Kurt T. Kreiter

Global Cerebral Edema After Subarachnoid Hemorrhage Frequency, Predictors, and Impact on Outcome

Background and Purpose— Cerebral edema visualized by CT is often seen after subarachnoid hemorrhage (SAH). Inflammatory or circulatory mechanisms have been postulated to explain this radiographic observation after SAH. We sought to determine the frequency, causes, and impact on outcome of early and delayed global cerebral edema after SAH. Methods— We evaluated the presence of global edema on admission and follow-up CT scans in 374 SAH patients admitted within 5 days of onset to our Neurological Intensive Care Unit between July 1996 and February 2001. Using multivariate analysis, we identified predictors of global cerebral edema and evaluated the impact of global edema on outcome 3 months after onset with the modified Rankin Scale. Results— Global edema was present on admission CT scans in 8% (n=29) and developed secondarily in 12% (n=44) of the patients. Global edema on admission was predicted by loss of consciousness at ictus and increasing Hunt-Hess grade. Delayed global edema was predicted by aneurysm size >10 mm, loss of consciousness at ictus, use of vasopressors, and increased SAH sum scores. Thirty-seven percent (n=137) of the patients were dead or severely disabled (modified Rankin Scale 4 to 6) at 3 months. Death or severe disability was predicted by any global edema, aneurysm size >10 mm, loss of consciousness at ictus, increased National Institutes of Health Stroke Scale scores, and older age. Conclusions— Global edema is an independent risk factor for mortality and poor outcome after SAH. Loss of consciousness, which may reflect ictal cerebral circulatory arrest, is a risk factor for admission global edema, and vasopressor-induced hypertension is associated with the development of delayed global edema. Critical care management strategies that minimize edema formation after SAH may improve outcome.

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.

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.

Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage.

Background: Cognitive dysfunction is the most common form of neurologic impairment after subarachnoid hemorrhage (SAH). Objective: To evaluate the impact of global and domain-specific cognitive impairment on functional recovery and quality of life (QOL) after SAH. Methods: One hundred thirteen patients (mean age 49 years; 68% women) were evaluated 3 months after SAH. Three simple tests of global mental status and neuropsychological tests to assess seven specific cognitive domains were administered. Four aspects of outcome (global handicap, disability, emotional status, and QOL) were compared between cognitively impaired and unimpaired patients with analysis-of-covariance models controlling for age, race/ethnicity, and education. Multiple linear regression was used to evaluate the relative contribution of global and domain-specific cognitive status for predicting concurrent modified Rankin Scale (mRS) and Sickness Impact Profile (SIP) scores. Results: Impairment of global mental status on the Telephone Interview of Cognitive Status (TICS) was associated with poor performance in all seven cognitive domains (all p < 0.0005) and was the only cognitive measure associated with poor recovery in all four aspects of outcome (all p ≤ 0.005). Cognitive impairment in four specific domains was also associated with functional disability or reduced QOL. After accounting for global cognitive impairment with the TICS, however, neuropsychological testing did not contribute additional predictive value for concurrent mRS or SIP total scores. Conclusions: Cognitive impairment impacts broadly on functional status, emotional health, and QOL after SAH. The TICS may be a useful alternative to more detailed neuropsychological testing for detecting clinically relevant global cognitive impairment after SAH.

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.

