Pain management and sedation/systematic review–meta-analysis
The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review

https://doi.org/10.1016/j.annemergmed.2014.06.018Get rights and content

Study objective

We synthesize the available evidence on the effect of ketamine on intracranial and cerebral perfusion pressures, neurologic outcomes, ICU length of stay, and mortality.

Methods

We developed a systematic search strategy and applied it to 6 electronic reference databases. We completed a gray literature search and searched medical journals as well as the bibliographies of relevant articles. We included randomized and nonrandomized prospective studies that compared the effect of ketamine with another intravenous sedative in intubated patients and reported at least 1 outcome of interest. Two authors independently performed title, abstract, and full-text reviews, and abstracted data from all studies, using standardized forms. Data from randomized controlled trials and prospective studies were synthesized in a qualitative manner because the study designs, patient populations, reported outcomes, and follow-up periods were heterogeneous. We used the Jadad score and Cochrane Risk of Bias tool to assess study quality.

Results

We retrieved 4,896 titles, of which 10 studies met our inclusion criteria, reporting data on 953 patients. One study was deemed at low risk of bias in all quality assessment domains. All others were at high risk in at least 1 domain. Two of 8 studies reported small reductions in intracranial pressure within 10 minutes of ketamine administration, and 2 studies reported an increase. None of the studies reported significant differences in cerebral perfusion pressure, neurologic outcomes, ICU length of stay, or mortality.

Conclusion

According to the available literature, the use of ketamine in critically ill patients does not appear to adversely affect patient outcomes.

Introduction

Ketamine is a rapidly acting dissociative agent that can provide analgesia, sedation, and amnesia for rapid sequence intubation in critically ill patients.1 It is associated with limited suppression of ventilatory drive and has stable hemodynamic properties,2, 3 yet North American emergency physicians have been reluctant to adopt its use when intubating critically ill patients with undifferentiated pathology. In a prospective registry of emergency department (ED) intubations including 22 hospitals, only 3% of ED intubations were performed with ketamine.4

Editor’s Capsule Summary

What is already known on this topic

Historically, ketamine has been considered contraindicated in the setting of potential elevation of intracranial pressure.

What question this study addressed

Does ketamine raise intracranial pressure or worsen neurologic outcomes?

What this study adds to our knowledge

This systematic review of 10 trials including 953 adults either intubated or undergoing intubation found mixed effect on intracranial pressure (all changes mild) and no adverse effect on cerebral perfusion pressure or neurologic outcomes.

How this is relevant to clinical practice

The best available evidence suggests that ketamine is unlikely to meaningfully elevate intracranial pressure.

Emergency physicians’ reluctance to use ketamine is based on case reports and case control studies—published more than 40 years ago—suggesting that ketamine increases intracranial pressure.5, 6, 7, 8 These reports are based on observations of patients with preexisting intracranial pathology, most with space-occupying lesions or obstructive hydrocephalus causing cerebrospinal fluid outflow tract obstruction. In the absence of additional safety data, and with the licensing of etomidate, another rapidly acting intravenous sedative agent with a favorable hemodynamic profile, most emergency physicians opted to use etomidate for critically ill patients for whom traumatic or other neurologic injuries had not been ruled out.4

However, in the past decade, important safety concerns about etomidate have reemerged because induction doses of etomidate have been linked with transient adrenal dysfunction,9, 10 and intact adrenal function has been associated with improved mortality in critical illness.11, 12 As a result, the use of ketamine in the management of undifferentiated critically ill patients has resurged, and with it, the debate over its potentially deleterious effects on neurologic outcomes.13, 14, 15

EDs see a high volume of undifferentiated critically ill patients who require imminent airway management before investigations to rule out neurologic injuries can be completed. Given the lack of alternative rapidly acting intravenous induction agents with favorable hemodynamic profiles, evidence to support the safety of ketamine for rapid sequence intubation in this group of patients would be reassuring.

Our main objective was to synthesize the available evidence on the effect of ketamine compared with other sedative agents on intracranial and cerebral perfusion pressures in a population of undifferentiated patients requiring intubation. Secondary objectives were to examine its effect on neurologic outcomes, ICU length of stay, and mortality.

Section snippets

Study Design

This was a systematic review of the literature. This study did not involve the use of human subjects or medical records and did not require ethics approval.

Search Strategy

We developed a systematic search strategy in collaboration with a professional librarian (M.M.D.-W.). We developed search terms by identifying key words and mapping them to Medical Subject Headings (MeSH) terms. We reviewed the scope notes to identify alternate and previous indexing terms. For our MEDLINE search, we combined relevant MeSH

Characteristics of Retrieved Studies

Our search identified 4,896 studies, of which 4,308 were excluded on title review and 396 on abstract review (Figure). We reviewed the full texts of 192 articles, of which 10 met inclusion criteria.18, 19, 20, 21, 22, 23, 24, 25, 26, 27 Five randomized trials reported data on 854 patients,19, 20, 21, 24, 25 and 5 prospective controlled studies reported data on 99 patients.18, 22, 23, 26, 27 Table 1, Table 2 characterize the individual studies. Three of 5 included randomized trials were

Limitations

There are several factors limiting our systematic review. Only few prospective comparator studies have been published comparing the effect of ketamine with that of other intravenous induction agents. We do not believe that selection or retrieval bias affected our results because we used an exhaustive search strategy constructed with the help of a professional librarian and updated our searches in March 2014 to ensure that no new data had been published since we began our review. The quality of

Discussion

This systematic review examined the effect of ketamine compared with other intravenous induction agents on intracranial and cerebral perfusion pressures, neurologic outcomes, ICU length of stay, and mortality. Although 2 studies reported small, clinically insignificant reductions in intracranial pressure shortly after ketamine administration and 2 studies reported increases in intracranial pressure, most reported no significant differences. We found no evidence of any sustained changes in

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    Please see page 44 for the Editor’s Capsule Summary of this article.

    Supervising editor: Steven M. Green, MD

    Author contributions: VA, NGWR, and CMH conceived the study, designed the protocol, and obtained funding. LC, VA, MMD-W, NGWR, and CMH designed the search strategy, and MMD-W and MEW completed the searches. LC, VA, and MEW collected the data. LC, VA, and CMH assessed the quality of the individual studies. All authors contributed to interpreting the data. LC drafted the first article. All authors provided feedback. CMH takes responsibility for the paper as a whole.

    Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: This work was supported by a grant from the Canadian Association of Emergency Physicians. During the study period, Dr. Hohl was supported by a CIHR New Investigator Award (grant #261895).

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