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1.  Outcomes in Severe Middle Cerebral Artery Ischemic Stroke 
Neurocritical care  2014;21(1):20-26.
Severe middle cerebral artery stroke (MCA) is associated with a high rate of morbidity and mortality. We assessed the hypothesis that patient specific variables may be associated with outcomes. We also sought to describe under-recognized patient-centered outcomes.
A consecutive, multi-institution, retrospective cohort of adult patients (≤70 years) was established from 2009-2011. We included patients with NIHSS score ≥ 15 and infarct volume ≥ 60 mL measured within 48 hours of symptom onset. Malignant edema was defined as the development of midline brain shift of ≥ 5 mm in the first 5 days. Exclusion criterion was enrollment in any experimental trial. A univariate and multivariate logistic regression analysis was performed to model and predict the factors related to outcomes.
46 patients (29 female, 17 male; mean age 57.3±1.5 years) met study criteria. The mortality rate was 28% (n=13). In a multivariate analysis, only concurrent anterior cerebral artery (ACA) involvement was associated with mortality (OR 9.78, 95% CI 1.15, 82.8, p=0.04). In the malignant edema subgroup (n=23, 58%), 4 died (17%), 7 underwent decompressive craniectomy (30%), 7 underwent tracheostomy (30%), and 15 underwent gastrostomy (65%).
Adverse outcomes after severe stroke are common. Concurrent ACA involvement predicts mortality in severe MCA stroke. It is useful to understand the incidence of life sustaining procedures, such as tracheostomy and gastrostomy, as well as factors that contribute to their necessity.
PMCID: PMC3880600  PMID: 23839704
Brain injuries; Brain edema; Intracranial pressure; Stroke; Fatal outcome; Tracheostomy; Gastrostomy; Decompressive craniectomy
2.  Endotracheal Intubation in Patients Treated for Prehospital Status Epilepticus 
Neurocritical care  2015;23(1):33-43.
Limited data describe the frequency, timing, or indications for endotracheal intubation (ETI) in patients with status epilepticus. A better understanding of the characteristics of patients with status epilepticus requiring airway interventions could inform clinical care. We sought to characterize ETI use in patients with prehospital status epilepticus.
This study was a secondary analysis of the Rapid Anticonvulsant Medication Prior to Arrival Trial, a multi-center, randomized trial comparing intravenous lorazepam to intramuscular midazolam for prehospital status epilepticus treatment. Subjects received ETI in the prehospital, Emergency Department (ED), or inpatient setting at the discretion of caregivers.
Of 1023 enrollments, 218 (21 %) received ETI. 204 (93.6 %) of the ETIs were performed in the hospital and 14 (6.4 %) in the prehospital setting. Intubated patients were older (52 vs 41 years, p < 0.001), and men underwent ETI more than women (26 vs 21 %, p = 0.047). Patients with ongoing seizures on ED arrival had a higher rate of ETI (32 vs 16 %, p < 0.001), as did those who received rescue anti-seizure medication (29 vs 20 %, p = 0.004). Mortality was higher for intubated patients (7 vs 0.4 %, p < 0.001). Most ETI (n = 133, 62 %) occurred early (prior to or within 30 min after ED arrival), and late ETI was associated with higher mortality (14 vs 3 %, p = 0.002) than early ETI.
ETI is common in patients with status epilepticus, particularly among the elderly or those with refractory seizures. Any ETI and late ETI are both associated with higher mortality.
PMCID: PMC4516705  PMID: 25623785
Status epilepticus; Seizures; Endotracheal intubation; Airway management; Respiratory insufficiency; Emergency medical services
3.  Characterization of the Relationship between Intracranial Pressure and Electroencephalographic Monitoring in Burst Suppressed Patients 
Neurocritical care  2015;22(2):212-220.
To characterize the relationship between ICP and EEG
Simultaneous ICP and EEG data were obtained from burst-suppressed patients and segmented by EEG bursts. Segments were categorized as increasing/decreasing and peak/valley to investigate relationship between ICP changes and EEG burst duration. A generalized ICP response was obtained by averaging all segments time-aligned at burst onsets. A vasodilatation index (VDI) was derived from the ICP pulse waveform and calculated on a sliding interval to investigate cerebrovascular changes post-burst.
