of the patient’s recovery, MRI with diffusion tensor imaging (DTI) and T2*-weighted imaging was performed on day 8 (coma), day 44 (minimally conscious state), day 198 (post-traumatic confusional state), and day 366 (community reintegration). Mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in the corpus callosum, cerebral hemispheric white matter and thalamus were compared with clinical assessments using the Disability Rating Scale (DRS).
Results
Extensive diffusion restriction in the corpus callosum and bihemispheric white matter was observed on day 8, with ADC values in a range typically associated with neurotoxic injury (230 to 400 × 10−6 mm2/sec). T2*-weighted MRI revealed widespread hemorrhagic axonal injury in the cerebral hemispheres, corpus callosum, and brainstem. Despite the presence of severe axonal injury on early MRI, the patient regained the ability to communicate and perform activities of daily living independently at one year post-injury (DRS = 8).
Conclusions
MRI data should be interpreted with caution when prognosticating for patients in traumatic coma. Recovery of consciousness and community reintegration are possible even when extensive traumatic axonal injury is demonstrated by early MRI.
doi:10.1007/s12028-013-9870-x
PMCID: PMC3902071  PMID: 23860665
Traumatic brain injury; Coma; Magnetic resonance imaging; Traumatic axonal injury; Diffusion-weighted imaging; Apparent diffusion coefficient; Diffusion tensor imaging
5.  High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods 
Neurocritical care  2013;19(2):257-266.
Background
Hemoglobin degradation products, in particular iron, have been implicated in secondary neuronal injury following intracerebral hemorrhage (ICH). The iron chelator Deferoxamine Mesylate (DFO) exerts diverse neuroprotective effects, reduces perihematoma edema (PHE) and neuronal damage, and improves functional recovery after experimental ICH. We hypothesize that treatment with DFO could minimize neuronal injury and improve outcome in ICH patients. As a prelude to test this hypothesis, we conducted a Phase I, open-label study to determine the tolerability, safety, and maximum tolerated dose (MTD) of DFO in patients with ICH. Intravenous infusions of DFO in doses up to 62 mg/kg/day (up to a maximum of 6000 mg/day) were well-tolerated and did not seem to increase serious adverse events (SAEs) or mortality. We have initiated a multi-center, double-blind, randomized, placebo-controlled, Phase II clinical trial (High Dose Deferoxamine [HI-DEF] in Intracerebral Hemorrhage) to determine if it is futile to move DFO forward to Phase III efficacy evaluation.
Methods
We will randomize 324 subjects with spontaneous ICH to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day) or saline placebo, given by intravenous infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. All subjects will be followed for 3 months and will receive standard of care therapy while participating in the study. At 3 months, the proportion of DFO-treated subjects with a good clinical outcome, assessed by modified Rankin Scale, will be compared to the placebo proportion in a futility analysis.
Conclusions
The Hi-Def trial is expected to advance our understanding of the pathopgysiology of secondary neuronal injury in ICH and will provide a crucial “Go/No Go” signal as to whether a Phase III trial to investigate the efficacy of DFO is warranted.
doi:10.1007/s12028-013-9861-y
PMCID: PMC3932442  PMID: 23943316
Intracerebral hemorrhage; Deferoxamine; Clinical trial; Futility design
6.  Stroke, IL-1ra, IL1RN, Infection and Outcome 
Neurocritical care  2014;21(1):140-146.
Background
Infection is common following stroke and adversely affects outcome. Previous studies suggest that interleukin-1 receptor antagonist (IL-1ra) and single nucleotide polymorphisms (SNPs) in the IL1RN gene might influence the risk of post-stroke infection and outcome. In this study, we addressed the effects of the rs4251961 SNP in IL1RN on infection risk and outcome.
Methods
Subjects with acute ischemic stroke were enrolled within 72 hours of symptom onset and followed up to one year. Plasma IL-1ra was measured at multiple time points and outcome assessed at 1, 3, 6, and 12 months. Active surveillance for infection occurred while subjects were hospitalized. Subjects were genotyped for the IL1RN rs4251961 polymorphism.
Results
In this population of 113 subjects, those with the minor C allele of rs4251961 polymorphism in IL1RN were more likely to be Caucasian, hypertensive and to have coronary heart disease. Higher plasma IL-1ra was associated with an increased risk of infection (other than pneumonia) and the minor C allele of rs4251961 was independently associated with a decreased risk of infection (other than pneumonia). Initial plasma IL-1ra was not predictive of long term outcome, but patients with the minor C allele of rs4251961 were more likely to experience good (modified Rankin Score <2) long-term outcome.
Conclusions
These data indicate that IL-1ra and IL1RN may influence the risk of infection after stroke, but this influence seems limited to infections other than pneumonia. Further studies are needed to better understand the complexities of immune regulation on infection and outcome after stroke.
doi:10.1007/s12028-013-9899-x
PMCID: PMC4161032  PMID: 24233813
IL-1ra; IL1RN; stroke; infection; outcome
7.  MRI Default Mode Network Connectivity is Associated with Functional Outcome after Cardiopulmonary Arrest 
Neurocritical care  2014;20(3):348-357.