Predictors and clinical impact of epilepsy after subarachnoid hemorrhage

Objective: To determine the frequency, predictors, and impact on outcome of epilepsy developing during the first year after subarachnoid hemorrhage (SAH). Methods: The authors prospectively analyzed 247 of 431 patients with SAH treated over a period of 5 years who were alive with follow-up at 12 months. Epilepsy was defined as two or more unprovoked seizures after hospital discharge. Results: New-onset epilepsy occurred in 7% (n = 17) of patients; an additional 4% (n = 10) had only one seizure after discharge. Independent predictors of epilepsy included subdural hematoma (OR 9.9, 95% CI 1.9 to 52.8) and cerebral infarction (OR 3.9, 95% CI 1.4 to 11.3). Unlike those without seizures, patients who developed epilepsy failed to experience functional recovery on the modified Rankin Scale (mRS) between 3 and 12 months after SAH. At 12 months epilepsy was independently associated with severe disability (score ≥ 3) on the mRS (OR 10.3, 95% CI 2.5 to 42.0), increased instrumental disability on the Lawton Instrumental Activities of Daily Living scale (OR 4.9; 95% CI 1.1 to 22.2), reduced quality of life on the Sickness Impact Profile (OR 4.5; 95% CI 1.1 to 18.0), and increased state anxiety on the Spielberger Anxiety Inventory (OR 4.8; 95% CI 1.1 to 20.4). Epilepsy was not associated with cognitive impairment, depression, or subjective life satisfaction. Conclusion: Epilepsy occurred in 7% of patients with SAH, was predicted by subdural hematoma and cerebral infarction, and was associated with poor functional recovery and quality of life. Our findings indicate that focal pathology, rather than diffuse injury from hemorrhage, is the principal cause of epilepsy after SAH.

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.

Decompressive hemicraniectomy for poor-grade aneurysmal subarachnoid hemorrhage patients with associated intracerebral hemorrhage: clinical outcome and quality of life assessment.

OBJECTIVE:Decompressive hemicraniectomy has been proposed as a potential treatment strategy in patients with poor-grade aneurysmal subarachnoid hemorrhage presenting with focal intracerebral hemorrhage causing significant mass effect. Although hemicraniectomy improves overall survival rates, the long-term quality of life (QoL) for survivors in this patient population has not been reported. METHODS:Using adjudicated outcome assessments, we compare long-term clinical outcomes and QoL between a group of patients with poor-grade aneurysmal subarachnoid hemorrhage receiving decompressive hemicraniectomy (n = 12) and a control group of similar patients managed more conservatively (n = 10). RESULTS:Patients receiving decompressive hemicraniectomy experienced a statistically insignificant decrease in short-term mortality compared with controls (25 versus 42%); however, long-term QoL in hemicraniectomy survivors was generally poor. Furthermore, hemicraniectomy patients did not experience an increase in mean quality-adjusted life years over control patients (2.31 versus 2.22 yr). CONCLUSION:Decompressive hemicraniectomy prolongs short-term survival in patients with poor-grade aneurysmal subarachnoid hemorrhage with associated intracerebral hemorrhage; however, this trend is not statistically significant, and the overall QoL experienced by survivors is poor. Decompressive hemicraniectomy may be indicated if performed early in a select subset of patients. On the basis of our preliminary data, large prospective studies to investigate this issue further may not be warranted.

Dobutamine versus milrinone after subarachnoid hemorrhage.

OBJECTIVE:Neurogenic stunned myocardium is a well-recognized complication of subarachnoid hemorrhage. Dobutamine and milrinone are both used for neurogenic stunned myocardium, but there are few data comparing them after subarachnoid hemorrhage. METHODS:We compared the physiological dose response of dobutamine and milrinone in patients with subarachnoid hemorrhage requiring a pulmonary artery catheter. We located 11 patients who received either inotrope. Physiological data were fitted to a mixed model accounting for drug, dose, and between-patient variation. RESULTS:There were 11 patients who had 152 pulmonary artery catheter measurements. Two received both inotropes (but not within 4 h of each other), 2 only milrinone, and 7 only dobutamine. The groups had similar clinical and physiological characteristics. After adjustment for vasopressin, milrinone was significantly more potent in increasing cardiac output (P < 0.0001) and stroke volume (P = 0.03), while decreasing vascular resistance (P < 0.0001) and systolic blood pressure (P = 0.008), than dobutamine. CONCLUSION:These data suggest that milrinone and dobutamine should be used in different clinical situations. Milrinone may be more effective in patients with severely depressed systolic function but who have at least normal vascular resistance and blood pressure and in whom raising cardiac output is the primary goal. Dobutamine may be superior when vascular resistance or blood pressure is low.