Andreas H. Kramer

Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group

Objective:To provide a uniform platform from which to study acute liver failure, the U.S. Acute Liver Failure Study Group has sought to standardize the management of patients with acute liver failure within participating centers. Methods:In areas where consensus could not be reached because of divergent practices and a paucity of studies in acute liver failure patients, additional information was gleaned from the intensive care literature and literature on the management of intracranial hypertension in non-acute liver failure patients. Experts in diverse fields were included in the development of a standard study-wide management protocol. Measurements and Main Results:Intracranial pressure monitoring is recommended in patients with advanced hepatic encephalopathy who are awaiting orthotopic liver transplantation. At an intracranial pressure of ≥25 mm Hg, osmotic therapy should be instituted with intravenous mannitol boluses. Patients with acute liver failure should be maintained in a mildly hyperosmotic state to minimize cerebral edema. Accordingly, serum sodium should be maintained at least within high normal limits, but hypertonic saline administered to 145–155 mmol/L may be considered in patients with intracranial hypertension refractory to mannitol. Data are insufficient to recommend further therapy in patients who fail osmotherapy, although the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation. Empirical broad-spectrum antibiotics should be administered to any patient with acute liver failure who develops signs of the systemic inflammatory response syndrome, or unexplained progression to higher grades of encephalopathy. Other recommendations encompassing specific hematologic, renal, pulmonary, and endocrine complications of acute liver failure patients are provided, including their management during and after orthotopic liver transplantation. Conclusions:The present consensus details the intensive care management of patients with acute liver failure. Such guidelines may be useful not only for the management of individual patients with acute liver failure, but also to improve the uniformity of practices across academic centers for the purpose of collaborative studies.

Complications associated with anemia and blood transfusion in patients with aneurysmal subarachnoid hemorrhage.

Objective:Patients with subarachnoid hemorrhage (SAH) frequently develop delayed cerebral ischemia and may be especially vulnerable to the effects of anemia. However, the potentially harmful effects of allogeneic red blood cells are increasingly being recognized. The optimal transfusion threshold is unknown, but current practice most often uses a liberal approach. We assessed the association between anemia or transfusion and subsequent adverse outcomes. Design:Retrospective cohort study. Setting:Neuroscience intensive care unit of a university hospital. Patients:A total of 245 consecutive patients with aneurysmal SAH. Interventions:None. Measurements:Logistic regression models were used to adjust for baseline differences in age, severity of neurologic impairment, and amount of blood on computed tomography. Patients were dichotomized based on whether symptomatic vasospasm was diagnosed. Main Results:Individually, anemia (nadir hemoglobin <10 g/dL) and the use of transfusions were both associated with the combined outcome of death, severe disability, or delayed infarction (odds ratio [OR] for anemia, 2.7; 95% confidence interval [CI] 1.5–5; p < .01; OR for transfusion, 4.8; 95% CI, 2.5–9.1; p < .01). When both variables were together introduced into a logistic regression model, only transfusion remained significantly predictive (OR, 4.3; 95% CI, 1.5–9.3; p < .01). The relationship between anemia and adverse outcomes was stronger among patients diagnosed with vasospasm, whereas for transfusion, it was stronger among patients without vasospasm. Transfusion also was associated with the development of nosocomial infections (OR, 3.2; 95% CI, 1.7–5.5; p < .01). There was no statistically significant difference in complications based on the duration of blood storage before transfusion. Conclusions:Although anemia is predictive of adverse outcomes in patients with SAH, this observation cannot be considered justification for a liberal transfusion strategy. Appropriate transfusion thresholds may vary depending on the presence or absence of clinical vasospasm. Randomized trials that compare liberal and restrictive transfusion strategies in patients with SAH are needed.

Statin use was not associated with less vasospasm or improved outcome after subarachnoid hemorrhage.