Introduction
We hypothesized that the degree of preserved functional connectivity within the DMN during the first week after cardiopulmonary arrest (CPA) would be associated with functional outcome at hospital discharge.
Methods
Initially comatose CPA survivors with indeterminate prognosis at 72 hours were enrolled. Seventeen CPA subjects between 4–7 days after CPA and 17 matched controls were studied with task-free fMRI. Independent component analysis was performed to delineate the DMN. Connectivity strength in the DMN was compared between CPA subjects and controls, as well as between CPA subjects with good outcome (discharge Cerebral Performance Category or CPC 1–2) and those with bad outcome (CPC 3–5). The relationship between connectivity strength in the posterior cingulate cortex (PCC) and precuneus (PC) within the DMN with discharge CPC was evaluated using linear regression.
Results
Compared to controls, CPA subjects had significantly lower connectivity strength in subregions of the DMN, the PCC and PC (p <0.0001). Furthermore, connectivity strength in the PCC and PC was greater in CPA subjects with good outcome (n=8) than those with bad outcome (n=9) (p <0.003). Among CPA subjects, the connectivity strength in the PCC and PC showed strong linear correlations with the discharge CPC (p <0.005).
Conclusion
Among initially comatose CPA survivors with indeterminate prognosis, task-free fMRI demonstrated graded disruption of DMN connectivity, especially in those with bad outcomes. If confirmed, connectivity strength in the PC/PCC may provide a clinically useful prognostic marker for functional recovery after CPA.
doi:10.1007/s12028-014-9953-3
PMCID: PMC4136809  PMID: 24464830
8.  Impact of Methamphetamine on Regional Metabolism and Cerebral Blood Flow after Traumatic Brain Injury 
Neurocritical care  2013;19(2):183-191.
Substance abuse is a frequent comorbid condition among patients with Traumatic Brain Injury (TBI), but little is known about its potential additive or interactive effects on tissue injury or recovery from TBI. This study aims to evaluate changes in regional metabolism and cerebral perfusion in subjects who used methamphetamine(METH) prior to sustaining a TBI. We hypothesized that METH use would decrease pericontusional cerebral perfusion and markers of neuronal metabolism, in TBI patients compared to those without METH use.
Methods
This is a single center prospective observational study. Adults with moderate and severe TBI were included. MRI scanning was performed on a 3 Tesla scanner. MP-RAGE and FLAIR sequences as well as Metabolite spectra of NAA and lactate in pericontusional and contralateral voxels identified on the MP-RAGE scans. A spiral-based FAIR sequence was used for the acquisition of cerebral blood flow (CBF) maps. Regional CBF images were analyzed using Image J open source software. Pericontusional and contralateral CBF, NAA and lactate were assessed in the entire cohort and in the METH and non-METH groups.
Results
17 subjects completed the MR studies. Analysis of entire cohort: Pericontusional NAA concentrations (5.81 ± 2.0 mM/kg) were 12% lower compared to the contralateral NAA (6.98 ± 1.2 mM/kg; p=0.03). Lactate concentrations and CBF were not significantly different between the two regions, however, regional cerebral blood flow was equally reduced in the two regions. Subgroup analysis: 41% of subjects tested positive for METH. The mean age, Glasgow Coma Scale and time to scan did not differ between groups. The two subject groups also had similar regional NAA and lactate. Pericontusional CBF was 60% lower in the METH users than the non-users, p=0.04; contralateral CBF did not differ between the groups.
Conclusion
This small study demonstrates that tissue metabolism is regionally heterogeneous after TBI and pericontusional perfusion was significantly reduced in the METH subgroup.
doi:10.1007/s12028-013-9871-9
PMCID: PMC4111452  PMID: 23836426
Adult brain injury; MRI; blood flow; metabolism; alcohol and drug abuse
9.  Predictors of Late Neurological Deterioration After Spontaneous Intracerebral Hemorrhage 
Neurocritical care  2013;19(3):299-305.
Background
Although intracerebral hemorrhage (ICH) is a common form of cerebrovascular disease, little is known about factors leading to neurological deterioration occurring beyond 48 h after hematoma formation. The purpose of this study was to characterize the incidence, consequences, and associative factors of late neurological deterioration (LND) in patients with spontaneous ICH.
Methods
Using the Duke University Hospital Neuroscience Intensive Care Unit database from July 2007 to June 2012, a cohort of 149 consecutive patients with spontaneous supratentorial ICH met criteria for analysis. LND was defined as a decrease of two or more points in Glasgow Coma Scale score or death during the period from 48 h to 1 week after ICH symptom onset. Unfavorable outcome was defined as a modified Rankin Scale score of >2 at discharge.
