Stephan A. Mayer

Introduction: Seizures refractory to third-line therapy are also labeled super-refractory status epilepticus (SRSE). These seizures are extremely difficult to control and associated with poor outcome. We aimed to characterize efficacy and side-effects of continuous infusions of pentobarbital (cIV-PTB) treating SRSE. Methods: We retrospectively reviewed continuous electroencephalography (cEEG) reports for all adults with RSE treated with cIV-PTB between May 1997 and April 2010 at our institution. Patients with post-anoxic SE and those receiving cIV-PTB for reasons other than RSE were excluded. We collected baseline information, cEEG findings, side-effects and functional outcome at discharge and one year. Results: Thirty one SRSE patients treated with cIV-PTB for RSE were identified. Mean age was 48 years old (interquartile range (IQR) 28,63), 26% (N = 8) had a history of epilepsy. Median SE duration was 6.5 days (IQR 4,11) and the mean duration of cIV-PTB was 6 days (IQR 3,14). 74% (N = 23) presented with convulsive SE. Underlying etiology was acute symptomatic seizures in 52% (N = 16; 12/16 with encephalitis), remote 30% (N = 10), and unknown 16% (N = 5). cIV-PTB controlled seizures in 90% (N = 28) of patients but seizures recurred in 48% (N = 15) while weaning cIV-PTB, despite the fact that suppression-burst was attained in 90% (N = 28) of patients and persisted >72 hours in 56% (N = 17). Weaning was successful after adding phenobarbital in 80% (12/15 of the patients with withdrawal seizures). Complications during or after cIV-PTB included pneumonia (32%, N = 10), hypotension requiring pressors (29%, N = 9), urinary tract infection (13%, N = 4), and one patient each with propylene glycol toxicity and cardiac arrest. One-third (35%, N = 11) had no identified new complication after starting cIV-PTB. At one year after discharge, 74% (N = 23) were dead or in a state of unresponsive wakefulness, 16% (N = 5) severely disabled, and 10% (N = 3) had no or minimal disability. Death or unresponsive wakefulness was associated with catastrophic etiology (p = 0.03), but none of the other collected variables. Conclusions: cIV-PTB effectively aborts SRSE and complications are infrequent; outcome in this highly refractory cohort of patients with devastating underlying etiologies remains poor. Phenobarbital may be particularly helpful when weaning cIV-PTB.

Introduction: Cerebral glucose metabolism and energy production are affected by serum glucose levels. Systemic glucose variability has been shown to be associated with poor outcome in critically ill patients. The objective of this study was to assess whether glucose variability is associated with cerebral metabolic distress and outcome after subarachnoid hemorrhage. Methods: A total of 28 consecutive comatose patients with subarachnoid hemorrhage, who underwent cerebral microdialysis and intracranial pressure monitoring, were studied. Metabolic distress was defined as lactate/pyruvate ratio (LPR) >40. The relationship between daily glucose variability, the development of cerebral metabolic distress and hospital outcome was analyzed using a multivariable general linear model with a logistic link function for dichotomized outcomes. Results: Daily serum glucose variability was expressed as the standard deviation (SD) of all serum glucose measurements. General linear models were used to relate this predictor variable to cerebral metabolic distress and mortality at hospital discharge. A total of 3,139 neuromonitoring hours and 181 days were analyzed. After adjustment for Glasgow Coma Scale (GCS) scores and brain glucose, SD was independently associated with higher risk of cerebral metabolic distress (adjusted odds ratio = 1.5 (1.1 to 2.1), P = 0.02). Increased variability was also independently associated with in hospital mortality after adjusting for age, Hunt Hess, daily GCS and symptomatic vasospasm (P = 0.03). Conclusions: Increased systemic glucose variability is associated with cerebral metabolic distress and increased hospital mortality. Therapeutic approaches that reduce glucose variability may impact on brain metabolism and outcome after subarachnoid hemorrhage.

