Rajat Dhar

Hypothermia for Refractory Status Epilepticus

IntroductionStatus epilepticus (SE) can be refractory to conventional anticonvulsants, requiring anesthetic doses of medications to suppress seizures. This approach carries significant morbidity, is associated with a high fatality rate, and may not always control SE. Hypothermia has been shown to suppress epileptiform activity experimentally, but has not previously been used as a primary modality to control SE in humans.MethodsFour patients with SE refractory to benzodiazepine and/or barbiturate infusions were treated with hypothermia (target temperature: 31–35°C) using an endovascular cooling system. All received continuous EEG monitoring, three were on midazolam infusions and one had recurrent seizures on weaning from pentobarbital.ResultsTherapeutic hypothermia was successful in aborting seizure activity in all four patients, allowing midazolam infusions to be discontinued; three achieved a burst-suppression pattern on EEG. After controlled rewarming, two patients remained seizure-free, and all four demonstrated a marked reduction in seizure frequency. Adverse events included shivering, coagulopathy without bleeding, and venous thromboembolism. Two death occurred, neither directly related to hypothermia; however, immunosuppression related to the use of barbiturates and hypothermia may have contributed to an episode of fatal sepsis in one patient.ConclusionsHypothermia was able to suppress seizure activity in patients with SE refractory to traditional therapies with minimal morbidity. It appears promising as an alternative or an adjunct to anesthetic doses of other agents, but requires further study to better evaluate its safety and efficacy.

The Burden of the Systemic Inflammatory Response Predicts Vasospasm and Outcome after Subarachnoid Hemorrhage

IntroductionSubarachnoid hemorrhage (SAH) can trigger immune activation sufficient to induce the systemic inflammatory response syndrome (SIRS). This may promote both extra-cerebral organ dysfunction and delayed cerebral ischemia, contributing to worse outcome. We ascertained the frequency and predictors of SIRS after spontaneous SAH, and determined whether degree of early systemic inflammation predicted the occurrence of vasospasm and clinical outcome.MethodsRetrospective analysis of prospectively collected data on 276 consecutive patients admitted to a neurosciences intensive care unit with acute, non-traumatic SAH between 2002 and 2005. A daily SIRS score was derived by summing the number of variables meeting standard criteria (HR >90, RR >20, Temperature >38°C, or <36°C, WBC count <4,000 or >12,000). SIRS was considered present if two or more criteria were met, while SIRS burden over the first four days was calculated by averaging daily scores. Regression modeling was used to determine the relationship among SIRS burden (after controlling for confounders including infection, surgery, and corticosteroid use), symptomatic vasospasm, and outcome, determined by hospital disposition.ResultsSIRS was present in over half the patients on admission and developed in 85% within the first four days. Factors associated with SIRS included poor clinical grade, thick cisternal blood, larger aneurysm size, higher admission blood pressure, and surgery for aneurysm clipping. Higher SIRS burden was independently associated with death or discharge to nursing home (OR 2.20/point, 95% CI 1.27–3.81). All of those developing clinical vasospasm had evidence of SIRS, with greater SIRS burden predicting increased risk for delayed ischemic neurological deficits (OR 1.77/point, 95% CI 1.12–2.80).ConclusionsSystemic inflammatory activation is common after SAH even in the absence of infection; it is more frequent in those with more severe hemorrhage and in those who undergo surgical clipping. Higher burden of SIRS in the initial four days independently predicts symptomatic vasospasm and is associated with worse outcome.

Red Blood Cell Transfusion Increases Cerebral Oxygen Delivery in Anemic Patients With Subarachnoid Hemorrhage