Results
Forty-three subjects (28.9 %) developed LND. Logistic regression models revealed hematoma volume (OR = 1.017, 95 % CI 1.003–1.032, p = 0.019), intraventricular hemorrhage (OR = 2.519, 95 % CI 1.142–5.554, p = 0.022) and serum glucose on admission (OR = 2.614, 95 % CI 1.146–5.965, p = 0.022) as independent predictors of LND. After adjusting for ICH score, LND was independently associated with unfavorable outcome (OR = 4.000, 95 % CI 1.280–12.500, p = 0.017). In 65 subjects with follow-up computed tomography images, an increase in midline shift, as a surrogate for cerebral edema, was independently associated with LND (OR = 3.822, 95 % CI 1.157–12.622, p = 0.028).
Conclusions
LND is a common phenomenon in patients with ICH; further, LND appears to affect outcome. Independent predictors of LND include hematoma volume, intraventricular hemorrhage, and blood glucose on admission. Progression of perihematomal edema may be one mechanism for LND.
doi:10.1007/s12028-013-9894-2
PMCID: PMC4100944  PMID: 23979796
Intracerebral hemorrhage; Neurological deterioration; Predictors; Outcome; Brain edema
10.  Post-Stroke Infection: A Role for IL-1ra? 
Neurocritical care  2011;14(2):244-252.
Background
Infection is common following stroke and is independently associated with worse outcome. Clinical studies suggest that infections occur more frequently in those individuals with stroke-induced immunologic dys-function. This study sought to explore the contribution of immunomodulatory cytokines and hormones to lymphocyte function and infection risk.
Methods
Patients (N = 112) were enrolled as soon as possible after the onset of ischemic stroke. Blood was drawn to assess plasma cortisol, IL-10, IL-1ra, lymphocyte numbers, and lymphocyte function at 72 h after stroke onset; infections were censored through 21 days after stroke onset.
Results
Infection occurred in 25% of patients. Stroke severity was the most important predictor of infection risk. Increased plasma cortisol, IL-10, and IL-1ra, as well as decreased lymphocyte numbers, at 72 h after stroke onset were associated with risk of subsequent infection. After controlling for stroke severity, only IL-1ra was independently associated with infection risk, and the degree of risk was consistent throughout the post-stroke period. Infection, but not IL-1ra itself, was associated with worse outcome at 3 months.
Conclusions
In this study cohort, increased plasma IL-1ra was independently associated with the risk of post-stroke infection. Further studies are needed to validate this finding, which could have important implications for stroke therapy.
doi:10.1007/s12028-010-9490-7
PMCID: PMC4096896  PMID: 21174170
Stroke; IL-1ra; Infection; IL-10; Cortisol
11.  Glibenclamide in Cerebral Ischemia and Stroke 
Neurocritical care  2014;20(2):319-333.
The sulfonylurea receptor 1 (Sur1)–transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and “accidental necrotic cell death.” Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1–2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.
doi:10.1007/s12028-013-9923-1
PMCID: PMC3954940  PMID: 24132564
Cerebral ischemia; Stroke; Sur1; Sur1–Trpm4 channel; Glibenclamide; RP-1127; Stroke Therapy Academic Industry Roundtable (STAIR)
12.  Infarct Volume After Hyperacute Infusion of Hypertonic Saline in a Rat Model of Acute Embolic Stroke 
Neurocritical care  2013;18(1):106-114.
Introduction
Hypertonic saline (HS) can treat cerebral edema arising from a number of pathologic conditions. However, physicians are reluctant to use it during the first 24 h after stroke because of experimental evidence that it increases infarct volume when administered early after reperfusion. Here, we determined the effect of HS on infarct size in an embolic clot model without planned reperfusion.
Methods
A clot was injected into the internal carotid artery of male Wistar rats to reduce perfusion in the middle cerebral artery territory to less than 40 % of baseline, as monitored by laser-Doppler flowmetry. After 25 min, rats were randomized to receive 10 mL/kg of 7.5 % HS (50:50 chloride:acetate) or normal saline (NS) followed by a 0.5 mL/h infusion of the same solution for 22 h.
Results
Infarct volume was similar between NS and HS groups (in mm3: cortex 102 ± 65 mm3 vs. 93 ± 49 mm3, p = 0.72; caudoputamenal complex 15 ± 9 mm3 vs. 21 ± 14, p = 0.22; total hemisphere 119 ± 76 mm3 vs. 114 ± 62, p = 0.88, respectively). Percent water content was unchanged in the infarcted hemisphere (NS 81.6 ± 1.5 %; HS 80.7 ± 1.3 %, p = 0.16), whereas the HS-treated contralateral hemisphere was significantly dehydrated (NS 79.4 ± 0.8 %; HS 77.5 ± 0.8 %, p < 0.01).
