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, α-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.
From the Departments of Surgery (DJR), Community Health Sciences (DJR, DAZ), Critical Care Medicine (AHK, DAZ), and Clinical Neurosciences (AHK, CNG, DAZ), and the Health Sciences Library (HLR), University of Calgary and the Foothills Medical Centre, Calgary, Alberta; Division of Critical Care Medicine (RIH), Department of Medicine, and the Departments of Anesthesia, Pharmacology, and Surgery, Dalhousie University and the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Drs. Richard I. Hall and Andreas H. Kramer contributed equally to this work.
Drs. Derek J. Roberts and David A. Zygun had full access to all data in the study and the final responsibility for the decision to submit for publication.
The work presented herein was conducted at the Foothills Medical Centre/University of Calgary and the Queen Elizabeth II Health Sciences Centre/Dalhousie University, which are located in Calgary, Alberta, and Halifax, Nova Scotia, respectively, both of which are in Canada.
Dr. Richard I. Hall is presently receiving funds from Hospira to investigate use of dexmedetomidine for intensive care unit sedation as well as the Heart and Stroke Foundation to study the effect of the peripheral inflammatory response on morphine pharmacokinetics in surgical patients.
The remaining authors have not disclosed any potential conflicts of interest.
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