OBJECTIVE The development of delayed ischemia caused by cerebral vasospasm remains a common cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Preliminary studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may decrease the risk of vasospasm, but additional study is required. METHODS Beginning in May 2006, our treatment protocol for patients presenting with subarachnoid hemorrhage was altered to routinely include the use of 80 mg of simvastatin per day for 14 days. Before this time, only patients with other indications for statins were treated. The charts of 203 consecutive patients over a period of 27 months were retrospectively reviewed, and 150 patients were included in the analysis, of whom 71 patients received statins. These patients were compared with 79 untreated patients to determine whether or not the use of statins was associated with a reduction in the occurrence of vasospasm, delayed infarction, or poor outcome (death, vegetative state, or severe disability). RESULTS Patients who were treated with statins and those who were not had similar baseline characteristics, although more patients in the former group were managed with endovascular coil embolization. There were no statistically significant differences in the proportion of patients developing at least moderate radiographic vasospasm (41% with statins versus 42% without, P = 0.91), symptomatic vasospasm (32% with statins versus 25% without, P = 0.34), delayed infarction (23% with statins versus 28% without, P = 0.46), or poor outcome (39% with statins versus 35% without, P = 0.61). After adjustment for differences in baseline characteristics, including the method of aneurysm treatment, statins were still not significantly protective. CONCLUSION The addition of statins to standard care was not associated with any reduction in the development of vasospasm or improvement in outcomes after aneurysmal subarachnoid hemorrhage. If there is a benefit to statin use, it may be smaller than suggested by previous studies. However, further randomized controlled trials are awaited.

Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials.

Objectives:To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury. Data Sources:PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles. Study Selection:Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, &agr;-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury. Data Extraction:In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results. Data Synthesis:Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure. Conclusions:This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.

Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis

IntroductionHyper- and hypoglycemia are strongly associated with adverse outcomes in critical care. Neurologically injured patients are a unique subgroup, where optimal glycemic targets may differ, such that the findings of clinical trials involving heterogeneous critically ill patients may not apply.MethodsWe performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing intensive insulin therapy with conventional glycemic control among patients with traumatic brain injury, ischemic or hemorrhagic stroke, anoxic encephalopathy, central nervous system infections or spinal cord injury.ResultsSixteen RCTs, involving 1248 neurocritical care patients, were included. Glycemic targets with intensive insulin ranged from 70-140 mg/dl (3.9-7.8 mmol/L), while conventional protocols aimed to keep glucose levels below 144-300 mg/dl (8.0-16.7 mmol/L). Tight glycemic control had no impact on mortality (RR 0.99; 95% CI 0.83-1.17; p = 0.88), but did result in fewer unfavorable neurological outcomes (RR 0.91; 95% CI 0.84-1.00; p = 0.04). However, improved outcomes were only observed when glucose levels in the conventional glycemic control group were permitted to be relatively high [threshold for insulin administration > 200 mg/dl (> 11.1 mmol/L)], but not with more intermediate glycemic targets [threshold for insulin administration 140-180 mg/dl (7.8-10.0 mmol/L)]. Hypoglycemia was far more common with intensive therapy (RR 3.10; 95% CI 1.54-6.23; p = 0.002), but there was a large degree of heterogeneity in the results of individual trials (Q = 47.9; p<0.0001; I2 = 75%). Mortality was non-significantly higher with intensive insulin in studies where the proportion of patients developing hypoglycemia was large (> 33%) (RR 1.17; 95% CI 0.79-1.75; p = 0.44).ConclusionsIntensive insulin therapy significantly increases the risk of hypoglycemia and does not influence mortality among neurocritical care patients. Very loose glucose control is associated with worse neurological recovery and should be avoided. These results suggest that intermediate glycemic goals may be most appropriate.