Background and Purpose— Anemia is common after subarachnoid hemorrhage and may exacerbate the reduction in oxygen delivery (DO2) underlying delayed cerebral ischemia. The association between lower hemoglobin and worse outcome, including more cerebral infarcts, supports a role for red blood cell transfusion to correct anemia. However, the cerebral response to transfusion remains uncertain, because higher hemoglobin may increase viscosity and further impair cerebral blood flow (CBF) in the setting of vasospasm. Methods— Eight patients with aneurysmal subarachnoid hemorrhage and hemoglobin <10 g/dL were studied with 15O-positron emission tomography before and after transfusion of 1 U red blood cells. Paired t tests were used to analyze the change in global and regional CBF, oxygen extraction fraction, and oxygen metabolism after transfusion. DO2 was calculated from CBF and arterial oxygen content. CBF, oxygen metabolism, and DO2 are reported in mL/100 g/min. Results— Transfusion resulted in a 15% rise in hemoglobin (8.7±0.8 to 10.0±1.0 g/dL) and arterial oxygen content (11.8±1.0 to 13.6±1.1 mL/dL; both P<0.001). Global CBF remained stable (40.5±8.1 to 41.6±9.9), resulting in an 18% rise in DO2 from 4.8±1.1 to 5.7±1.4 (P=0.017). This was associated with a fall in oxygen extraction fraction from 0.49±0.11 to 0.41±0.11 (P=0.11) and stable oxygen metabolism. Rise in DO2 was greater (28%) in regions with oligemia (low DO2 and oxygen extraction fraction ≥0.5) at baseline but was attenuated (10%) within territories exhibiting angiographic vasospasm, where CBF fell 7%. Conclusions— Transfusion of red blood cells to anemic patients with subarachnoid hemorrhage resulted in a significant rise in cerebral DO2 without lowering global CBF. This was associated with reduced oxygen extraction fraction, which may improve tolerance of vulnerable brain regions to further impairments of CBF. Further studies are needed to confirm the benefit of transfusion on delayed cerebral ischemia and balance this against potential systemic and cerebral risks.

The morbidity and outcome of patients with Guillain-Barré syndrome admitted to the intensive care unit.

UNLABELLED One third of patients with Guillain-Barré syndrome (GBS) require admission to the intensive care unit (ICU), associated with significant risk of morbidity, mortality, and incomplete recovery. METHODS 76 adult patients with GBS admitted to the ICU at a regional referral center over a 20-year period were studied. We determined the frequency, nature, and predictors of complications they experienced while in the ICU; this morbidity was related to long-term functional recovery and time to regain independent ambulation, extracted from longitudinal follow-up data. RESULTS ICU stay was a median 21 days and mechanical ventilation (MV) was required in 78% (median duration 28 days). Two-thirds suffered at least one major complication, most commonly pneumonia (54%). Morbidity was strongly associated with MV and male sex. Mortality occurred in only 5 patients (6.5%). Over an average 3 years follow-up, recovery of independent ambulation was seen in 75%, with advanced age being the most powerful predictor of poor outcome. Prolonged MV and severe axonal loss did not preclude a favorable recovery. Time to ambulate was a median 198 days, although recovery could occur as late as ten years after onset; slower recovery was associated with ICU complications, prolonged MV, and early axonal abnormalities. CONCLUSION Although patients with GBS suffer significant morbidity during protracted ICU stays, with meticulous supportive care, many make gratifying functional recoveries. In severely afflicted patients, this may only be appreciated after extended follow-up.

The relationship between delayed infarcts and angiographic vasospasm after aneurysmal subarachnoid hemorrhage.

BACKGROUND Delayed cerebral ischemia is common after aneurysmal subarachnoid hemorrhage (aSAH) and is a major contributor to poor outcome. Yet, although generally attributed to arterial vasospasm, neurological deterioration may also occur in the absence of vasospasm. OBJECTIVE To determine the relationship between delayed infarction and angiographic vasospasm and compare the characteristics of infarcts related to vasospasm vs those unrelated. METHODS A retrospective review of patients with aSAH admitted from July 2007 through June 2011. Patients were included if they were admitted within 48 hours of SAH, had a computed tomography scan both 24 to 48 hours following aneurysm treatment and ≥7 days after SAH, and had a catheter angiogram to evaluate for vasospasm. Delayed infarcts seen on late computed tomography but not postprocedurally were attributed to vasospasm if there was moderate or severe vasospasm in the corresponding vascular territory on angiography. Infarct volume was measured by perimeter tracing. RESULTS Of 276 aSAH survivors, 134 had all imaging requisite for inclusion. Fifty-four (34%) had moderate or severe vasospasm, of whom 17 (31%) had delayed infarcts, compared with only 3 (4%) of 80 patients without vasospasm (P < .001). There were a total of 29 delayed infarcts in these 20 patients; 21 were in a territory with angiographic vasospasm, but 8 (28%) were not. Infarct volume did not differ between vasospasm-related (18 ± 25 mL) and vasospasm-unrelated (11 ± 12 mL) infarcts (P = .54), but infarcts in the absence of vasospasm were more likely watershed (50% vs. 10%, P = .03). CONCLUSION Delayed infarcts following aSAH can occur in territories without angiographic vasospasm and are more likely watershed in distribution.

