Use of Conivaptan (Vaprisol) for hyponatremic neuro-ICU patients.

BACKGROUND: Hyponatremia is common in neurocritical care and is associated with poor outcome, but the optimal treatment is not known. We wished to test the hypothesis that for neurocritical care patients with severe hyponatremia (Na < 130 mmol/l) or hyponatremia (Na < 135 mmol/l) with depressed Glasgow Coma Scale (GCS) that conivaptan use would lead to increased serum sodium compared to usual care. METHODS: We prospectively screened 249 neurocritical care patients with hyponatremia for a prospective, randomized pilot (goal N = 20) trial. Study interventions were usual care, or usual care plus conivaptan 20 mg IV as a bolus followed by 20 mg IV over 24 h, the lower FDA-approved dose. Patients were prospectively followed for changes in serum and urine electrolytes and clinical examinations with a blinded examiner. This study is registered at www.clinicaltrials.gov (NCT00727090). RESULTS: Despite the prevalence of hyponatremia, recruitment was difficult, and the study was terminated after six patients were enrolled, three in each group. Most hyponatremia in screened but non-randomized patients was transient or not associated with depressed GCS. Conivaptan led to higher serum sodium compared to usual care. The change in serum sodium from baseline, the pre-specified endpoint, was significantly different between groups at six (7.0 +/- 1.7 vs. -0.6 +/- 2.1 mmol/l, P = 0.008), 24 (9.7 +/- 3.2 vs. 0 +/- 1.0 mmol/l), and 36 h (8.0 +/- 5.6 vs. -1.7 +/- 2.1 mmol/l, P = 0.05). There were no apparent differences in clinical examination as a result of treatment. Adverse events were similar, and all randomized patients completed the protocol. CONCLUSIONS: Despite an inclusive protocol, most patients were not candidates for conivaptan therapy for hyponatremia. The role of conivaptan in the Neuro-ICU remains to be defined.

Cerebral spinal fluid penetration of tigecycline in a patient with Acinetobacter baumannii cerebritis.

OBJECTIVE: To describe cerebral spinal fluid (CSF) penetration of tigecycline. CASE SUMMARY: A 38-year-old woman experienced a right internal carotid artery dissection and right anterior and middle cerebral artery strokes due to unknown causes and subsequently developed vasogenic edema requiring right hemi-craniectomy. Her postoperative course was complicated by multiple infections, and she developed multidrug, carbapenem-resistant Acinetobacter baumannii cerebritis. She was treated with a prolonged course of multiple antibiotics, including 18 days of therapy with tigecycline. Time-paired serum and CSF samples were obtained, and tigecycline concentrations were analyzed by high-performance liquid chromatography. We report serial, steady-state, serum, and CSF concentrations of tigecycline when administered in the Food and Drug Administration-approved dose of 50 mg every 12 hours. CSF concentrations remained relatively stable, suggesting that tigecycline did not accumulate in the CSF, at least in our patient. Tigecycline concentrations in the CSF were between 0.035 and 0.048 mg/L, while corresponding serum concentrations were 0.097-0.566 mg/L. The calculated tigecycline penetration ratio in this patient ranged from 0% to 52%, depending on the calculation methodology utilized. DISCUSSION: Concentrations, regardless of sample timing relative to dose, remained relatively stable in the CSF of our patient. The pharmacodynamic profile of tigecycline is not completely elucidated; however, it is presumed that the drug must be at the site of infection for efficacy. Our patient never obtained tigecycline concentrations in excess of the minimum inhibitory concentration for A. baumannii in either the serum or the CSF. CONCLUSIONS: Our patient experienced low CSF tigecycline concentrations and failed to achieve a clinical response while on therapy. CSF drug disposition of tigecycline requires further systematic study to fully elucidate the pharmacokinetic profile. Reduced CSF concentrations urge caution in the treatment of cerebritis with standard dosing of tigecycline.

Moderate Hypoglycemia is associated with vasospasm, cerebral infarction, and 3-month disability after subarachnoid hemorrhage.