Background The brain is dependent on glucose to meet its energy demands. We sought to evaluate the potential importance of impaired glucose transport by assessing the relationship between brain/serum glucose ratios, cerebral metabolic distress, and mortality after severe brain injury. Methods We studied 46 consecutive comatose patients with subarachnoid or intracerebral hemorrhage, traumatic brain injury, or cardiac arrest who underwent cerebral microdialysis and intracranial pressure monitoring. Continuous insulin infusion was used to maintain target serum glucose levels of 80–120 mg/dL (4.4–6.7 mmol/L). General linear models of logistic function utilizing generalized estimating equations were used to relate predictors of cerebral metabolic distress (defined as a lactate/pyruvate ratio [LPR] ≥ 40) and mortality. Results A total of 5,187 neuromonitoring hours over 300 days were analyzed. Mean serum glucose was 133 mg/dL (7.4 mmol/L). The median brain/serum glucose ratio, calculated hourly, was substantially lower (0.12) than the expected normal ratio of 0.40 (brain 2.0 and serum 5.0 mmol/L). In addition to low cerebral perfusion pressure (P = 0.05) and baseline Glasgow Coma Scale score (P < 0.0001), brain/serum glucose ratios below the median of 0.12 were independently associated with an increased risk of metabolic distress (adjusted OR = 1.4 [1.2–1.7], P < 0.001). Low brain/serum glucose ratios were also independently associated with in-hospital mortality (adjusted OR = 6.7 [1.2–38.9], P < 0.03) in addition to Glasgow Coma Scale scores (P = 0.029). Conclusions Reduced brain/serum glucose ratios, consistent with impaired glucose transport across the blood brain barrier, are associated with cerebral metabolic distress and increased mortality after severe brain injury.

Introduction: Daily interruption of sedation (IS) has been implemented in 30 to 40% of intensive care units worldwide and may improve outcome in medical intensive care patients. Little is known about the benefit of IS in acutely brain-injured patients. Methods: This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (P_btO₂) during IS trials. Results: Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics were not considered safe on 28 days (34%). An increase in the FOUR Score (Full Outline of UnResponsiveness score) was observed in 50% of IS-trials by a median of three (two to four) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one-third of IS-trials the trial had to be stopped due to an ICP-crisis (> 20 mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in P_btO₂ (P < 0.05), including 67% with critical values of P_btO₂ < 20 mmHg, a tendency to brain metabolic distress (P < 0.07) was observed. Conclusions: Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome the clinical benefit.

Periodic epileptiform discharges (PEDs) are a frequent finding in comatose patients undergoing continuous EEG (cEEG) monitoring, but their clinical significance is unclear. PET and SPECT studies indicate that PEDs can be associated with focal hypermetabolism and hyperemia, suggesting that in some cases this pattern may be ictal and potentially harmful. We hypothesized that frequent PED activity in comatose patients is associated with reduced likelihood of recovery of consciousness. We identified all comatose patients treated in the Columbia neuro-ICU between June 2008 and August 2009 who underwent ten or more consecutive days of video cEEG monitoring (N = 67), and classified them into three groups: those with (1) prolonged PEDs (five or more consecutive days), (2) intermittent PEDs (at least one but fewer than five consecutive days), and (3) no PEDs. Outcome at discharge was assessed by the Glasgow Outcome Scale and classified as dead (GOS 1), vegetative (GOS 2), and command-following (GOS 3–5). Mean age was 56 years, mean admission Glasgow Coma Scale score was seven, and the median duration of cEEG monitoring was 18 (range 10–111) days. The most common diagnoses were hypoxic-ischemic encephalopathy (18 %), subarachnoid hemorrhage (16 %), epilepsy (15 %), encephalitis (15 %), metabolic encephalopathy (13 %), and intracerebral hemorrhage (12 %). 37 % of patients (N = 25) had prolonged PEDs, 31 % (N = 21) had intermittent PEDs, and 31 % (N = 21) had no PEDs. Prolonged PEDs were associated with the presence of SIRPIDS (P = 0.009), electrographic seizures (P = 0.019), and number of AEDs administered (P < 0.0001). However, the presence of intermittent or prolonged PED activity had no impact on mortality (31 % overall) or recovery of consciousness (command-following) at the time of discharge (36 % overall). Persistent spontaneous PED activity in comatose patients is associated with SIRPIDs and electrographic seizures, but has no impact on the likelihood of survival or recovery of consciousness.

