Augusto Parra

Impact of medical complications on outcome after subarachnoid hemorrhage.

Objective:Medical complications occur frequently after subarachnoid hemorrhage (SAH). Their impact on outcome remains poorly defined. Design:Inception cohort study. Patients:Five-hundred eighty patients enrolled in the Columbia University SAH Outcomes Project between July 1996 and May 2002. Setting:Neurologic intensive care unit. Interventions:Patients were treated according to standard management protocols. Measurements and Main Results:Poor outcome was defined as death or severe disability (modified Rankin score, 4–6) at 3 months. We calculated the frequency of medical complications according to prespecified criteria and evaluated their impact on outcome, using forward stepwise multiple logistic regression after adjusting for known predictors of poor outcome. Thirty-eight% had a poor outcome; mortality was 21%. The most frequent complications were temperature >38.3°C (54%), followed by anemia treated with transfusion (36%), hyperglycemia >11.1 mmol/L (30%), treated hypertension (>160 mm Hg systolic; 27%), hypernatremia >150 mmol/L (22%), pneumonia (20%), hypotension (<90 mm Hg systolic) treated with vasopressors (18%), pulmonary edema (14%), and hyponatremia <130 mmol/L (14%). Fever (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.1–3.4; p = .02), anemia (OR, 1.8; 95% CI, 1.1–2.9; p = .02), and hyperglycemia (OR, 1.8; 95% CI, 1.1–3.0; p = .02) significantly predicted poor outcome after adjustment for age, Hunt-Hess grade, aneurysm size, rebleeding, and cerebral infarction due to vasospasm. Conclusions:Fever, anemia, and hyperglycemia affect 30% to 54% of patients with SAH and are significantly associated with mortality and poor functional outcome. Critical care strategies directed at maintaining normothermia, normoglycemia, and prevention of anemia may improve outcome after SAH. LEARNING OBJECTIVESOn completion of this article, the reader should be able to: Identify common medical complications after subarachnoid hemorrhage. Describe complications that influence outcome. Use this inofrmation in a clinical setting. Dr. Connolly has disclosed that he is/was the recipient of direct grant/research funds from the National Institutes of Health. The remaining authors have disclosed that they have no financial relationships with or interests in any commercial companies pertaining to the educational activity. Wolters Kluwer has identified and resolved all faculty conflicts of interest regarding the educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Cardiac Troponin Elevation, Cardiovascular Morbidity, and Outcome After Subarachnoid Hemorrhage

Background— Cardiac troponin I (cTI) release occurs frequently after subarachnoid hemorrhage (SAH) and has been associated with a neurogenic form of myocardial injury. The prognostic significance and clinical impact of these elevations remain poorly defined. Methods and Results— We studied 253 SAH patients who underwent serial cTI measurements for clinical or ECG signs of potential cardiac injury. These patients were drawn from an inception cohort of 441 subjects enrolled in the Columbia University SAH Outcomes Project between November 1998 and August 2002. Peak cTI levels were divided into quartiles or classified as undetectable. Adverse in-hospital events were prospectively recorded, and outcome at 3 months was assessed with the modified Rankin Scale. Admission predictors of cTI elevation included poor clinical grade, intraventricular hemorrhage, loss of consciousness at ictus, global cerebral edema, and a composite score of physiological derangement (all P≤0.01). Peak cTI level was associated with an increased risk of echocardiographic left ventricular dysfunction (odds ratio [OR], 1.3 per quintile; 95% CI, 1.0 to 1.7; P=0.03), pulmonary edema (OR, 2.1 per quintile; 95% CI, 1.6 to 2.7; P<0.001), hypotension requiring pressors (OR, 1.9 per quintile; 95% CI, 1.5 to 2.3; P<0.001), and delayed cerebral ischemia from vasospasm (OR, 1.3 per quintile; 95% CI, 1.07 to 1.7; P=0.01). Peak cTI levels were predictive of death or severe disability at discharge after controlling for age, clinical grade, and aneurysm size (adjusted OR, 1.4 per quintile; 95% CI, 1.1 to 1.9; P=0.02), but this association was no longer significant at 3 months. Conclusions— cTI elevation after SAH is associated with an increased risk of cardiopulmonary complications, delayed cerebral ischemia, and death or poor functional outcome at discharge.