Data from two patients contained 309 bursts. 246 ICP segments initially increased, of which 154 peaked. 63 ICP segments decreased, and zero reached a valley. The change in ICP (0.54±0.85mmHg) was significantly correlated with the burst duration (p<0.001). Characterization of the ICP segments showed a peak at 8.1s and a return to baseline at 14.7s. The VDI for increasing segments was significantly elevated (median 0.56, IQR 0.31, p<0.001) and correlated with burst duration (p<0.001).
Changes in the ICP and pulse-waveform shape after EEG burst suggest that these signals can be related within the context of neurovascular coupling.
Existence of a physiological relationship between ICP and EEG may allow the study of neurovascular coupling in acute brain injury patients.
PMCID: PMC4336620  PMID: 25142827
Neurovascular Coupling; Intracranial Pressure; Electroencephalogram; Multi-modality Monitoring; Acute Brain Injury
4.  Regional Brain Injury on Conventional and Diffusion Weighted MRI is Associated with Outcome after Pediatric Cardiac Arrest 
Neurocritical care  2013;19(1):31-40.
To assess regional brain injury on magnetic resonance imaging (MRI) after pediatric cardiac arrest (CA) and to associate regional injury with patient outcome and effects of hypothermia therapy for neuroprotection.
We performed a retrospective chart review with prospective imaging analysis. Children between 1 week and 17 yrs of age who had a brain MRI in the first 2 weeks after CA without other acute brain injury between 2002-2008 were included. Brain MRI (1.5 T General Electric, Milwaukee, WI, USA) images were analyzed by 2 blinded neuroradiologists with adjudication; images were visually graded. Brain lobes, basal ganglia, thalamus, brain stem, and cerebellum were analyzed using T1, T2, and diffusion-weighted images (DWI).
Signal intensity alterations in the basal ganglia on T2 and brain lobes on DWI were associated with unfavorable outcome (all p < .05). Therapeutic hypothermia had no effect on regional brain injury. Repeat brain MRI was infrequently performed but demonstrated evolution of lesions.
Children with lesions in the basal ganglia on conventional MRI and brain lobes on DWI within the first 2 weeks after CA represent a group with increased risk of poor outcome. These findings may be important for developing neuroprotective strategies based on regional brain injury and for evaluating response to therapy in interventional clinical trials.
PMCID: PMC4480371  PMID: 22535278
cardiac arrest; neurological outcome; MRI; pediatric; brain injury
5.  Continuous Optical Monitoring of Cerebral Hemodynamics during Head-of-Bed Manipulation in Brain-Injured Adults 
Neurocritical care  2014;20(3):443-453.
Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering.
Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30° and then at 0°. Relative CBF (rCBF) and concurrent changes in oxy- (ΔHbO2), deoxy- (ΔHb), and total-hemoglobin concentrations (ΔTHC) from left/right frontal cortices were monitored for 5 minutes at each position. Patient and control response differences were assessed.
rCBF, ΔHbO2, and ΔTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P<0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3% ± 28.2%, P=0.938). rCBF increased in controls (18.6% ± 9.4%, P<0.001). ΔHbO2, ΔHb, and ΔTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R=0.40, P<0.001), but not intracranial pressure.
DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of-bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts.
PMCID: PMC3883971  PMID: 23653267
Diffuse correlation spectroscopy; Near-infrared spectroscopy; Diffuse optical spectroscopy; Head-of-bed; Cerebral blood flow; Neurocritical care; Cerebral hemodynamics
6.  Heart Rate Variability for Preclinical Detection of Secondary Complications after Subarachnoid Hemorrhage 
Neurocritical care  2014;20(3):382-389.
We sought to determine if monitoring heart rate variability (HRV) would enable preclinical detection of secondary complications after subarachnoid hemorrhage (SAH).
We studied 236 SAH patients admitted within the first 48 hours of bleed onset, discharged after SAH day 5, and had continuous electrocardiogram records available. The diagnosis and date of onset of infections and DCI events were prospectively adjudicated and documented by the clinical team. Continuous ECG was collected at 240 Hz using a high-resolution data acquisition system. The Tompkins Hamilton algorithm was used to identify R-R intervals excluding ectopic and abnormal beats. Time, frequency, and regularity domain calculations of HRV were generated over the first 48 hours of ICU admission and 24 hours prior to the onset of each patient's first complication, or SAH day 6 for control patients. Clinical prediction rules to identify infection and DCI events were developed using bootstrap aggregation and cost sensitive meta-classifiers.
