SGEM#93: Ketamine, A Bad Reputation?

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Date: October 8th, 2014

Guest Skeptic: Meghan Groth (@EMPharmGirl). Meghan is the emergency medicine pharmacy specialist at Fletcher Allen Health Care in Burlington, Vermont and an adjunct professor of pharmacy at the Albany College of Pharmacy and Health Sciences.

Case: A 25 year old male presents to your emergency department as a trauma alert after an alleged assault. EMS reports that the patient has been minimally responsive during transport, and witnesses at the scene claimed the patient experienced blunt force trauma to the head after being beaten by another man. During the primary survey, you observe that the patient is not protecting his airway with a GCS of 6. You prepare for a rapid sequence intubation prior to the patient getting a CT scan.

His vital signs are HR 98 bpm, BP of 110/75 mmHg, RR 12/min, and SpO2 87% on a non-rebreather. You ask your ED pharmacist to prepare ketamine 2 mg/kg IV and succinylcholine 1.5 mg/kg for intubation. Additionally, you plan to use intermittent fentanyl boluses as needed after intubation to keep the patient comfortable and facilitate further evaluation, in this case a CT scan of his head.

Questions: Does ketamine raise intracranial pressure and adversely affect cerebral perfusion pressures, neurologic outcomes, or mortality compared with other intravenous induction agents commonly used to intubate adult patients in the emergency department?

Background: Ketamine is an NMDA receptor antagonist that exerts sedative, amnestic, and analgesic effects as a dissociative anesthetic. It can be used as an induction agent for rapid sequence intubation in the emergency department, and has relatively stable hemodynamic effects, especially when compared with other agents such as midazolam, propofol, or the ultra-short acting barbiturates. Despite this, the use of ketamine for RSI among ED physicians is low.

Emergency department physicians have been reluctant to use Ketamine. We have been warned not to use it in certain situations. One concern is that it could raise intracranial pressure.

Ketamine’s bad reputation comes from several small case-control series from approximately 30-40 years ago that suggested that ketamine increases ICP through sympathetic stimulation. These case-control series evaluated patients with intracranial pathology including space-occupying lesions or obstructive hydrocephalus, and were not necessarily representative of the majority of emergency department patients.

Up until just recently, etomidate may have been regarded by emergency physicians to be the induction agent of choice in RSI. However, it too now has a bad reputation. There are concerns about adrenal suppression (in the setting of sepsis) and acute lung injury (in the setting of trauma). See SGEM#44: Pause – Etomidate and Rapid Sequence Intubation for more information.

Reference: The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Ann Emerg Med. 2014

Population: 10 studies with 953 patients at least 16 years of age either intubated prior to or at the point of data collection.
- Exclusions: Studies were excluded if they evaluated the effects of ketamine on non-intubated patients, were written in languages other than English, or if they lacked a comparison group
Intervention: Ketamine (either by bolus or infusion)
Comparison: Any other sedative drug that might be used for RSI in the ED (comparisons included sufentanil, remifentanil, etomidate, and fentanyl; in case control studies the cointerventions included propofol, benzodiazepines, and thiopental)
Outcome: Primary outcomes were measures of ICP/CPP; secondary outcomes included neurologic outcomes, ICU LOS, and mortality

Authors’ Conclusions: “The available data suggest that ketamine does not adversely affect intracranial or cerebral perfusion pressures, neurologic outcomes, or mortality compared with other intravenous induction agents commonly used to intubate adult patients in the ED.

Quality Checklist for Systematic Review:

The clinical question is sensible and answerable. Yes
The search for studies was detailed and exhaustive. Yes
The primary studies were of high methodological quality. No
The assessments of studies were reproducible. Yes
The outcomes were clinically relevant. Yes
There was low statistical heterogeneity for the primary outcome. No
The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: Data was available on 168 of the included 953 patients regarding ICP and/or CPP. The populations and designs in these studies were too heterogeneous to pool the results; however examination of many of these studies showed that there were no differences in ICP or CPP between ketamine and the control group.

Two studies showed a small decrease in ICP in the ketamine group compared to the control group immediately post-dose, but that turned into an increased ICP at 30 minutes in one of the studies. One study reported an increase in ICP measurements after prolonged infusions of ketamine, and another reported an increase in ICP after bolus doses of ketamine, but statistical significance was not reported-this study evaluated patients with space-occupying intracranial lesions or obstructive hydrocephalus.

Four of the five clinical trials included in this analysis had a measurement of neurologic outcome. All measurements were too heterogeneous to perform any pooled analysis.

The largest study (n=655), by Jabre and colleagues, used GCS as a primary outcome and found no differences between the ketamine and control groups.

Other smaller studies found no differences with respect to GCS at ICU discharge or scores on neuropsychometric testing.

Two trials reported mortality data (total of 680 patients) as a secondary outcome and found no significant differences between groups.