Relationship Between Angiographic Vasospasm and Regional Hypoperfusion in Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— Angiographic vasospasm frequently complicates subarachnoid hemorrhage and has been implicated in the development of delayed cerebral ischemia. Whether large-vessel narrowing adequately accounts for the critical reductions in regional cerebral blood flow underlying ischemia is unclear. We sought to clarify the relationship between angiographic vasospasm and regional hypoperfusion. Methods— Twenty-five patients with aneurysmal subarachnoid hemorrhage underwent cerebral catheter angiography and 15O-positron emission tomographic imaging within 1 day of each other (median of 7 days after subarachnoid hemorrhage). Severity of vasospasm was assessed in each intracranial artery, whereas cerebral blood flow and oxygen extraction fraction were measured in 28 brain regions distributed across these vascular territories. We analyzed the association between vasospasm and perfusion and compared frequency of hypoperfusion (cerebral blood flow <25 mL/100 g/min) and oligemia (low oxygen delivery with oxygen extraction fraction ≥0.5) in territories with versus without significant vasospasm. Results— Twenty-four percent of 652 brain regions were supplied by vessels with significant vasospasm. Cerebral blood flow was lower in such regions (38.6±12 versus 48.7±16 mL/100 g/min), whereas oxygen extraction fraction was higher (0.48±0.19 versus 0.37±0.14, both P<0.001). Hypoperfusion was seen in 46 regions (7%), but 66% of these were supplied by vessels with no significant vasospasm; 24% occurred in patients without angiographic vasospasm. Similarly, oligemia occurred more frequently outside territories with vasospasm. Conclusions— Angiographic vasospasm is associated with reductions in cerebral perfusion. However, regional hypoperfusion and oligemia frequently occurred in territories and patients without vasospasm. Other factors in addition to large-vessel narrowing must contribute to critical reductions in perfusion.

Comparison of induced hypertension, fluid bolus, and blood transfusion to augment cerebral oxygen delivery after subarachnoid hemorrhage

OBJECT Critical reductions in oxygen delivery (DO(2)) underlie the development of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). If DO(2) is not promptly restored, then irreversible injury (that is, cerebral infarction) may result. Hemodynamic therapies for DCI (that is, induced hypertension [IH] and hypervolemia) aim to improve DO(2) by raising cerebral blood flow (CBF). Red blood cell (RBC) transfusion may be an alternate strategy that augments DO(2) by improving arterial O(2) content. The authors compared the relative ability of these 3 interventions to improve cerebral DO(2), specifically their ability to restore DO(2) to regions where it is impaired. METHODS The authors compared 3 prospective physiological studies in which PET imaging was used to measure global and regional CBF and DO(2) before and after the following treatments: 1) fluid bolus of 15 ml/kg normal saline (9 patients); 2) raising mean arterial pressure 25% (12 patients); and 3) transfusing 1 U of RBCs (17 patients) in 38 individuals with aneurysmal SAH at risk for DCI. Response between groups in regions with low DO(2) (< 4.5 ml/100 g/min) was compared using repeated-measures ANOVA. RESULTS Groups were similar except that the fluid bolus cohort had more patients with symptoms of DCI and lower baseline CBF. Global CBF or DO(2) did not rise significantly after any of the interventions, except after transfusion in patients with hemoglobin levels < 9 g/dl. All 3 treatments improved CBF and DO(2) to regions with impaired baseline DO(2), with a greater improvement after transfusion (23%) than hypertension (14%) or volume loading (10%); p < 0.001. Transfusion also resulted in a nonsignificantly greater (47%) reduction in the number of brain regions with low DO(2) when compared with fluid bolus (7%) and hypertension (12%) (p = 0.33). CONCLUSIONS The IH, fluid bolus, and blood transfusion interventions all improve DO(2) to vulnerable brain regions at risk for ischemia after SAH. Transfusion appeared to provide a physiological benefit at least comparable to IH, especially among patients with anemia, but transfusion is associated with risks. The clinical significance of these findings remains to be established in controlled clinical trials.

Comparison of high- and low-dose corticosteroid regimens for organ donor management.