The combined infection and DCI model predicted events 24 hours prior to clinical onset with high sensitivity (87%) and moderate specificity (66%), and was more sensitive than models that predicted either infection or DCI. Models including clinical and HRV variables together substantially improved diagnostic accuracy (AUC 0.83) compared to models with only HRV variables (AUC 0.61).
Changes in HRV after SAH reflect both delayed ischemic and infectious complications. Incorporation of concurrent disease severity measures substantially improves prediction compared to using HRV alone. Further research is needed to refine and prospectively evaluate real-time bedside HRV monitoring after SAH.
PMCID: PMC4436968  PMID: 24610353
Subarachnoid hemorrhage; nosocomial infection; delayed cerebral ischemia; cerebral vasospasm; sepsis; heart rate variability
7.  Prolonged Elevated Heart Rate is a Risk Factor for Adverse Cardiac Events and Poor Outcome after Subarachnoid Hemorrhage 
Neurocritical care  2014;20(3):390-398.
Sympathetic nervous system hyperactivity is common after subarachnoid hemorrhage (SAH). We sought to determine whether uncontrolled prolonged heart rate elevation is a risk factor for adverse cardiopulmonary events and poor outcome after SAH.
We prospectively studied 447 SAH patients between March 2006 and April 2012. Prior studies define prolonged elevated heart rate (PEHR) as heart rate >95 beats/min for >12 hours. Major adverse cardiopulmonary events were documented according to predefined criteria. Global outcome at 3 months was assessed with the modified Rankin Scale (mRS).
175 (39%) patients experienced PEHR. Nonwhite race/ethnicity, admission Hunt-Hess grade ≥4, elevated APACHE-2 physiological subscore, and modified Fisher score were significant admission predictors of PEHR, whereas documented pre-hospital beta-blocker use was protective. After controlling for admission Hunt-Hess grade, Cox regression using time-lagged covariates revealed that PEHR onset in the previous 48 hours was associated with an increased hazard for delayed cerebral ischemia, myocardial injury and pulmonary edema. PEHR was associated with 3-month poor outcome (mRS 4-6) after controlling for known predictors.
PEHR is associated with major adverse cardiopulmonary events and poor outcome after SAH. Further study is warranted to determine if early sympatholytic therapy targeted at sustained heart rate control can improve outcome after SAH.
PMCID: PMC4437199  PMID: 24043479
heart rate; subarachnoid hemorrhage; cardiopulmonary complications; functional outcome
8.  Exploratory Analysis of Glyburide as a Novel Therapy for Preventing Brain Swelling 
Neurocritical care  2014;21(1):43-51.
Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82 cm3 treated with RP-1127 (glyburide for injection). In this secondary analysis, we tested the hypothesis that RP-1127 may be efficacious in preventing poor outcome when compared to controls.
Controls suffering large hemispheric infarction were obtained from the EPITHET and MMI-MRI studies. We first screened subjects for controls with the same DWI threshold used for enrollment into GAMES-Pilot, 82 cm3. Next, to address imbalances, we applied a weighted Euclidean matching. Ninety day mRS 0–4, rate of decompressive craniectomy, and mortality were the primary clinical outcomes of interest.
The mean age of the GAMES cohort was 51 years and initial DWI volume was 102 ± 23 cm3. After Euclidean matching, GAMES subjects showed similar NIHSS, higher DWI volume, younger age and had mRS 0–4—90 % versus 50 % in controls p = 0.049; with a similar trend in mRS 0–3 (40 vs. 25 %; p = 0.43) and trend toward lower mortality (10 vs. 35 %; p = 0.21).
In this pilot study, RP-1127-treated subjects showed better clinical outcomes when compared to historical controls. An adequately powered and randomized phase II trial of patients at risk for malignant infarction is needed to evaluate the potential efficacy of RP-1127.
PMCID: PMC4435684  PMID: 24671831
Malignant edema; Stroke; Cerebral edema; Brain swelling; Hemorrhage; Hemorrhagic transformation; Clinical trial; Decompressive craniectomy
9.  Improving the Prognosis: Developing the Right Tool for the Right Patients 
Neurocritical care  2014;20(3):345-347.