Phenytoin Exposure Is Associated With Functional and Cognitive Disability After Subarachnoid Hemorrhage

Background and Purpose— Phenytoin (PHT) is routinely used for seizure prophylaxis after subarachnoid hemorrhage (SAH), but may adversely affect neurologic and cognitive recovery. Methods— We studied 527 SAH patients and calculated a “PHT burden” for each by multiplying the average serum level of PHT by the time in days between the first and last measurements, up to a maximum of 14 days from ictus. Functional outcome at 14 days and 3 months was measured with the modified Rankin scale, with poor functional outcome defined as dependence or worse (modified Rankin Scale ≥4). We assessed cognitive outcomes at 14 days and 3 months with the telephone interview for cognitive status. Results— PHT burden was associated with poor functional outcome at 14 days (OR, 1.5 per quartile; 95% CI, 1.3 to 1.8; P<0.001), although not at 3 months (P=0.09); the effect remained (OR, 1.6 per quartile; 95% CI, 1.2 to 2.1; P<0.001) after correction for admission Glasgow Coma Scale, fever, stroke, age, National Institutes of Health Stroke Scale ≥10, hydrocephalus, clinical vasospasm, and aneurysm rebleeding. Seizure in hospital (OR, 4.1; 95% CI, 1.5 to 11.1; P=0.002) was associated with functional disability in a univariate model only. Higher quartiles of PHT burden were associated with worse telephone interview for cognitive status scores at hospital discharge (P<0.001) and at 3 months (P=0.003). Conclusions— Among patients treated with PHT, burden of exposure to PHT predicts poor neurologic and cognitive outcome after SAH.

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

Background and Purpose— Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. Methods— Mice were treated with subcutaneous simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27=normal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but simvastatin treatment was started after SAH or sham surgery. Results— In SAH mice, simvastatin pretreatment increased middle cerebral artery diameter (SAH-simvastatin=74±22 &mgr;m, SAH-vehicle=52±18 &mgr;m, P =0.03; sham-simvastatin=102±8 &mgr;m, sham-vehicle=105±6 &mgr;m). Pretreatment reduced neurological deficits (SAH-simvastatin=25±2, SAH-vehicle=20±2, P =0.005; sham-simvastatin and sham-vehicle=27±0). Simvastatin pretreatment also increased eNOS protein. Simvastatin posttreatment caused a modest increase in middle cerebral artery diameter in SAH mice (SAH-simvastatin=56±12 &mgr;m, SAH-vehicle=45±4 &mgr;m, P =0.03; sham-simvastatin=92±13 &mgr;m, sham-vehicle=99±10 &mgr;m) and reduced neurological deficits (SAH-simvastatin=21±1, SAH-vehicle=19±2, P =0.009). Simvastatin posttreatment did not significantly increase eNOS protein. Conclusions— Simvastatin treatment before or after SAH attenuated cerebral vasospasm and neurological deficits in mice. The mechanism may be attributable in part to eNOS upregulation.

Clinical trial of a novel surface cooling system for fever control in neurocritical care patients

Objective:To compare the efficacy of a novel water-circulating surface cooling system with conventional measures for treating fever in neuro-intensive care unit patients. Design:Prospective, unblinded, randomized controlled trial. Setting:Neurologic intensive care unit in an urban teaching hospital. Patients:Forty-seven patients, the majority of whom were mechanically ventilated and sedated, with fever ≥38.3°C for >2 consecutive hours after receiving 650 mg of acetaminophen. Interventions:Subjects were randomly assigned to 24 hrs of treatment with a conventional water-circulating cooling blanket placed over the patient (Cincinnati SubZero, Cincinnati OH) or the Arctic Sun Temperature Management System (Medivance, Louisville CO), which employs hydrogel-coated water-circulating energy transfer pads applied directly to the trunk and thighs. Measurements and Main Results:Diagnoses included subarachnoid hemorrhage (60%), cerebral infarction (23%), intracerebral hemorrhage (11%), and traumatic brain injury (4%). The groups were matched in terms of baseline variables, although mean temperature was slightly higher at baseline in the Arctic Sun group (38.8 vs. 38.3°C, p = .046). Compared with patients treated with the SubZero blanket (n = 24), Arctic Sun-treated patients (n = 23) experienced a 75% reduction in fever burden (median 4.1 vs. 16.1 C°-hrs, p = .001). Arctic Sun-treated patients also spent less percent time febrile (T ≥38.3°C, 8% vs. 42%, p < .001), spent more percent time normothermic (T ≤37.2°C, 59% vs. 3%, p < .001), and attained normothermia faster than the SubZero group median (2.4 vs. 8.9 hrs, p = .008). Shivering occurred more frequently in the Arctic Sun group (39% vs. 8%, p = .013). Conclusion:The Arctic Sun Temperature Management System is superior to conventional cooling-blanket therapy for controlling fever in critically ill neurologic patients.