Conclusions
HS reduced contralateral hemispheric water content but did not affect ipsilateral brain water content when compared to NS. Infarct volume was unaffected by HS administration at all evaluated locations.
doi:10.1007/s12028-012-9768-z
PMCID: PMC3565002  PMID: 22886394
Embolic stroke; Hypernatremia; Hypertonic saline; Normal saline; Tissue water content; Wistar rats
13.  Safety of Intraventricular Hemorrhage (IVH) Thrombolysis Based on CT Localization of External Ventricular Drain (EVD) Fenestrations and Analysis of EVD Tract Hemorrhage 
Neurocritical care  2013;19(1):103-110.
Background
The purpose of the study is to review the CT findings associated with ventriculostomy placement in regards to the safety of an EVD plus recombinant tissue plasminogen activator (rt-PA) for IVH.
Methods
A retrospective review was conducted for patients receiving intraventricular rt-PA for IVH from January 2004 to September 2009. Safety was assessed by the presence of EVD tract hemorrhage by CT at baseline after EVD placement, worsening hemorrhage after rt-PA, and CSF infection. IVH volumetrics were assessed by the Le Roux score and outcomes by Glasgow Outcome Scale and modified Rankin Scale.
Results
Twenty-seven patients received rt-PA for IVH. Median dose was 2 mg (range 0.3–8) and a median of two doses (range 1–17) were given. Worsening EVD catheter tract hemorrhage after rt-PA was 46.7 %, with a significantly higher incidence of worsening tract hemorrhage seen with incorrectly placed EVDs (p = 0.04). IVH hematoma burden decreased by a median Le Roux score of 10 (range 3–16) prior to rt-PA to 4 (range 0–16) after rt-PA. There were no central nervous system bacterial infections.
Conclusion
Intraventricular rt-PA appears to be relatively safe especially when all EVD fenestrations are within the ventricle and reduces IVH burden similar to other studies. We describe a CT-based EVD tract hemorrhage grading scale to evaluate EVD tract hemorrhage before and after thrombolysis, and a bone-window technique to evaluate EVD fenestrations prior to IVH thrombolysis. Further research is needed evaluating these imaging techniques in regard to intraventricular thrombolytic safety and EVD tract hemorrhage.
doi:10.1007/s12028-012-9713-1
PMCID: PMC3785325  PMID: 22544476
Intracerebral hemorrhage; Intraventricular hemorrhage; Cerebrovascular disease; Stroke; Critical care
14.  A Population-Based Analysis of Ethnic Differences in Admission to the Intensive Care Unit after Stroke 
Neurocritical care  2012;17(3):348-353.
Background
Mexican Americans (MAs) have shown lower post-stroke mortality compared to non-Hispanic whites (NHWs). Limited evidence suggests race/ethnic differences exist in intensive care unit (ICU)admissions following stroke. Our objective was to investigate the association of ethnicity with admission to the ICU following stroke.
Methods
Cases of intracerebral hemorrhage and acute ischemic stroke were prospectively ascertained as part of the Brain Attack Surveillance in Corpus Christi (BASIC) project for the period January, 2000 through December, 2009. Logistic regression models fitted within the generalized additive model framework were used to test associations between ethnicity and ICU admission and potential confounders. An interaction term between age and ethnicity was investigated in the final model.
Results
A total 1,464 cases were included in analysis. MAs were younger, more likely to have diabetes, and less likely to have atrial fibrillation, health insurance, or high school diploma than NHWs. On unadjusted analysis, there was a trend toward MAs being more likely to be admitted to ICU than NHWs (34.6% versus 30.3%; OR=1.22; 95% CI 0.98–1.52; p=0.08). However, on adjusted analysis, no overall association between MA ethnicity and ICU admission (OR=1.13; 95% CI 0.85–1.50) was found. When an interaction term for age and ethnicity was added to this model, there was only borderline evidence for effect modification by age of the ethnicity/ICU relationship (p=0.16).
Conclusions
No overall association between ethnicity and ICU admission was observed in this community. ICU utilization alone does not likely explain ethnic differences in survival following stroke between MAs and NHWs.
doi:10.1007/s12028-012-9770-5
PMCID: PMC3520600  PMID: 22892883
Intracerebral hemorrhage; Acute ischemic stroke; Mexican Americans; Intensive care unit
15.  Prolonged Emergency Department Length of Stay is not Associated with Worse Outcomes in Patients with Intracerebral Hemorrhage 
Neurocritical care  2012;17(3):334-342.
Background
Prolonged emergency department length of stay (EDLOS) has been associated with worse patient outcomes, longer inpatient stays, and failure to meet quality measures in several acute medical conditions, but these findings have not been consistently reproduced. We performed this study to explore the hypothesis that longer EDLOS would be associated with worse outcomes in a large cohort of patients presenting with spontaneous intracerebral hemorrhage (ICH).