Do Neurocritical Care Units Save Lives? Measuring The Impact of Specialized ICUs

A variety of organizational models have been used to deliver care to critically ill patients with neurologic disorders. Primary care may be provided by general intensivists, who often rely heavily on consultative support from neurosurgeons and neurologists. This approach is especially common in Australia, New Zealand, Canada and some European countries. Intensive care units (ICUs) organized in this fashion are usually ‘‘closed’’, meaning that admissions and discharges are largely the responsibility of the attending intensivist. In this case, there are typically daily multidisciplinary rounds with a single team of clinicians. An alternative method is for primary care to be delivered by neurosurgeons or neurologists, in this case depending greatly on consultative input from various subspecialists. The corresponding ICUs are frequently ‘‘open’’; that is, at any given time, there may be multiple attending physicians with patients admitted under their care, each of which, in turn, has numerous consultants involved. This approach has, historically, been the most common to be used in the United States. The skill set of ICU bedside nurses and ancillary health professionals (e.g., respiratory therapists, pharmacists, social workers, and rehabilitation staff) may also vary. In ‘‘general ICUs’’, these individuals are usually well-trained in the provision of physiologic support, especially to patients with multi-organ failure; however, specific nuances that are important to neurocritical care patients may sometimes be under-recognized. In contrast, in specialized ICUs, nurses are specifically trained to detect and treat neurologic deterioration in a timely fashion; in this case, however, there may be less experience in the management of systemic complications. As a specialty, neurocritical care seeks to combine the advantages of each of these preceding models. Neurointensivists and neurocritical care nurses are content experts in both critical care and neurologic disorders. These individuals are trained especially to recognize when brainand spinalcord-injured individuals have unique physiologic considerations in relation to other critically ill patients. Thus, their presence influences the ‘‘ICU culture’’ to become highly focused on neuroprotection; treatment targets (e.g., blood pressure or temperature) are consistently chosen with the aim of preventing ‘‘secondary injury’’, increasingly with the aid of advanced multi-modal monitoring. Furthermore, these clinicians are well equipped to deal with the non-neurologic organ dysfunction that is commonly encountered in critically ill neurologic patients [1]. Allied health professionals in neurocritical care units become familiar with the specific implications of the therapeutic interventions that they provide. For example, respiratory therapists are keenly aware that even minor variations in the partial pressure of carbon dioxide can have major implications on cerebral blood flow and intracranial pressure; ‘‘neuro-pharmacists’’ become particularly knowledgeable about the neurologic complications of Electronic supplementary material The online version of this article (doi:10.1007/s12028-011-9530-y) contains supplementary material, which is available to authorized users.

Do Endothelin-Receptor Antagonists Prevent Delayed Neurological Deficits and Poor Outcomes After Aneurysmal Subarachnoid Hemorrhage? A Meta-Analysis

Background and Purpose— Delayed ischemic neurological deficits (DINDs) contribute to poor outcomes after aneurysmal subarachnoid hemorrhage (SAH). Endothelin-1 is an important mediator involved in the development of vasospasm. Methods— We performed a systematic review and meta-analysis of randomized controlled trials assessing the use of endothelin-receptor antagonists (ETRAs) in patients with SAH. Results— Three studies met eligibility criteria, enrolling 867 patients. ETRAs significantly reduced the occurrence of DINDs (OR 0.68 [0.49 to 0.95]) and radiographic vasospasm (OR 0.31 [0.19 to 0.49]), but did not have any impact on mortality (OR 1.09 [0.69 to 1.72]) or poor neurological outcomes (OR 0.87 [0.63 to 1.20]). Any benefit of ETRAs may have been partially offset by adverse effects, including hypotension(OR 2.39 [1.37 to 4.17]) and pulmonary complications (OR 2.12 [1.51 to 2.98]). Conclusions— Although ETRAs reduce radiographic vasospasm and DINDs, there is currently no evidence that they improve outcomes.

Early Ketamine to Treat Refractory Status Epilepticus

BackgroundManagement of refractory status epilepticus (SE) involves administration of intravenous γ-aminobutyric acid (GABAA) receptor agonists, such as benzodiazepines, barbiturates, or propofol. Animal models suggest that reductions in synaptic GABAA receptors may cause these drugs to become less effective as the duration of SE increases. This may explain the large doses that are commonly required to control seizures, which in turn contributes to a high incidence of complications, including hypotension and the need for vasopressors. In contrast, expression of excitatory N-methyl-d-aspartate (NMDA) receptors increases with prolonged SE and their stimulation by glutamate may propagate seizure activity. Ketamine is a NMDA-receptor antagonist that is considered promising as treatment for refractory SE. Compared with other anaesthetic drugs, ketamine produces less hypotension.MethodsThis report describes a patient who developed worsening hypotension with escalating doses of midazolam and propofol in the context of non-convulsive SE. He was therefore treated with ketamine within hours of being diagnosed.ResultsKetamine was immediately efficacious at reducing the frequency, amplitude, and duration of seizures. The dose was rapidly titrated upwards using quantitative continuous EEG monitoring, until seizures were completely abolished. SE did not recur with weaning of sedatives and he went on to have an excellent recovery. A small number of previous reports have found ketamine to abort late SE. In most cases, ketamine was administered several days into the course, and outcomes were poor even though seizures were controlled.ConclusionLarger series and phase I clinical trial(s) of ketamine for treatment of refractory SE seem warranted.