PMCID: PMC4428590  PMID: 24859167
10.  PAI-1-Derived Peptide EEIIMD Prevents Hypoxia/Ischemia-Induced Aggravation of Endothelin- and Thromboxane-Induced Cerebrovasoconstriction 
Neurocritical care  2014;20(1):111-118.
Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery or post delivery respiratory management. The sole FDA approved treatment for acute stroke is tissue-type plasminogen activator (tPA). Endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after H/I in pigs. Mitogen-activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to impaired vasodilation. This study examined the hypothesis that H/I aggravates the vascular response to two important procontractile mediators released during CNS ischemia, endothelin-1 (ET-1) and thromboxane, which is further enhanced by tPA and ERK MAPK.
Cerebral hypoxia (pO2 35 mmHg for 10 min via inhalation of N2) followed immediately by ischemia (global intracranial pressure elevation for 20 min) was produced in chloralose anesthetized piglets equipped with a closed cranial window.
H/I aggravated pial artery vasconstriction induced by ET-1 and the thromboxane mimetic U 46619. Potentiated vasoconstrictor responses were blocked by EEIIMD, an inhibitor of tPA’s signaling and vascular activities, but unchanged by its inactive analogue EEIIMR. The cerebrospinal fluid concentration of ERK MAPK determined by ELISA was increased by H/I, potentiated by tPA, but blocked by EEIIMD. The ERK MAPK antagonist U 0126 blocked H/I augmented enhancement of ET-1 and U 46619 vasoconstriction.
These data indicate that H/I aggravates ET-1 and thromboxane mediated cerebral vasoconstriction by upregulating endogenous tPA and ERK MAPK.
PMCID: PMC4423732  PMID: 24248736
Cerebral ischemia; Pediatric; Signaling pathways; Cerebral circulation; Pial arteries; Endothelin; Prostaglandins
11.  Metabolic Crisis After Traumatic Brain Injury is Associated with a Novel Microdialysis Proteome 
Neurocritical care  2010;12(3):324-336.
To examine if the metabolic distress after traumatic brain injury (TBI) is associated with a unique proteome.
Patients with severe TBI prospectively underwent cerebral microdialysis for the initial 96 h after injury. Hourly sampling of metabolism was performed and patients were categorized as having normal or abnormal metabolism as evidenced by the lactate/pyruvate ratio (LPR) threshold of 40. The microdialysate was frozen for proteomic batch processing retrospectively. We employed two different routes of proteomic techniques utilizing mass spectrometry (MS) and categorized as diagnostic and biomarker identification approaches. The diagnostic approach was aimed at finding a signature of MS peaks which can differentiate these two groups. We did this by enriching for intact peptides followed by MALDI-MS analysis. For the biomarker identification approach, we applied classical bottom-up (trypsin digestion followed by LC-MS/MS) proteomic methodologies.
Five patients were studied, 3 of whom had abnormal metabolism and 2 who had normal metabolism. By comparison, the abnormal group had higher LPR (1609 ± 3691 vs. 15.5 ± 6.8, P < 0.001), higher glutamate (157 ± 84 vs. 1.8 ± 1.4 μM, P < 0.001), and lower glucose (0.27 ± 0.35 vs. 1.8 ± 1.1 mmol/l, P < 0.001). The abnormal group demonstrated 13 unique proteins as compared with the normal group in the microdialysate. These proteins consisted of cytoarchitectural proteins, as well as blood breakdown proteins, and a few mitochondrial proteins. A unique as yet to be characterized peptide was found at m/z (mass/charge) 4733.5, which may represent a novel biomarker of metabolic distress.
Metabolic distress after TBI is associated with a differential proteome that indicates cellular destruction during the acute phase of illness. This suggests that metabolic distress has immediate cellular consequences after TBI.
PMCID: PMC4347948  PMID: 20225002
Traumatic brain injury; Microdialysis; Proteomics; Metabolic crisis; Biomarkers
12.  Influence of ATP-Binding Cassette Polymorphisms on Neurological Outcome After Traumatic Brain Injury 
Neurocritical care  2013;19(2):192-198.
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.
ABCB1, ABCC1, and ABCC2 SNPs are associated with Glasgow Outcome Scale (GOS) score after TBI.