Methods
We performed a secondary analysis of a prospective cohort of consecutive patients with spontaneous ICH who presented to a single academic referral center from February 2005 to October 2009. The primary exposure variable was EDLOS, and our primary outcome was neurologic status at hospital discharge, measured with a modified Rankin scale (mRS). Secondary outcomes were ICU length of stay, total hospital length of stay, and total hospital costs.
Results
Our cohort included 616 visits of which 42 were excluded, leaving 574 patient encounters for analysis. Median age was 75 years (IQR 63–82), median EDLOS 5.1 h (IQR 3.7–7.1) and median discharge mRS 4 (IQR 3–6). Thirty percent of the subjects died in-hospital. Multivariable proportional odds logistic regression, controlling for age, initial Glasgow Coma Scale, initial hematoma volume, ED occupancy at registration, and the need for intubation or surgical intervention, demonstrated no association between EDLOS and outcome. Furthermore, multivariable analysis revealed no association of increased EDLOS with ICU or hospital length of stay or hospital costs.
Conclusion
We found no effect of EDLOS on neurologic outcome or resource utilization for patients presenting with spontaneous ICH.
doi:10.1007/s12028-011-9629-1
PMCID: PMC3684176  PMID: 21912953
Emergency medicine; Emergency department crowding; Emergency department length of stay; Intracerebral hemorrhage
16.  CTA Spot Sign Predicts Hematoma Expansion in Patients with Delayed Presentation After Intracerebral Hemorrhage 
Neurocritical care  2012;17(3):421-428.
Background
Hematoma expansion after acute intracerebral hemorrhage occurs most frequently in patients presenting within 3 h of symptom onset. However, the majority of patients present outside this window or with an unknown onset time. We investigated the prevalence of hematoma expansion in these patients and assessed the accuracy of the CT angiography (CTA) spot sign for identifying risk of hematoma expansion.
Methods
We analyzed 391 consecutive patients undergoing CTA and a followup CT. CTA spot sign readings were performed by two experienced readers and hematoma expansion was assessed by means of semi-automated software.
Results
Hematoma expansion occurred in 18 % of patients. When stratified by time from symptom onset to initial CT, hematoma expansion rates were: 39 % within 3 h; 11 % between 3 and 6 h, 11 % beyond 6 h (but with known onset), and 20 % in patients with unknown symptom onset. Of patients who developed hematoma expansion, only 38 % presented within 3 h. The accuracy of the spot sign in predicting hematoma expansion was 0.67 for patients presenting within 3 h, 0.83 between 3 and 6 h, 0.88 after 6 h, and 0.76 for patients presenting with an unknown onset time.
Conclusions
A substantial number of patients destined to suffer from hematoma expansion present either late or with an unknown symptom onset time. The CTA spot sign accurately identifies patients destined to expand regardless of time from symptom onset, and may therefore open a path to offer clinical trials and novel therapies to the many patients who do not present acutely.
doi:10.1007/s12028-012-9765-2
PMCID: PMC3707619  PMID: 22878870
Intracerebral hemorrhage; CT angiography; CTA spot sign; Hematoma expansion; Late presentation
17.  Increased CSF Concentrations of Myelin Basic Protein After TBI in Infants and Children: Absence of Significant Effect of Therapeutic Hypothermia 
Neurocritical care  2012;17(3):10.1007/s12028-012-9767-0.
Background
The objectives of this study were to determine effects of severe traumatic brain injury (TBI) on cerebrospinal fluid (CSF) concentrations of myelin basic protein (MBP) and to assess relationships between clinical variables and CSF MBP concentrations.
Methods
We measured serial CSF MBP concentrations in children enrolled in a randomized controlled trial evaluating therapeutic hypothermia (TH) after severe pediatric TBI. Control CSF was obtained from children evaluated, but found not to be having CNS infection. Generalized estimating equation models and Wilcoxon Rank-Sum test were used for comparisons of MBP concentrations.
Results
There were 27 TBI cases and 57 controls. Overall mean (±SEM) TBI case MBP concentrations for 5 days after injury were markedly greater than controls (50.49 ± 6.97 vs. 0.11 ± 0.01 ng/ml, p < 0.01). Mean MBP concentrations were lower in TBI patients < 1 year versus >1 year (9.18 ± 1.67 vs. 60.22 ± 8.26 ng/ml, p = 0.03), as well as in cases with abusive head trauma (AHT) versus non-abusive TBI (14.46 ± 3.15 vs. 61.17 ± 8.65 ng/ml, p = 0.03). TH did not affect MBP concentrations.
Conclusions
Mean CSF MBP increases markedly after severe pediatric TBI, but is not affected by TH. Infancy and AHT are associated with low MBP concentrations, suggesting that age-dependent myelination influences MBP concentrations after injury. Given the magnitude of MBP increases, axonal injury likely represents an important therapeutic target in pediatric TBI.
doi:10.1007/s12028-012-9767-0
PMCID: PMC3836276  PMID: 22890910
Axonal injury; Pediatrics; Secondary injury
18.  Confounding by Indication in Retrospective Studies of Intracerebral Hemorrhage: Antiepileptic Treatment and Mortality 
Neurocritical care  2012;17(3):361-366.
