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SGEM#93: Ketamine, A Bad Reputation?

SGEM#93: Ketamine, A Bad Reputation?

Podcast Link: SGEM93 Ketamine
Date: October 8th, 2014

Guest Skeptics: 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 ED 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?


generics-ketamine-lg-1Background: 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 ED, 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.

ED 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 ED 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.

Article: 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. 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.

checklist-cartoonQuality Checklist for Systematic Review:

  1. The clinical question is sensible and answerable. Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. Disagree
  4. The assessments of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcome. Disagree
  7. The treatment effect was large enough and precise enough to be clinically significant. Disagree 

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.

Meghan Groth

Meghan Groth

Commentary: 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.

Ketamine qualityTwo 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.

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.


Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.


  • Nadia Awad

    Another myth busted in the EM world (again) related to ketamine and its effects on ICP and patient-oriented outcomes with publication of this article. Some shops may not have a slew of agents available for induction for the purposes of RSI to choose from to begin with, which may make it all the more challenging yet essential to ensure that this myth does not dictate practice in those settings. Bringing our EM and trauma colleagues up to speed related to this with the literature reviewed in this article is certainly key.

    • TheSGem

      Trying to shorten the KT window down to <1year by sharing data between Pharm, EM, Trauma, Neurosurg etc.

  • Lauren Westafer

    Of note, ketamine IS Rosenalli approved and the notion of the ICP rise has even made it into these texts. Thanks for continuing to bring up this “myth” to translate that knowledge that is so old…it’s even been taken out of the textbooks. Excellent job, y’all!

    • TheSGem

      Always feels good to get a “Y’all” from the FOAMcast. Working together to cut the KT window down to <1year.

  • jeff riddell

    Preach it man.
    Good review of meta vs systematic, Jadad, etc.
    We have used exclusivley ketamine for all trauma intubations for several years now.
    Strong work Ken and Meghan.

    • Ken Milne

      Thank you for the comments and sharing your experience with ketamine.

  • Loice Swisher

    Great to have the background where this decades-old myth came from and likely not even similar at our ED population. Great discussion.

    • Ken Milne

      It is great to discover where the evidence originally came from in the first place.

  • Minh Le Cong

    hey great post on this topic! I podcasted on this a while ago ..
    http://prehospitalmed.com/2013/07/17/pharm-podcast-75-ketamine-mythbusters-part-1-blowing-your-mind/

    so its good to have it revisited on the eminent site of SGEM!

    thanks!

    • Ken Milne

      Not sure about “eminent” but thank you. We need to keep talking about these topics to ensure from line providers have the best evidence so they can make wise choices.

  • Jeffery Hill

    Excellent breakdown of this article. One thing not mentioned in the analysis is the possibility of confounders in the original articles that went into the systematic review. To my knowledge, in all of the primary studies, there was concurrent administration of a sedative agent (propofol, benzos, or barbiturates) with the administration of ketamine. It is possible that these agents could blunt ICP rise from the administration of ketamine.

    Indeed another systematic review on this same topic was published in Neurocritical Care earlier this year and came to similar conclusions as the Annals article. And in their discussion they point out “Third, the use of
    background sedative compounds, in addition to ketamine and the control medications, makes it difficult to make comments on the use/safety of ketamine in isolation for TBI patients.”
    Zeiler, et al. The Ketamine Effect on ICP in Traumatic Brain Injury. Neurocritical Care. 21 (1) 2014
    http://www.ncbi.nlm.nih.gov/pubmed/24515638

    Before we consider this “myth” completely busted, lets take time to accept that their is no high quality evidence on either side of this debate. Ketamine is an absolutely reasonable choice in a patient with a TBI with borderline to low blood pressure, but may not be the ideal induction agent (if used in isolation) in a patient with a severe TBI and who has known elevated ICP or signs of herniation.

    • Meghan Groth

      Hi Jeffery, thank you for your thoughtful comments! I certainly agree with your conclusion that the quality of evidence available leaves a bit to be desired. What we do know is that the original evidence to suggest that you absolutely cannot use ketamine in a patient who could potentially have an elevated ICP is not necessarily appropriate to extrapolate to our ED patients, and there’s even some data to show small decreases in ICP after ketamine administration. I think it’s just nice to have another “tool in the toolbox” so to speak that allows for tailoring appropriate drug therapy in dynamic resuscitations and an era of never-ending drug shortages.
      I would also agree with your observation that it’s difficult to comment on the effect of ketamine on ICP when it’s used in isolation. However, I would say that many of these trauma patients may also have a reason to be in pain, so it’s not inconceivable to co-administer or pre-administer an agent like fentanyl. This may have a blunting effect on ICP rise, but is reflective of real world practice and how ketamine is likely to be utilized in the resus room.

  • D. Beam

    Great podcast, would be interesting to hear what people think of using ketamine in the pediatric population? Also the review from EM Basic on airway management a few months back is great and has a hilarious slide on ketamine : http://embasic.org/page/2/

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