Fever after subarachnoid hemorrhage. Risk factors and impact on outcome

Objective: To identify risk factors for refractory fever after subarachnoid hemorrhage (SAH), and to determine the impact of temperature elevation on outcome. Methods: We studied a consecutive cohort of 353 patients with SAH with a maximum daily temperature (Tmax) recorded on at least 7 days between SAH days 0 and 10. Fever (>38.3 °C) was routinely treated with acetaminophen and conventional water-circulating cooling blankets. We calculated daily Tmax above 37.0 °C, and defined extreme Tmax as daily excess above 38.3 °C. Global outcome at 90 days was evaluated with the modified Rankin Scale (mRS), instrumental activities of daily living (IADLs) with the Lawton scale, and cognitive functioning with the Telephone Interview of Cognitive Status. Mixed-effects models were used to identify predictors of Tmax, and logistic regression models to evaluate the impact of Tmax on outcome. Results: Average daily Tmax was 1.15 °C (range 0.04 to 2.74 °C). The strongest predictors of fever were poor Hunt-Hess grade and intraventricular hemorrhage (IVH) (both p < 0.001). After controlling for baseline outcome predictors, daily Tmax was associated with an increased risk of death or severe disability (mRS ≥ 4, adjusted OR 3.0 per °C, 95% CI 1.6 to 5.8), loss of independence in IADLs (OR 2.6, 95% CI 1.2 to 5.6), and cognitive impairment (OR 2.5, 95% CI 1.2 to 5.1, all p ≤ 0.02). These associations were even stronger when extreme Tmax was analyzed. Conclusion: Treatment-refractory fever during the first 10 days after subarachnoid hemorrhage (SAH) is predicted by poor clinical grade and intraventricular hemorrhage, and is associated with increased mortality and more functional disability and cognitive impairment among survivors. Clinical trials are needed to evaluate the impact of prophylactic fever control on outcome after SAH.

Hyperglycemia After SAH: Predictors, Associated Complications, and Impact on Outcome

Background and Purpose— Hyperglycemia is common after subarachnoid hemorrhage (SAH). The extent to which prolonged hyperglycemia contributes to in-hospital complications and poor outcome after SAH is unknown. Methods— We studied an inception cohort of 281 SAH patients with an initial serum glucose level obtained within 3 days of SAH onset and who had at least 7 daily glucose measurements between SAH days 0 and 10. We defined mean glucose burden (GB) as the average peak daily glucose level >5.8 mmol/L (105 mg/dL). Hospital complications were recorded prospectively, and 3-month outcome was assessed with the modified Rankin scale. Results— The median GB was 1.8 mmol/L (33 mg/dL). Predictors of high-GB included age ≥54 years, Hunt and Hess grade III–V, poor Acute Physiology and Chronic Health Evaluation (APACHE)-2 physiological subscores, and a history of diabetes mellitus (all P≤0.001). In a multivariate analysis, GB was associated with increased intensive care unit length of stay (P=0.003) and the following complications: congestive heart failure, respiratory failure, pneumonia, and brain stem compression from herniation (all P<0.05). After adjusting for Hunt-Hess grade, aneurysm size, and age, GB was an independent predictor of death (odds ratio, 1.10 per mmol/L; 95% CI, 1.01 to 1.21; P=0.027) and death or severe disability (modified Rankin scale score of 4 to 6; odds ratio, 1.17 per mmol/L; 95% CI 1.07 to 1.28, P<0.001). Conclusions— Hyperglycemia after SAH is associated with serious hospital complications, increased intensive care unit length of stay, and an increased risk of death or severe disability.

Higher hemoglobin is associated with improved outcome after subarachnoid hemorrhage