Introduction
Intracerebral hemorrhage (ICH) is a highly fatal disease with few proven treatments. Data to guide clinician decisions for therapies, including antiepileptic drugs (AED), are limited. Published studies on AED treatment in ICH have provided conflicting results. We investigated the effect of AED treatment on 90-day mortality after ICH in a large prospectively ascertained cohort.
Methods
We conducted a retrospective analysis of a prospectively assembled cohort of patients with ICH in the Electronic supplementary material The online version of this article (doi:10.1007/s12028-012-9776-z) contains supplementary material, which is available to authorized users. supratentorial regions, comparing 90-day mortality and modified Rankin Score among 543 patients treated with AED during hospitalization and 639 AED-free ICH. Supratentorial ICH location was categorized as lobar or deep hemispheric.
Results
Multivariate analysis demonstrated an association between AED treatment and reduced 90-day mortality in supratentorial ICH (OR = 0.62, 95 % CI 0.42–0.90, p = 0.01) and the subset of lobar ICH (OR = 0.49, 95 % CI 0.25–0.96, p = 0.04). When analyses were restricted to subjects surviving longer than 5 days from ICH, however, no association between AED treatment and a 90-day outcome, regardless of hemorrhage location (all p > 0.15), was detected, despite more than adequate power to detect the originally observed association.
Conclusion
These results suggest that AED treatment in acute ICH is not associated with 90-day mortality or outcome and that any detected association could arise by confounding by indication, in which the most severely affected patients are those in whom AEDs are prescribed. They provide a cautionary example of the limitations of drawing conclusions about treatment effects from observational data.
doi:10.1007/s12028-012-9776-z
PMCID: PMC3707622  PMID: 22965324
Intracerebral hemorrhage; Antiepileptic; Outcome; Confounding; Confounding by indication
19.  Factors Predicting Extubation Success in Patients with Guillain-Barré Syndrome 
Neurocritical care  2006;5(3):10.1385/NCC:5:3:230.
Introduction
Accurate prediction of successful extubation in patients with Guillain-Barré syndrome (GBS) is an important clinical problem. We hypothesized that reversal of clinical indices used to intubate a patient (i.e., declining vital capacity [VC]) predict extubation.
Methods
This was a retrospective study in neurocritical care units at two teaching hospitals identifying all mechanically-ventilated patients with GBS.
Results
A total of 44 patients with GBS were included. Of these, 14 patients were successfully extubated. There were 10 failed extubations among six patients; and 20 patients underwent tracheostomy without an extubation trial. On the day of extubation, lower negative inspiratory force (NIF) (−50.3 ± 12.7 versus −28.6 ± 16.5 cm H2O, p = 0.0005) and higher VC (21.9 ± 8.4 versus 13.0 ± 5.9 mL/kg, p = 0.003) correlated with successful extubation. Change in VC preintubation to preextubation by greater than 4 mL/kg correlated with 82% sensitivity and 90% positive predictive value for successful extubation. Failed extubations were associated with the presence of pulmonary comorbidities (79 versus 36%, p = 0.008) and autonomic dysfunction (73 versus 27%, p = 0.008). Length of stay (LOS) in the intensive care unit (ICU) was increased in patients who failed extubation and in those patients who underwent tracheostomy (21.5 ± 11.1 versus 12.5 ± 8.7, p = 0.005). In multivariate analysis, higher VC at extubation was associated with successful extubation (p = 0.05).
Conclusions
In mechanically-ventilated patients with respiratory failure secondary to GBS, NIF less than −50 cm H2O, and VC improvement preextubation to preintubation by 4 mL/kg were significantly associated with successful extubation. Failed extubation or need for tracheostomy correlated with autonomic dysfunction, pulmonary comorbidities, and prolonged LOS in the ICU. Such parameters may be helpful in identifying patients with GBS likely to succeed extubation versus early referral for tracheostomy.
doi:10.1385/NCC:5:3:230
PMCID: PMC3817284  PMID: 17290095
Extubation; Guillain-Barré syndrome; mechanical ventilation; vital capacity
20.  Research and Technology in Neurocritical Care 
Neurocritical care  2012;16(1):42-54.
The daily practice of neurointensivists focuses on the recognition of subtle changes in the neurological examination, interactions between the brain and systemic derangements, and brain physiology. Common alterations such as fever, hyperglycemia, and hypotension have different consequences in patients with brain insults compared with patients of general medical illness. Various technologies have become available or are currently being developed. The session on ‘‘research and technology’’ of the first neurocritical care research conference held in Houston in September of 2009 was devoted to the discussion of the current status, and the research role of state-of-the art technologies in neurocritical patients including multi-modality neuromonitoring, biomarkers, neuroimaging, and ‘‘omics’’ research (proteomix, genomics, and metabolomics). We have summarized the topics discussed in this session. We have provided a brief overview of the current status of these technologies, and put forward recommendations for future research applications in the field of neurocritical care.
doi:10.1007/s12028-011-9609-5
PMCID: PMC3790471  PMID: 21796494
Neurocritical care; Neuromonitoring; Genomics; Neuroimaging; Biomarkers
21.  The Pattern and Pace of Hyperacute Hemorrhage Expansion 
Neurocritical care  2012;17(2):250-254.
