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Magdy Selim,
Sharon Yeatts,
Joshua N Goldstein,
Joao Gomes,
Steven Greenberg,
Lewis B Morgenstern,
Gottfried Schlaug, Michel Torbey,
Bonnie Waldman,
Guohua Xi,
Yuko Palesch
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ABSTRACT: Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies.
This was a multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and computed tomography neuroimaging pre- and post-drug-administration.
Twenty subjects were enrolled onto 5 dose tiers, starting with 7 mg/kg per day and ending with 62 mg/kg per day as the maximum tolerated dose. Median age was 68 years (range, 50-90); 60% were men; and median Glasgow Coma Scale and National Institutes of Health Stroke Scale scores on admission were 15 (5-15) and 9 (0-39), respectively. ICH location was lobar in 40%, deep in 50%, and brain stem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued because of adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events, none of which were drug-related. DFO infusions were associated with mild blood-pressure-lowering effects. Fifty percent of patients had modified Rankin scale scores ≤2, and 39% had modified Rankin scale scores of 4 to 6 on day 90; 15% died.
Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive serious adverse events or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.
Stroke 08/2011; 42(11):3067-74. · 5.73 Impact Factor
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ABSTRACT: Hypothermia is neuroprotectant but currently available cooling methods are laborious, invasive, and require whole-body cooling. There is a need for less invasive cooling of the brain. This study was conducted to assess the safety and efficacy of temperature reduction of the RhinoChill transnasal cooling device.
We conducted a prospective single-arm safety and feasibility study of intubated patients for whom temperature reduction was indicated. After rhinoscopy, the device was activated for 1 hour. Brain, tympanic, and core temperatures along with vital signs and laboratory studies were recorded. All general and device-related adverse events were collected for the entire hypothermia treatment.
A total of 15 patients (mean age, 50.3 ± 17.1 years) were enrolled. Brain injury was caused by intracerebral hemorrhage, trauma, and ischemic stroke in equal numbers. Hypothermia was induced for fever control in 9 patients and for neuroprotection/intracranial pressure control in 6. Core temperature, brain temperature, and tympanic temperature were reduced an average of 1.1 ± 0.6°C (range, 0.3 to 2.1°C), 1.4 ± 0.4°C (range, 0.8 to 5.1°C), and 2.2 ± 2°C (range, 0.5 to 6.5°C), respectively. Only 2 patients did not achieve the goal of ≥1°C decrease in temperature. Brain temperature, tympanic temperature, and core temperature reductions were similar between the afebrile and febrile patients. There were no unanticipated adverse events and only 1 anticipated adverse event: hypertension in 1 subject that led to discontinuation of cooling after 30 minutes. There were no nasal complications.
Intranasal cooling with the RhinoChill device appears safe and effectively lowers brain and core temperatures. Further study is warranted to assess the efficacy of hypothermia through intranasal cooling for brain-injured patients.
Stroke 06/2011; 42(8):2164-9. · 5.73 Impact Factor
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ABSTRACT: Takotsubo syndrome is a reversible neuromyocardial failure that has been thought to be related to an acute catecholamine toxicity of the myocardium brought upon by a stressful event. The neurocritical care unit population is particularly vulnerable for this condition given the acute presentation of neurological emergencies, which most often can be catastrophic. We present a case series of this syndrome and a review of the literature.
Our recent experience with three cases that were prospectively identified with the diagnosis of Takotsubo syndrome is reported with clinical presentation, evaluation, and management approach. Review of the literature is presented in the discussion.
We present three episodes of Takotsubo neuromyocardial syndrome in two patients that were admitted to our neurointensive care unit that presented with seizures and had typical clinical presentation, echocardiographic and cardiac catheterization findings. All the episodes were treated with vasoactive medications, ventilatory support, afterload and preload reduction, and treatment of the underlying condition. There was complete reversal of their symptoms and findings in each episode.
Patients with critical neurological illnesses such as large ischemic or hemorrhagic stroke, status epilepticus, recurrent seizure activities as in our study may be at a higher risk for Takotsubo neuromyocardial syndrome.