Objective:There are few data regarding anemia and transfusion after subarachnoid hemorrhage (SAH). We addressed the hypothesis that higher hemoglobin (HGB) levels are associated with less death and disability after SAH. Design:Prospective registry with automated data retrieval. Patients:Six hundred eleven patients enrolled in the Columbia University SAH Outcomes Project between August 1996 and June 2002. Setting:Neurologic intensive care unit. Interventions:Patients were treated according to standard management protocols. Measurements and Main Results:We electronically retrieved all HGB readings during the acute hospital stay for 611 consecutively admitted SAH patients. Outcomes were measured with the modified Rankin Scale at 14 days or discharge, and at 3 months. Patients who were independent (modified Rankin Scale, 0–3) at discharge or 14 days had higher mean (11.7 ± 1.5 vs. 10.9 ± 1.2, p < .001) and nadir (9.9 ± 2.1 vs. 8.6 ± 1.8, p < .001) HGB, and had higher HGB values every day in the hospital. There were similar results when patients were stratified by mortality. Higher HGB was associated with reduced risk of poor outcome (modified Rankin Scale, 4–6) at 14 days/discharge and 3 months after correcting for Hunt and Hess grade, age, history of diabetes, and cerebral infarction. Length of stay and HGB interacted such that lower HGB has a more pronounced effect with length of stay > 14 days. Conclusions:Higher HGB values are associated with improved outcomes after SAH at 14 days/discharge and 3 months. In contrast to general critical care patients, SAH patients may benefit from higher HGB. Determination of the optimal goal HGB after SAH will require separate prospective research.

Possible Role for Vascular Cell Proliferation in Cerebral Vasospasm After Subarachnoid Hemorrhage

Background and Purpose— During vasospasm after subarachnoid hemorrhage (SAH), cerebral blood vessels show structural changes consistent with the actions of vascular mitogens. We measured platelet-derived vascular growth factors (PDGFs) in the cerebrospinal fluid (CSF) of patients after SAH and tested the effect of these factors on cerebral arteries in vivo and in vitro. Methods— CSF was sampled from 14 patients after SAH, 6 patients not suffering SAH, and 8 normal controls. ELISA was performed for PDGF-AB, transforming growth factor-&bgr;1, and vascular endothelial growth factor. A mouse model was used to compare cerebral vascular cell proliferation and PDGF staining in SAH compared with sham-operated controls. Normal human pial arteries were incubated for 7 days in vitro, 2 groups with human blood clot and 1 with and 1 without PDGF antibodies. Results— PDGF-AB concentrations in CSF from SAH patients were significantly higher than those from non-SAH patients and normal controls, both during the first week after SAH and for all time points measured. Smooth muscle and fibroblast proliferation was observed after SAH in the mouse model, and this cellular replication was observed in conjunction with PDGF protein at the sites of thrombus. In human pial arteries, localized thrombus stimulated vessel wall proliferation, and proliferation was blocked by neutralizing antibodies directed against PDGFs. Conclusions— Vascular mitogens are increased in the CSF of patients after SAH. Proliferation of cells in the vascular wall is associated with perivascular thrombus. Cellular proliferation and subsequent vessel wall thickening may contribute to the syndrome of delayed cerebral vasospasm.

Effect of prior statin use on functional outcome and delayed vasospasm after acute aneurysmal subarachnoid hemorrhage: a matched controlled cohort study.

OBJECTIVE:Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which exhibit beneficial cerebrovascular effects by modulating inflammation and nitric oxide production, have not been evaluated in acute aneurysmal subarachnoid hemorrhage (SAH) patients. The effect of prior statin use on 14-day functional outcome and on prevention of vasospasm-induced delayed cerebral ischemia (DCI) or stroke during hospitalization was analyzed. METHODS:We conducted a 1:2 matched (age, admission Hunt and Hess grade, vascular disease/risk history) cohort study of 20 SAH patients on statins and 40 SAH controls. The primary outcome was functional outcome at 14 days (Modified Lawton Physical Self-Maintenance Scale and Barthel Index scale scores). Secondary outcomes were 14-day mortality, Modified Rankin Scale score, DCI, DCI supported by angiography/transcranial Doppler [TCD], cerebral infarctions of any type, and TCD highest mean velocity elevation. RESULTS:Statin users demonstrated a significant protective effect on 14-day Barthel Index scale and Modified Lawton Physical Self-Maintenance Scale scores (77 ± 10 versus 39 ± 8, P = 0.003; 12 ± 7 versus 19 ± 9, P = 0.03, respectively). Moreover, statin users demonstrated a significantly lower incidence of DCI and DCI supported by angiography/TCD (10% versus 43%, P = 0.02; 5% versus 35%, P = 0.01, respectively), cerebral infarctions of any type (25% versus 63%, P = 0.01), and baseline-to-final TCD highest mean velocity change of 50 cm/s or greater (18% versus 51%, P = 0.03). CONCLUSION:SAH statin users demonstrated significant improvement in 14-day functional outcome, a significantly lower incidence of DCI and cerebral infarctions of any type, as well as prevention of TCD highest mean velocity elevation. However, we did not find a significant statin impact on mortality or global outcome (Modified Rankin Scale) in this small sample. This study provides clinical evidence for the potential therapeutic benefit of statins after acute SAH.