Background
Intracerebral hemorrhage (ICH) expansion is common during the first 24 hours after onset, but the pattern and pace of hyperacute hemorrhage growth have not been described because serial imaging is typically performed over the course of hours and days, not minutes. The purpose of this study is to elucidate the spatial and temporal characteristics of hyperacute hemorrhage expansion within minutes of ICH onset.
Methods
An 86-year-old man with probable cerebral amyloid angiopathy developed an ICH while in the MRI scanner. Hyperacute hemorrhage growth was captured at three time points over a 14-minute interval of MRI data acquisition and at a fourth time point with CT 22 hours later. MRI and CT datasets were spatially coregistered, and three-dimensional models of ICH expansion were generated.
Results
Longitudinal analysis revealed that the spatial pattern of ICH growth was asymmetric at each time point. Maximal expansion occurred along the anterior-posterior plane during the first four minutes but along the superior-inferior plane during the next 10 minutes. The temporal pace of ICH expansion was also non-uniform, as growth along the anterior-posterior plane outpaced medial-lateral growth during the first 4 minutes (2.8 cm vs. 2.5 cm), but medial-lateral growth outpaced anterior-posterior growth over the next 10 minutes (1.0 cm vs. 0.2 cm).
Conclusions
We provide evidence for asymmetric, non-uniform expansion of a hyperacute hemorrhage. These serial imaging observations suggest that hemorrhage expansion may be caused by local cascades of secondary vessel rupture as opposed to ongoing bleeding from a single ruptured vessel.
doi:10.1007/s12028-012-9738-5
PMCID: PMC3552298  PMID: 22826138
intracerebral hemorrhage; MRI; cerebral amyloid angiopathy; cerebral microbleed
22.  Calculating the Risk Benefit Equation for Aggressive Treatment of Non-convulsive Status Epilepticus 
Neurocritical care  2013;18(2):216-227.
Objective
To address the question: does non-convulsive status epilepticus warrant the same aggressive treatment as convulsive status epilepticus?
Method
We used a decision model to evaluate the risks and benefits of treating non-convulsive status epilepticus with intravenous anesthetics and ICU-level aggressive care. We investigated how the decision to use aggressive versus non-aggressive management for non-convulsive status epilepticus impacts expected patient outcome for four etiologies: absence epilepsy, discontinued antiepileptic drugs, intraparenchymal hemorrhage, and hypoxic ischemic encephalopathy. Each etiology was defined by distinct values for five key parameters: baseline mortality rate of the inciting etiology; efficacy of non-aggressive treatment in gaining control of seizures; the relative contribution of seizures to overall mortality; the degree of excess disability expected in the case of delayed seizure control; and the mortality risk of aggressive treatment.
Results
Non-aggressive treatment was favored for etiologies with low morbidity and mortality such as absence epilepsy and discontinued antiepileptic drugs. The risk of aggressive treatment was only warranted in etiologies where there was significant risk of seizure-induced neurologic damage. In the case of post-anoxic status epilepticus, expected outcomes were poor regardless of the treatment chosen. The favored strategy in each case was determined by strong interactions of all five model parameters.
Conclusions
Determination of the optimal management approach to non-convulsive status epilepticus is complex and is ultimately determined by the inciting etiology.
doi:10.1007/s12028-012-9785-y
PMCID: PMC3767472  PMID: 23065689
Non-convulsive status epilepticus; Risk benefit analysis; NCSE; Decision analysis
23.  Continuous Cerebral Blood Flow Autoregulation Monitoring in Patients Undergoing Liver Transplantation 
Neurocritical care  2012;17(1):77-84.
Background
Clinical monitoring of cerebral blood flow (CBF) autoregulation in patients undergoing liver transplantation may provide a means for optimizing blood pressure to reduce the risk of brain injury. The purpose of this pilot project is to test the feasibility of autoregulation monitoring with transcranial Doppler (TCD) and near infrared spectroscopy (NIRS) in patients undergoing liver transplantation and to assess changes that may occur perioperatively.
Methods
We performed a prospective observational study in 9 consecutive patients undergoing orthotopic liver transplantation. Patients were monitored with TCD and NIRS. A continuous Pearson’s correlation coefficient was calculated between mean arterial pressure (MAP) and CBF velocity and between MAP and NIRS data, rendering the variables mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Both Mx and COx were averaged and compared during the dissection phase, anhepatic phase, first 30 mins of reperfusion, and remaining reperfusion phase. Impaired autoregulation was defined as Mx ≥ 0.4.
