David A. Zygun

Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial

BACKGROUND The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. METHODS The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. FINDINGS Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). INTERPRETATION This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.

Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury

Preclinical studies have attributed neuroprotective properties to the antibiotic minocycline. Animal studies and early clinical trials support its use in several neurological diseases. In animal spinal cord injury models, minocycline improved neurological and histological outcomes, reduced neuronal and oligodendroglial apoptosis, decreased microglial activation and reduced inflammation. A single-centre, human, double-blind, randomized, placebo-controlled study of minocycline administration after spinal cord injury was undertaken for the purposes of dose optimization, safety assessment and to estimate outcome changes and variance. Neurological, functional, pharmacological and adverse event outcomes were compared between subjects administered 7 days of intravenous minocycline (n = 27) or placebo (n = 25) after acute traumatic spinal cord injury. The secondary outcome used to assess neurological differences between groups that may warrant further investigation was motor recovery over 1 year using the American Spinal Cord Injury Association examination. Recruitment and analyses were stratified by injury severity and injury location a priori given the expected influence of these on the sensitivity of the motor exam. Minocycline administered at higher than previously reported human doses produced steady-state concentrations of 12.7 µg/ml (95% confidence interval 11.6-13.8) in serum and 2.3 µg/ml (95% confidence interval 2.1-2.5) in cerebrospinal fluid, mimicking efficacious serum levels measured in animal studies. Transient elevation of serum liver enzymes in one patient was the only adverse event likely related to the study drug. Overall, patients treated with minocycline experienced six points greater motor recovery than those receiving placebo (95% confidence interval -3 to 14; P = 0.20, n = 44). No difference in recovery was observed for thoracic spinal cord injury (n = 16). A difference of 14 motor points that approached significance was observed in patients with cervical injury (95% confidence interval 0-28; P = 0.05, n = 25). Patients with cervical motor-incomplete injury may have experienced a larger difference (results not statistically significant, n = 9). Functional outcomes exhibited differences that lacked statistical significance but that may be suggestive of improvement in patients receiving the study drug. The minocycline regimen established in this study proved feasible, safe and was associated with a tendency towards improvement across several outcome measures. Although this study does not establish the efficacy of minocycline in spinal cord injury the findings are encouraging and warrant further investigation in a multi-centre phase III trial. ClinicalTrials.gov number NCT00559494.

The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury.

Objective:There is evidence to suggest that anemia after severe traumatic brain injury (sTBI) is detrimental. However, there is a paucity of evidence supporting the use of transfusion of packed red blood cells in patients with sTBI. To understand the acute effect of packed red blood cell transfusion on cerebral oxygenation and metabolism in patients with sTBI. Design:Prospective clinical study. Setting:Addenbrooke’s Neurosciences Critical Care Unit, a 21-bed tertiary academic unit. Patients:Thirty patients with sTBI. Interventions:Patients were randomized by computer random number generator to one of three transfusion thresholds: 8, 9, or 10 g/dL. When the patients’ hemoglobin concentration fell below their assigned threshold, two units of packed red blood cells were transfused over 2 hours. A 1-hour period of stabilization was observed before final data collection. Measurements and Main Results:The primary outcome was change in brain tissue oxygen (Pbto2). Secondary outcomes included dependence of baseline hemoglobin concentration and baseline Pbto2 on the relationship of transfusion and Pbto2, and the effect of transfusion on lactate pyruvate ratio (LPR) and brain pH as markers of cerebral metabolic state. Fifty-seven percent of patients experienced an increase in Pbto2 during the course of the study, whereas in 43% of patients, Pbto2 either did not change or decreased. Multivariable generalized estimating equation analysis revealed change in hemoglobin concentration to significantly and positively associated with change in Pbto2 [0.10 kPa/(g/dL) 95% confidence interval 0.03–0.17, p = 0.003]. Improvement in Pbto2 was not associated with baseline hemoglobin concentration or low Pbto2 (<1 kPa). Fifty-six percent of patients experienced an increase in LPR. No significant relationship between change in LPR or transfusion on pHbt and change in hemoglobin could be demonstrated. Conclusions:Transfusion of packed red blood cells acutely results in improved brain tissue oxygen without appreciable effect on cerebral metabolism. Trial Registration:ISRCTN89085577.

Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study

Background: Severe traumatic brain injury often leads to death from withdrawal of life-sustaining therapy, although prognosis is difficult to determine. Methods: To evaluate variation in mortality following the withdrawal of life-sustaining therapy and hospital mortality in patients with critical illness and severe traumatic brain injury, we conducted a two-year multicentre retrospective cohort study in six Canadian level-one trauma centres. The effect of centre on hospital mortality and withdrawal of life-sustaining therapy was evaluated using multivariable logistic regression adjusted for baseline patient-level covariates (sex, age, pupillary reactivity and score on the Glasgow coma scale). Results: We randomly selected 720 patients with traumatic brain injury for our study. The overall hospital mortality among these patients was 228/720 (31.7%, 95% confidence interval [CI] 28.4%–35.2%) and ranged from 10.8% to 44.2% across centres (χ2 test for overall difference, p < 0.001). Most deaths (70.2% [160/228], 95% CI 63.9%–75.7%) were associated with withdrawal of life-sustaining therapy, ranging from 45.0% (18/40) to 86.8% (46/53) (χ2 test for overall difference, p < 0.001) across centres. Adjusted odd ratios (ORs) for the effect of centre on hospital mortality ranged from 0.61 to 1.55 (p < 0.001). The incidence of withdrawal of life-sustaining therapy varied by centre, with ORs ranging from 0.42 to 2.40 (p = 0.001). About one half of deaths that occurred following the withdrawal of life-sustaining therapies happened within the first three days of care. Interpretation: We observed significant variation in mortality across centres. This may be explained in part by regional variations in physician, family or community approaches to the withdrawal of life-sustaining therapy. Considering the high proportion of early deaths associated with the withdrawal of life-sustaining therapy and the limited accuracy of current prognostic indicators, caution should be used regarding early withdrawal of life-sustaining therapy following severe traumatic brain injury.

Implementation of a nutrition support protocol increases the proportion of mechanically ventilated patients reaching enteral nutrition targets in the adult intensive care unit.

BACKGROUND Despite the evidence that enteral feeding reduces morbidity in critically ill patients and is preferred to parenteral nutrition, the delivery of enteral nutrition (EN) is often inadequate. The purpose of this study was to determine whether implementation of an evidence-based nutrition support (NS) protocol could improve EN delivery. METHODS An NS protocol incorporating available scientific evidence; data from a retrospective survey of 30 intensive care unit (ICU) patients; and input from dietitians, intensive care physicians, surgeons, nurses, and pharmacists was developed. The impact of this protocol was evaluated prospectively in 123 consecutive adult patients admitted to a multisystem ICU who were eligible for EN. RESULTS The percentage of patients who received at least 80% of their estimated energy requirements during their ICU stay increased from 20% before implementation of the NS protocol to 60% after implementation (p < .001). After adjusting for confounders, those in the postimplementation group received significantly more kcal/kg/d than the preimplementation group (3.71 kcal/kg/d; 95% confidence interval, 1.64 to 5.78; p = .001). Parenteral nutrition use [corrected] was reduced in the postimplementation group (1.6 vs 13%, p = .02). There was no difference in time to initiation of enteral nutrition between groups (1.76 days preprotocol vs 1.44 days postprotocol implementation, p = .9). CONCLUSIONS The development and use of an evidence-based NS protocol improved the proportion of enterally fed ICU patients meeting their calculated nutrition requirements.