Red blood cell transfusion in patients with subarachnoid hemorrhage: a multidisciplinary North American survey.

IntroductionAnemia is associated with poor outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). It remains unclear whether this association can be modified with more aggressive use of red blood cell (RBC) transfusions. The degree to which restrictive thresholds have been adopted in neurocritical care patients remains unknown.MethodsWe performed a survey of North American academic neurointensivists, vascular neurosurgeons and multidisciplinary intensivists who regularly care for patients with SAH to determine hemoglobin (Hb) concentrations which commonly trigger a decision to initiate transfusion. We also assessed minimum and maximum acceptable Hb goals in the context of a clinical trial and how decision-making is influenced by advanced neurological monitoring, clinician characteristics and patient-specific factors.ResultsThe survey was sent to 531 clinicians, of whom 282 (53%) responded. In a hypothetical patient with high-grade SAH (WFNS 4), the mean Hb concentration at which clinicians administered RBCs was 8.19 g/dL (95% CI, 8.07 to 8.30 g/dL). Transfusion practices were comparatively more restrictive in patients with low-grade SAH (mean Hb 7.85 g/dL (95% CI, 7.73 to 7.97 g/dL)) (P < 0.0001) and more liberal in patients with delayed cerebral ischemia (DCI) (mean Hb 8.58 g/dL (95% CI, 8.45 to 8.72 g/dL)) (P < 0.0001). In each setting, there was a broad range of opinions. The majority of respondents expressed a willingness to study a restrictive threshold of ≤8 g/dL (92%) and a liberal goal of ≥10 g/dl (75%); in both cases, the preferred transfusion thresholds were significantly higher for patients with DCI (P < 0.0001). Neurosurgeons expressed higher minimum Hb goals than intensivists, especially for patients with high-grade SAH (β = 0.46, P = 0.003), and were more likely to administer two rather than one unit of RBCs (56% vs. 19%; P < 0.0001). Institutional use of transfusion protocols was associated with more restrictive practices. More senior clinicians preferred higher Hb goals in the context of a clinical trial. Respondents were more likely to transfuse patients with brain tissue oxygen tension values <15 mmHg and lactate-to-pyruvate ratios >40.ConclusionsThere is widespread variation in the use of RBC transfusions in SAH patients. Practices are heavily influenced by the specific dynamic clinical characteristics of patients and may be further modified by clinician specialty and seniority, the use of protocols and advanced neurological monitoring.

Intraventricular hemorrhage volume predicts poor outcomes but not delayed ischemic neurological deficits among patients with ruptured cerebral aneurysms.

BACKGROUND:Intraventricular hemorrhage (IVH) predicts worse outcomes following aneurysmal subarachnoid hemorrhage (SAH). One potential mechanism is that IVH predisposes to the development of delayed ischemic neurological deficits (DINDs). No previous studies have evaluated the association between IVH volume (in milliliters) and subsequent development of DINDs or poor outcomes. OBJECTIVE:To assess the association between the volume of IVH and the subsequent development of DINDs, delayed cerebral infarction, death, and poor neurological outcomes, specifically among patients with concomitant SAH and IVH. METHODS:We performed a cohort study involving 152 consecutive patients with concomitant SAH and IVH. To determine volume of IVH, we used the IVH Score, shown to correlate well with computerized volumetric assessment. To determine the relative quantity of subarachnoid blood, we applied the SAH Sum Score. Multivariate logistic regression was used to adjust for potential confounders. RESULTS:There was no significant association between IVH volume and the development of DINDs or delayed infarction. In contrast, patients with poor neurological outcomes had significantly larger baseline IVH volume (mean, 11.8 mL vs 3.8 mL, P = .001). In the multivariate analysis, IVH volume was an independent predictor of poor outcomes (OR per mL: 1.11 [1.04-1.18]). Patients in the highest quartile for IVH volume were far more likely to progress to poor outcome compared with those in the lowest quartile (OR 4.09 [1.32-12.65]). Interobserver agreement in the determination of IVH Score was moderate to good. CONCLUSIONS:IVH volume is an independent predictor of poor neurological outcomes, even after adjusting for the amount of subarachnoid blood. The pathophysiology of this association does not appear to involve an increased risk of DINDs or delayed infarction. Measures aimed at accelerating IVH clearance, such as intraventricular thrombolysis, merit further evaluation.