Neurocritical Care 04/2008; 9(1):112-7. · 2.47 Impact Factor
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ABSTRACT: Dopamine receptors regulate glutamatergic neurotransmission and Na(+),K(+)-ATPase via protein kinase A (PKA) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32)-dependent signaling. Consequently, dopamine receptor activation may modulate neonatal hypoxic-ischemic (H-I) neuronal damage in the selectively vulnerable putamen enriched with dopaminergic receptors. Piglets subjected to two durations of hypoxia followed by asphyxic cardiac arrest were treated with a D1-like (SCH23390) or D2-like (sulpiride) receptor antagonist. At 4 days of recovery from less severe H-I, the remaining viable neurons in putamen were 60% of control, but nearly completely salvaged by pretreatment with SCH23390 or sulpiride. After more severe H-I in which only 18% of neurons were viable, partial neuroprotection was seen with SCH23390 pretreatment (50%) and posttreatment (39%) and with sulpiride pretreatment (35%), but not with sulpiride posttreatment (24%). Dopamine was significantly elevated in microdialysis samples from putamen during asphyxia and the first 15 mins of reoxygenation. Pretreatment with SCH23390 or sulpiride largely attenuated the increased nitrotyrosine and the decreased Na(+),K(+)-ATPase activity that occurred at 3 h after severe H-I. Pretreatment with SCH23390, but not sulpiride, also attenuated H-I-induced increases in PKA-dependent phosphorylation of Thr34 on DARPP-32, Ser943 on the alpha subunit of Na(+),K(+)-ATPase, and Ser897 of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit. These findings indicate that D1 and D2 dopamine receptor activation contribute to neuronal death in newborn putamen after H-I in association with increased protein nitration and decreased Na(+),K(+)-ATPase activity. Furthermore, mechanisms of D1 receptor toxicity may involve DARPP-32-dependent phosphorylation of NMDA receptor NR1 and Na(+),K(+)-ATPase.
Journal of Cerebral Blood Flow & Metabolism 08/2007; 27(7):1339-51. · 5.01 Impact Factor
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ABSTRACT: Intraventricular (IVen) hemorrhage is considered a predictor of poor outcome after subarachnoid hemorrhage (SAH). This prospective study examines the feasibility and outcome of administration of IVen tissue plasminogen activator (tPA) after aneurysmal SAH.
Ten patients with SAH who received IVen tPA after the aneurysm had been secured were compared with 10 age-, sex-, and Glasgow Coma Scale score-matched control patients. The primary end point was third and fourth ventricle clot resolution. IVen blood was quantified by use of the Graeb and Le Roux scales on admission and at an additional time (equal or longer for the control group) after the injection was terminated.
Six men and four women with a mean age of 52 years in each group were evaluated. On average, 3.5 mg tPA was injected 68 +/- 51 hours after admission without ensuing complications. Although the treated group had significantly more IVen blood on admission than control subjects (mean Le Roux scale +/- standard deviation, 11 +/- 3 versus 7.6 +/- 4.2, P = 0.055, and mean Graeb scale +/- standard deviation, 8.5 +/- 2.3 in tPA versus 5.3 +/- 3, P < 0.02), it also had a significant decrease in the amount of IVen blood (mean Le Roux and Graeb scale decrease +/- standard deviation, 6.7 +/- 3.3 and 4.8 +/- 2 in tPA patients versus 0.9 +/- 3.2 and 0.5 +/- 2.6 in control subjects, P = 0.002). The tPA group had a non-statistically significantly shorter length of stay, decreased mortality, and better Glasgow Outcome Scale and modified Rankin Scale scores at discharge. Treated survivors showed a decreased need for shunt placement (2 [22%] of 9 patients versus 5 [83%] of 6 control subjects, P = 0.04).
This pilot study shows that IVen tPA administration is feasible without complications after SAH and may be associated with better outcomes. These results warrant a randomized clinical trial.
Neurosurgery 03/2005; 56(2):205-13; discussion 205-13. · 2.79 Impact Factor
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ABSTRACT: Increases in cerebral blood flow velocity (CBFV) as measured by transcranial Doppler (TCD) sonography are reflective of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). In serial TCD measurements, some patients exhibit CBFV temporal profiles with two peaks (biphasic). The significance of this finding remains unclear. This retrospective case-control study was conducted to investigate the characteristics and possible predictors of biphasic CBFV profiles.
Biphasic CBFV profiles were identified in serial TCD examinations (every 1-2 days) of 182 consecutive patients admitted for aneurysmal SAH based on CBFV profiles of the middle cerebral artery on the side of higher maximum velocity. Patients undergoing angioplasty were excluded. Patients meeting these criteria (study patients) were compared to control patients matched for age and Hunt and Hess grade.
Eighteen patients (9.9%) demonstrated biphasic CBFV profiles. The first CBFV (134 +/- 11 cm/second) peak occurred on post-SAH day 6 +/- 1, and the second peak (148 +/- 12 cm/second) on day 13 +/- 1. Study patients more often exhibited focal (p < 0.05) symptoms at the time of the first peak. No patient deteriorated neurologically at the time of the second peak. No correlation was observed between CBVF and mean arterial pressure or central venous pressure trends.
Serial TCD assessment identifies patients with SAH and a biphasic CBFV temporal profile. Although the second peak usually is not associated with a worsening of symptoms, these patients were more likely to exhibit clinical symptoms during the first CBFV peak.
Neurocritical Care 01/2004; 1(4):455-9. · 2.47 Impact Factor