PURPOSE Corticosteroids are used to promote hemodynamic stability and reduce inflammatory organ injury after brain death. High-dose (HD) methylprednisolone has become the standard regimen based on comparisons to untreated/historical controls. However, this protocol may exacerbate hyperglycemia. Our objective was to compare a lower-dose (LD) steroid protocol (adequate for hemodynamic stabilization in adrenal insufficiency and sepsis) to the traditional HD regimen in the management of brain-dead organ donors. METHODS We evaluated 132 consecutive brain-dead donors managed before and after changing the steroid protocol from 15 mg/kg methylprednisolone (HD) to 300 mg hydrocortisone (LD). Primary outcome measures were glycemic control, oxygenation, hemodynamic stability, and organs transplanted. RESULTS Groups were balanced except for nonsignificantly higher baseline Pao(2) in the LD cohort. Final Pao(2) remained higher (394 mm Hg LD vs 333 mm Hg HD, P=.03); but improvement in oxygenation was comparable (+37 mm Hg LD vs +28 mm Hg HD, P=.43), as was the proportion able to come off vasopressor support (39% LD vs 47% HD, P=.38). Similar proportions of lungs (44% vs 33%) and hearts (31% vs 27%) were transplanted in both groups. After excluding diabetics, median glucose values at 4 hours (170 mmol/L vs 188 mmol/L, P=.06) and final insulin requirements (2.9 U/h vs 8.4 U/h, P=.01) were lower with LD steroids; and more patients were off insulin infusions (74% LD vs 53% HD, P=.02). CONCLUSIONS A lower-dose corticosteroid protocol did not result in worsened donor pulmonary or cardiac function, with comparable organs transplanted compared with the traditional HD regimen. Insulin requirements and glycemic control were improved. High-dose methylprednisolone may not be required to support brain-dead donors.

Effect of osmotic agents on regional cerebral blood flow in traumatic brain injury

PURPOSE Cerebral blood flow (CBF) is reduced after severe traumatic brain injury (TBI) with considerable regional variation. Osmotic agents are used to reduce elevated intracranial pressure (ICP), improve cerebral perfusion pressure, and presumably improve CBF. Yet, osmotic agents have other physiologic effects that can influence CBF. We sought to determine the regional effect of osmotic agents on CBF when administered to treat intracranial hypertension. MATERIALS AND METHODS In 8 patients with acute TBI, we measured regional CBF with positron emission tomography before and 1 hour after administration of equi-osmolar 20% mannitol (1 g/kg) or 23.4% hypertonic saline (0.686 mL/kg) in regions with focal injury and baseline hypoperfusion (CBF <25 mL per 100 g/min). RESULTS The ICP fell (22.4 ± 5.1 to 15.7 ± 7.2 mm Hg, P = .007), and cerebral perfusion pressure rose (75.7 ± 5.9 to 81.9 ± 10.3 mm Hg, P = .03). Global CBF tended to rise (30.9 ± 3.7 to 33.1 ± 4.2 mL per 100 g/min, P = .07). In regions with focal injury, baseline flow was 25.7 ± 9.1 mL per 100 g/min and was unchanged; in hypoperfused regions (15% of regions), flow rose from 18.6 ± 5.0 to 22.4 ± 6.4 mL per 100 g/min (P < .001). Osmotic therapy reduced the number of hypoperfused brain regions by 40% (P < .001). CONCLUSION Osmotic agents, in addition to lowering ICP, improve CBF to hypoperfused brain regions in patients with intracranial hypertension after TBI.

Comparison of Short-Duration Levetiracetam with Extended-Course Phenytoin for Seizure Prophylaxis After Subarachnoid Hemorrhage

BACKGROUND The optimal regimen for seizure prophylaxis after subarachnoid hemorrhage (SAH) remains uncertain. Based on data suggesting that a short course may be adequate, coupled with an association between phenytoin exposure and poor cognitive outcome, our institution modified their seizure prophylaxis protocol for patients with SAH from an extended course of phenytoin to 3 days of levetiracetam. This study sought to compare the incidence of seizures before and after this change to evaluate whether a short course of levetiracetam would be as effective in preventing in-hospital seizures. METHODS This study analyzed 442 consecutive patients admitted with SAH between January 2003 and January 2008, including 297 patients treated before the protocol change (PHT group) and 145 treated afterward (LEV group). Occurrence of all seizures was extracted from a prospectively collected intensive care unit database and further review of medical records. In-hospital seizures were divided into early (occurring on or before day 3, all patients on prophylaxis) and those occurring late (after day 3, LEV group off prophylaxis). RESULTS In-hospital seizures occurred in 3.4% of the PHT group and 8.3% of the LEV group (P = 0.03). Although the rate of early seizures was not different (1.4% PHT vs. 2.8% LEV, P = 0.45), there was a higher rate of late seizures (2% PHT vs. 5.5% LEV, P = 0.05). CONCLUSIONS The use of short-duration levetiracetam for seizure prophylaxis after SAH was associated with a higher rate of in-hospital seizures than an extended course of phenytoin, mainly related to an increase in late seizures, when the levetiracetam had been discontinued. This suggests that a longer duration of prophylaxis may be required to minimize seizures in patients with SAH, although confirmatory studies are required.