The authors in this study set out to evaluate whether or not there was definitive evidence that ketamine had detrimental effects on ICP, CPP, and neurologic outcomes when compared to other induction agents. However, only 168 of the 953 patients had the primary outcome of interest evaluated. In fact, the largest study included in this analysis (Jabre, et al.), which included 655 patients, never measured an ICP or CPP. So it’s difficult to say that this analysis conclusively shows a lack of effect of ketamine on the ICP.

Secondary outcomes in this analysis included some LOS and mortality measures, as well as markers of neurologic function such as the GCS and some neuropsychometric tests. Unfortunately, markers such as the GCS and neuropsychometric testing are subject to interobserver variability, and in the included studies were only used as secondary outcomes (thus, were not powered to find a difference in most cases).

They did to a reasonable job of searching the literature using internet databases and the gray literature. However, studies were excluded if they were not printed in English, which may have missed research conducted in non-English speaking centers.

The authors of this analysis used a Jadad score to determine the methodological quality of the RCTs included. The Jadad score is a procedure intended to independently assess the methodologic quality of a clinical trial, and is based on three aspects of the design (1) randomization, (2) blinding, and (3) a full account of all patients randomized, included those who withdrew or dropped out. Scores on the scale range from zero (very poor quality) to five (rigorous).

The Jadad score was widely used in the past. New scoring systems with more dimensions have been developed over time. Berger and Alperson published an article called A General Framework for the Evaluation of Clinical Trial Quality discussing the various aspects of four different scoring systems.

Two of the clinical controlled trials included in this analysis had a Jadad score of 2, two trials had a score of 3, and only one trial had a score of 5. The authors also used the Cochrane Risk of Bias Tool to rate the likelihood of selection, performance, attrition and detection bias. This is Table 2 of the manuscript.

All of the outcomes that the authors set out to evaluate in this study were not able to be pooled due to heterogeneity of the populations, interventions, and outcome measures. This is what differentiates a systematic review from a meta-analysis.

Systematic reviews are a qualitative analysis intended to simply describe the existing data, where meta-analyses are quantitative in nature and try to combine evidence from the populations of smaller studies to make assumptions about the group as a whole.

Unfortunately, it’s difficult to draw larger conclusions about the effects of ketamine on ICP with the collection of studies in this systematic review because each of them are relatively different.

What we can see is the lack of demonstrable harm that ketamine has on our neurologic parameters of interest when compared to the control arm in each of the papers.

Comment on Authors’ Conclusion Compared to Our Conclusion: The authors conclude that ketamine does not adversely affect ICP, CPP, neurologic outcomes, or mortality compared with other induction agents. These are difficult conclusions based upon small sample sizes and secondary outcomes not necessarily powered to find a difference.

However, given the questionable original evidence suggesting that ketamine has detrimental effects on ICP, it seems that the best available evidence we have at this point does not demonstrate an appreciable negative effect on ICP, CPP, or neurologic outcomes.

Bottom Line: Ketamine seems to be a reasonable alternative induction agent for undifferentiated patients requiring RSI in the ED. Evidence to show that ketamine has negative effects on neurologic outcomes is weak and has been largely extrapolated from non-ED patients. This systematic review found no compelling evidence that ketamine worsens ICP, CPP, or neurologic outcomes as measured.

Case Resolution: You discuss with your trauma surgery and neurosurgery teams that in undifferentiated patients requiring RSI in the ED, there is no good evidence to say that ketamine has an appreciable negative effect on ICP, CPP, or neurologic outcomes. Ketamine represents a reasonable induction agent for RSI in this patient. The patient is intubated after receiving the drugs you ordered during the initial resuscitation (above) and remains hemodynamically stable throughout the procedure. After undergoing the appropriate diagnostic testing, the patient is diagnosed with a traumatic subarachnoid hemorrhage and is transferred to the trauma-surgery intensive care unit for further management.

Meghan Groth

Clinical Application In patients who require RSI in the ED, ketamine is a reasonable alternative to other available induction agents, especially if patients have normal or low blood pressure. Other agents would be preferred in the setting of hypertension, as ketamine can increase blood pressure through sympathetic stimulation.

What Do I Tell My Patient (or in this case the trauma/surgery if you as the EM pharmacist were asked): I would tell them in undifferentiated patients requiring RSI in the ED, there is no good evidence to say that ketamine has an appreciable negative effect on ICP, CPP, or neurologic outcomes. In my opinion, ketamine is a reasonable induction agent for RSI in this patient.

Keener Kontest: Winner last week was Dylan Norton a 4th year medical student at the University of Colorado. He knew that mortality increases by 7.6% for every hour delay in providing antibiotics to patients with sepsis after the onset of hypotension.

Listen to the podcast to hear this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

Upcoming Conferences: SkiBEEM 2015 is January 26th-28th in Beautiful Sun Peaks, BC.