Results
Autoregulation was impaired in one patient during all phases of surgery, in two patients during the anhepatic phase, and in one patient during reperfusion. Impaired autoregulation was associated with a MELD score > 15 (p=0.015) and postoperative seizures or stroke (p<0.0001). Analysis of Mx categorized in 5-mmHg bins revealed that MAP at the lower limit of autoregulation (MAP when Mx increased to ≥ 0.4) ranged between 40 and 85 mmHg. Average Mx and average COx were significantly correlated (p=0.0029). The relationship between COx and Mx remained when only patients with bilirubin > 1.2 mg/dL were evaluated (p=0.0419). There was no correlation between COx and baseline bilirubin (p=0.2562) but MELD score and COx were correlated (p=0.0458). Average COx was higher for patients with a MELD score > 15 (p=0.073) and for patients with a neurologic complication than for patients without neurologic complications (p=0.0245).
Conclusions
These results suggest that autoregulation is impaired in patients undergoing liver transplantation, even in the absence of acute, fulminant liver failure. Identification of patients at risk for neurologic complications after surgery may allow for prompt neuroprotective interventions, including directed pressure management.
doi:10.1007/s12028-012-9721-1
PMCID: PMC3748944  PMID: 22644887
24.  Process Improvement Methods Increase the Efficiency, Accuracy and Utility of a Neurocritical Care Research Repository 
Neurocritical Care  2012;17(1):90-96.
Background
Reliable and efficient data repositories are essential for the advancement of research in Neurocritical care. Various factors, such as the large volume of patients treated within the Neuro ICU, their differing length and complexity of hospital stay and the substantial amount of desired information can complicate the process of data collection.
Methods
We adapted the tools of process improvement to the data collection and database design of a research repository for a Neuroscience intensive care unit. Using the Shewhart-Deming method, we implemented an iterative approach to improve the process of data collection for each element. After an initial design phase, we re-evaluated all data fields that were challenging or time-consuming to collect. We then applied root-cause analysis to optimize the accuracy and ease of collection, and to determine the most efficient manner of collecting the maximal amount of data.
Results
During a six month period, we iteratively analyzed the process of data collection for various data elements. For example, the pre-admission medications were found to contain numerous inaccuracies after comparison with a gold standard (sensitivity 71% and specificity 94%). Also, our first method of tracking patient admissions and discharges contained higher than expected errors (sensitivity 94% and specificity 93%). In addition to increasing accuracy, we focused on improving efficiency. Through repeated incremental improvements, we reduced the number of subject records that required daily monitoring from 40 to 6 per day, and decreased daily effort from 4.5 to 1.5 hours per day.
Conclusions
By applying process improvement methods to the design of a Neuroscience ICU data repository, we achieved a three-fold improvement in efficiency and increased accuracy. Although individual barriers to data collection will vary from institution to institution, a focus on process improvement is critical to overcoming these barriers.
doi:10.1007/s12028-012-9689-x
PMCID: PMC3401358  PMID: 22434546
25.  Cerebral hemodynamic and metabolic effects of equi-osmolar doses mannitol and 23.4% saline in patients with edema following large ischemic stroke 
Neurocritical care  2011;14(1):11-17.
Cerebral edema following ischemic stroke is frequently treated with mannitol and hypertonic saline (HS) although their relative cerebrovascular and metabolic effects are incompletely understood, and may operate independent of their ability to lower intracranial pressure. We compared the effects of 20% mannitol and 23.4% saline on cerebral blood flow (CBF), blood volume (CBV), oxygen extraction fraction (OEF) and oxygen metabolism (CMRO2), in nine ischemic stroke patients who deteriorated and had >2 mm midline shift on imaging. 15O-PET was performed before and one hour after randomly assigned equi-osmolar doses of mannitol (1.0 g/kg) or 23.4% saline (0.686 mL/kg). Baseline CBF (ml/100g/min) in the infarct core, peri-infarct region, remaining ipsilateral hemisphere and contralateral hemisphere in the mannitol group was 5.0±3.9, 25.6±4.4, 35.6±8.6 and 45.5±2.2 and in the HS group was 8.3±9.8, 35.3±10.9, 38.2±15.1, and 35.2±12.4. There was a trend for CBF to rise in the contralateral hemisphere after mannitol from 45.5±12.2 to 57.6±21.7, p=0.098, but not HS. CBV, OEF and CMRO2 did not change after either agent. Change in CBF in the contralateral hemisphere following osmotic therapy was strongly correlated with baseline blood pressure (R2= 0.879, p=0.002). We conclude that at higher perfusion pressures osmotic agents may raise CBF in non-ischemic tissue.
doi:10.1007/s12028-010-9465-8
PMCID: PMC3727965  PMID: 21042881
osmotic; hypertonic saline; mannitol; cerebral blood flow; cerebral blood volume

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