BACKGROUND: Many ICUs have implemented protocols for tight glucose control, but there are few data on hypoglycemia and neurologic outcomes in patients with subarachnoid hemorrhage (SAH). METHODS: We prospectively ascertained 172 patients with SAH, who were treated according to a standard protocol for target glucose 80-110 mg/dl. Outcomes were assessed with the modified Rankin scale (mRS) at 14 days, 28 days, and 3 months. RESULTS: Worse neurologic injury at admission (P < 0.001) and a history of diabetes (P = 0.002) were associated with increased glucose variance. There was lower nadir glucose in patients with radiographic cerebral infarction (81 +/- 15 vs. 87 +/- 16 mg/dl, P = 0.02), symptomatic vasospasm (78 +/- 12 vs. 84 +/- 16 mg/dl, P = 0.04) and angiographic vasospasm (79 +/- 14 vs. 86 +/- 16 mg/dl, P = 0.01), but maximum and mean glucose values were not different. Glucose < 80 mg/dl was earlier and more frequent in patients with worse functional outcome at 3 months (P < 0.001). Progressive reductions in nadir glucose were associated with increasing functional disability at 3 months (P = 0.001) after accounting for neurologic grade and mean glucose. Severe hypoglycemia (<40 mg/dl) occurred in one patient. CONCLUSIONS: In patients with SAH, nadir glucose < 80 mg/dl is associated with cerebral infarction, vasospasm, and worse functional outcomes in multivariate models. Protocols for target glucose 80-110 mg/dl effectively control hyperglycemia, but may place patients with SAH at risk for vasospasm, cerebral infarction, and poor outcome even when severe hypoglycemia does not occur.

Anticonvulsant use and outcomes after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: There are few data on the effectiveness and side effects of antiepileptic drug therapy after intracerebral hemorrhage. We tested the hypothesis that antiepileptic drug use is associated with more complications and worse outcome after intracerebral hemorrhage. METHODS: We prospectively enrolled 98 patients with intracerebral hemorrhage and recorded antiepileptic drug use as either prophylactic or therapeutic along with clinical characteristics. Antiepileptic drug administration and free phenytoin serum levels were retrieved from the electronic medical records. Patients with depressed mental status underwent continuous electroencephalographic monitoring. Outcomes were measured with the National Institutes of Health Stroke Scale and modified Rankin Scale at 14 days or discharge and the modified Rankin Scale at 28 days and 3 months. We constructed logistic regression models for poor outcome at 3 months with a forward conditional model. RESULTS: Seven (7%) patients had a clinical seizure, 5 on the day of intracerebral hemorrhage. Phenytoin was associated with more fever (P=0.03), worse National Institutes of Health Stroke Scale at 14 days (23 [9 to 42] versus 11 [4 to 23], P=0.003), and worse modified Rankin Scale at 14 days, 28 days, and 3 months. In a forward conditional logistic regression model, phenytoin prophylaxis was associated with an increased risk of poor outcome (OR, 9.8; 1.4 to 68.6; P=0.02), entering after admission National Institutes of Health Stroke Scale and age. Excluding patients with a seizure did not change the results. Levetiracetam was not associated with demographics, seizures, complications, or outcomes. CONCLUSIONS: Phenytoin was associated with more fever and worse outcomes after intracerebral hemorrhage.

Platelet activity and outcome after intracerebral hemorrhage.

There are few data on platelet function in intracerebral hemorrhage (ICH). We prospectively enrolled 69 patients with ICH and measured platelet function on admission. Aspirin use before ICH was associated with reduced platelet activity. Less platelet activity was associated with intraventricular hemorrhage (516.5 [interquartile range (IQR), 454-629.25] vs 637 [IQR, 493-654] aspirin reaction units; p = 0.04) and death at 14 days (480.5 [IQR, 444.5-632.5] vs 626 [IQR, 494-652] aspirin reaction units; p = 0.04). Objective measures of platelet function on admission are associated with intraventricular hemorrhage and death after ICH.