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.
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)].
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.
PMCID: PMC4332629  PMID: 23896815
Blood-brain barrier; Head trauma; Membrane transporter; Multidrug resistance protein; Multidrug resistance-associated protein; P-Glycoprotein
13.  [No title available] 
PMCID: PMC4049542  PMID: 24233812
14.  Risk of Thromboembolism Following Acute Intracerebral Hemorrhage 
Neurocritical care  2008;10(1):28-34.
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.
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.
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).
The incidence of TEs in an unselected ICH population was 7.2%. Patients with OAT-related ICH were not at increased risk of TEs.
PMCID: PMC4307935  PMID: 18810667
Cerebral hemorrhage; Warfarin; Venous thrombosis; Pulmonary embolism; Brain ischemia; Myocardial ischemia
15.  Unexpected Recovery of Function after Severe Traumatic Brain Injury: The Limits of Early Neuroimaging-Based Outcome Prediction 
Neurocritical care  2013;19(3):364-375.
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.
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).
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).
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.
PMCID: PMC3902071  PMID: 23860665
Traumatic brain injury; Coma; Magnetic resonance imaging; Traumatic axonal injury; Diffusion-weighted imaging; Apparent diffusion coefficient; Diffusion tensor imaging
16.  High Dose Deferoxamine in Intracerebral Hemorrhage (Hi-Def) Trial: Rationale, Design, and Methods 
Neurocritical care  2013;19(2):257-266.
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.
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.
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.
PMCID: PMC3932442  PMID: 23943316
Intracerebral hemorrhage; Deferoxamine; Clinical trial; Futility design
17.  Stroke, IL-1ra, IL1RN, Infection and Outcome 
Neurocritical care  2014;21(1):140-146.
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.
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.
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.
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.
PMCID: PMC4161032  PMID: 24233813
IL-1ra; IL1RN; stroke; infection; outcome
18.  MRI Default Mode Network Connectivity is Associated with Functional Outcome after Cardiopulmonary Arrest 
Neurocritical care  2014;20(3):348-357.
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.
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.
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).
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.
PMCID: PMC4136809  PMID: 24464830
19.  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.
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.
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.
This small study demonstrates that tissue metabolism is regionally heterogeneous after TBI and pericontusional perfusion was significantly reduced in the METH subgroup.
PMCID: PMC4111452  PMID: 23836426
Adult brain injury; MRI; blood flow; metabolism; alcohol and drug abuse
20.  Predictors of Late Neurological Deterioration After Spontaneous Intracerebral Hemorrhage 
Neurocritical care  2013;19(3):299-305.
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.
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.
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).
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.
PMCID: PMC4100944  PMID: 23979796
Intracerebral hemorrhage; Neurological deterioration; Predictors; Outcome; Brain edema
21.  Post-Stroke Infection: A Role for IL-1ra? 
Neurocritical care  2011;14(2):244-252.
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.
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.
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.
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.
PMCID: PMC4096896  PMID: 21174170
Stroke; IL-1ra; Infection; IL-10; Cortisol
22.  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.
PMCID: PMC3954940  PMID: 24132564
Cerebral ischemia; Stroke; Sur1; Sur1–Trpm4 channel; Glibenclamide; RP-1127; Stroke Therapy Academic Industry Roundtable (STAIR)
23.  Infarct Volume After Hyperacute Infusion of Hypertonic Saline in a Rat Model of Acute Embolic Stroke 
Neurocritical care  2013;18(1):106-114.
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.
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.
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).
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.
PMCID: PMC3565002  PMID: 22886394
Embolic stroke; Hypernatremia; Hypertonic saline; Normal saline; Tissue water content; Wistar rats
24.  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.
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.
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.
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.
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.
PMCID: PMC3785325  PMID: 22544476
Intracerebral hemorrhage; Intraventricular hemorrhage; Cerebrovascular disease; Stroke; Critical care
25.  A Population-Based Analysis of Ethnic Differences in Admission to the Intensive Care Unit after Stroke 
Neurocritical care  2012;17(3):348-353.
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.
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.
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).
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.
PMCID: PMC3520600  PMID: 22892883
Intracerebral hemorrhage; Acute ischemic stroke; Mexican Americans; Intensive care unit

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