Intracerebral hemorrhage is by far the most destructive form of stroke. Apart from the management in a specialized stroke or neurological intensive care unit (NICU), no specific therapies have been shown to consistently improve outcomes after ICH. Current guidelines endorse early aggressive optimization of physiologic derangements with ventilatory support when indicated, blood pressure control, reversal of any preexisting coagulopathy, intracranial pressure monitoring for certain cases, osmotherapy, temperature modulation, seizure prophylaxis, treatment of hyerglycemia, and nutritional support in the stroke unit or NICU. Ventriculostomy is the cornerstone of therapy for control of intracranial pressure patients with intraventricular hemorrhage. Surgical hematoma evacuation does not improve outcome for more patients, but is a reasonable option for patients with early worsening due to mass effect due to large cerebellar or lobar hemorrhages. Promising experimental treatments currently include ultra-early hemostatic therapy, intraventricular clot lysis with thrombolytics, pioglitazone, temperature modulation, and deferoxamine to reduce iron-mediated perihematomal inflammation and tissue injury.

Objective: Although brain swelling is an important cause of neurological deterioration, real time measurement of brain edema does not currently exist. Because thermal conductivity is proportional to percentage water content, we used the thermal conductivity constant to estimate brain water content (BWC).Methods: Between June 2008 and November 2010, 36 comatose brain‐injured patients underwent cerebral blood flow monitoring using a thermal diffusion probe in our neurocritical care unit. BWC was estimated hourly utilizing the measured thermal conductivity and the known temperature‐adjusted thermal conductivity of water. In vitro experiments were performed to validate this formula using agar, glycerol, and water mixtures with different water content.Results: Thermal conductivity was highly correlated (R² = 0.99) and estimated water content was well correlated with actual water content (mean difference, 0.58%) in the in vitro preparations. The majority of the 36 patients (median age, 57 years; 44% female) had subarachnoid hemorrhage (n = 14) or cardiac arrest (n = 9). Initial BWC at the time of monitoring ranged from 67.3 to 85.5%. Brain regions appearing edematous on computed tomography showed higher estimated BWC than normal‐appearing brain regions (79.1 vs 70.2%; p < 0.01). Bolus osmotherapy (20% mannitol or 23.4% hypertonic saline) decreased BWC from 77.2 ± 0.7% (mean ± standard error) at baseline to 76.1 ± 0.5% at 1 hour, 76.5 ± 0.3% at 2 hours, and 76.7± 0.2% at 3 hours (all p ≤ 0.03).Interpretation: Real time monitoring of BWC is feasible using thermal conductivity. Further studies are needed to confirm the clinical utility of this technique. ANN NEUROL 2012;72:344–350

Introduction: We sought to determine the effect of nutritional support and insulin infusion therapy on serum and brain glucose levels and cerebral metabolic crisis after aneurysmal subarachnoid hemorrhage (SAH). Methods: We used a retrospective observational cohort study of 50 mechanically ventilated poor-grade (Hunt-Hess 4 or 5) aneurysmal SAH patients who underwent brain microdialysis monitoring for an average of 109 hours. Enteral nutrition was started within 72 hours of admission whenever feasible. Intensive insulin therapy was used to maintain serum glucose levels between 5.5 and 7.8 mmol/l. Serum glucose, insulin and caloric intake from enteral tube feeds, dextrose and propofol were recorded hourly. Cerebral metabolic distress was defined as a lactate to pyruvate ratio (LPR) > 40. Time-series data were analyzed using a general linear model extended by generalized estimation equations (GEE). Results: Daily mean caloric intake received was 13.8 ± 6.9 cal/kg and mean serum glucose was 7.9 ± 1 mmol/l. A total of 32% of hourly recordings indicated a state of metabolic distress and < 1% indicated a state of critical brain hypoglycemia (< 0.2 mmol/l). Calories received from enteral tube feeds were associated with higher serum glucose concentrations (Wald = 6.07, P = 0.048), more insulin administered (Wald = 108, P < 0.001), higher body mass index (Wald = 213.47, P < 0.001), and lower body temperature (Wald = 4.1, P = 0.043). Enteral feeding (Wald = 1.743, P = 0.418) was not related to brain glucose concentrations after accounting for serum glucose concentrations (Wald = 67.41, P < 0.001). In the presence of metabolic distress, increased insulin administration was associated with a relative reduction of interstitial brain glucose concentrations (Wald = 8.26, P = 0.017), independent of serum glucose levels. Conclusions: In the presence of metabolic distress, insulin administration is associated with reductions in brain glucose concentration that are independent of serum glucose levels. Further study is needed to understand how nutritional support and insulin administration can be optimized to minimize secondary injury after subarachnoid hemorrhage.