Negative-pressure wound therapy for critically ill adults with open abdominal wounds: A systematic review

BACKGROUND Open abdominal management with negative-pressure wound therapy (NPWT) is increasingly used for critically ill trauma and surgery patients. We sought to determine the comparative efficacy and safety of NPWT versus alternate temporary abdominal closure (TAC) techniques in critically ill adults with open abdominal wounds. METHODS We conducted a systematic review of published and unpublished comparative studies. We searched MEDLINE, PubMed, EMBASE, Scopus, Web of Science, the Cochrane Database, the Center for Reviews and Dissemination, clinical trials registries, and bibliographies of included articles. Two authors independently abstracted data on study design, methodological quality, patient characteristics, and outcomes. RESULTS Among 2,715 citations identified, 2 randomized controlled trials and 9 cohort studies (3 prospective/6 retrospective) met inclusion criteria. Methodological quality of included prospective studies was moderate. One randomized controlled trial observed an improved fascial closure rate (relative risk [RR], 2.4; 95% confidence interval [CI], 1.0–5.3) and length of hospital stay after addition of retention sutured sequential fascial closure to the Kinetic Concepts Inc. (KCI) vacuum-assisted closure (VAC). Another reported a trend toward enhanced fascial closure using the KCI VAC versus Barker’s vacuum pack (RR, 2.6; 95% CI, 0.95–7.1). A prospective cohort study observed improved mortality (RR, 0.48; 95% CI, 0.25–0.92) and fascial closure (RR, 1.5; 95% CI, 1.1–2.0) for patients who received the ABThera versus Barker’s vacuum pack. Another noted a reduced arterial lactate, intra-abdominal pressure, and hospital stay for those fitted with the KCI VAC versus Bogotá bag. Most included retrospective studies exhibited low methodological quality and reported no mortality or fascial closure benefit for NPWT. CONCLUSION Limited prospective comparative data suggests that NPWT versus alternate TAC techniques may be linked with improved outcomes. However, the clinical heterogeneity and quality of available studies preclude definitive conclusions regarding the preferential use of NPWT over alternate TAC techniques. LEVEL OF EVIDENCE Systematic review, level III.

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.

Ventilator-associated pneumonia in severe traumatic brain injury.

Introduction p Pneumonia is an important cause of morbidity following severe traumatic brain injury (TBI). However, previous studies have been limited by inclusion of specific patient subgroups or by selection bias. The primary objective of this study wastoo describe the incidence, risk factors for, and outcome of ventilator-associated pneumonia in an unselected population-based cohort of patients with severe TBI. An additional goal was to define the relationship of ventilator-associated pneumonia (VAP) with nonneurological organ dysfunction.Methods p A prospective, observational cohort study was performed at Foothills Medical Centre, the sole adult tertiary-care trauma center servicing southern Alberta. All patients with severe TBI requiring ventilation for more than 48 hours between May 1, 2000 and December 30, 2002 were included.Results p A total of 60 patients (45%) acquired VAP for an incidence density of 42.7/1000 ventilator days. Patients with polytrauma were at higher risk (risk ratio 1.7,95% confidence interval, 0.9–3.1) for development of VAP than those with isolated head injury. Development of VAP was associated with a significantly greater degree of nonneurological organ svstem dysfunction. Although VAP was not associated with increased hospital mortality, patients who developed VAP had a longer duration of mechanical ventilation (15 versus 8 days, p < 0.0001), longer intensive care unit (17 versus 9 days, p < 0.0001) and hospital (60 versus 28 days, p =0.003) lengths of stay, and more often required tracheostomy (35 versus 18%, p =0.003).ConclusionsVAP occurs frequently and is associated with significant morbidity in patients with severe TBI.

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.

Role of transcranial Doppler in neurocritical care.

Transcranial Doppler has several practical applications in neurocritical care. It has its main application in the diagnosis and monitoring of vasospasm in patients with subarachnoid hemorrhage. In addition, it holds promise for the detection of critical elevations of intracranial pressure. Its ability to measure CO2 reactivity and autoregulation may ultimately allow intensivists to optimize cerebral perfusion pressure and ventilatory therapy for the individual patient. Transcranial Doppler findings of brain death are well described and can be useful as a screening tool.