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Date: March 11th, 2015

Guest Skeptic: Billy Sin is an Assistant Professor of Pharmacy Practice Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Clinical Pharmacy Educator Emergency Medicine, The Brooklyn Hospital Center

Case: 27-year-old woman presents to the emergency department again with severe back pain radiating to her legs. She has tried analgesics, anti-inflammatories, narcotics and even trigger point injections. You have been reading more and more papers suggesting a sub dissociative-dose of ketamine (SDDK) could work.

SGEM-HOP Process:

We pick a manuscript in conjunction with AEM’s Editorial Board that has been submitted, peer-reviewed, and ultimately accepted for AEM but not published yet. The SGEM then put a skeptical eye upon the manuscript using a modified BEEM critical appraisal tool. One of the authors of the paper is invited to discuss the strengths, weakness, limitations and clinical application their study. A SGEM Hot Off the Press podcast is posted the week the manuscript gets published. The SGEM audience gets a chance to respond via the blog, twitter or on Facebook. A summary of the SGEM critical appraisal gets published in a subsequent issue of AEM including the top social media feedback.

Background: Ketamine was developed more than 50 years ago and been used mainly as an anesthetic agent. It has a number of other medical uses including procedural sedation in the ED as well as chronic pain syndromes like neuropathic pain or cancer pain.

Ketamine is a N-Methyl-D-aspartate (NMDA) receptor antagonist that exerts sedative, amnestic, and analgesic effects as a dissociative anesthetic.

Ketamine also has some other non-medical uses. It is used as a street drug and goes by some other names such as Special K and cat valium. If recreational users take too much they referred to it as heading down the K-hole.

Ketamine historically had a bad reputation of raising intracranial pressure. EM Pharmacist, Meghan Groth debunked that myth on SGEM#93. The bottom Line from that episode was: “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.”

There are a group of doctors out there who like to combine ketamine with propofol into Ketofol. We have a podcast coming up on that topic with Steve Carroll from EM Basic.

Clinical Question: Is the administration of subdissociative dose ketamine for acute pain control safe and effective compared with placebo?

Reference: Sin B, Ternas T, Motov SM. The use of subdissociative-dose ketamine for acute pain in the emergency department. Acad Emerg Med (in press)

Population: English-language randomized controlled trials assessing adult or paediatric emergency department patients with acute pain (fracture, dislocation, abscess, burns). Exclusion criteria varied across studies, but included obesity, substance abuse, acute intoxication, psychiatric disorders, respiratory/renal/hepatic failure, pregnancy, severe shock, or allergy to ketamine.

English-language randomized controlled trials assessing adult or paediatric emergency department patients with acute pain (fracture, dislocation, abscess, burns). Intervention: Ketamine 0.20-0.30 mg/kg IV over 3-10 minutes versus placebo. One trial used morphine (0.1 mg/kg) with the ketamine

Ketamine 0.20-0.30 mg/kg IV over 3-10 minutes versus placebo. One trial used morphine (0.1 mg/kg) with the ketamine Comparison: One trial used morphine (0.1 mg/kg IV + 0.1 mg/kg every 4 hours), one used morphine + placebo, one used midazolam (0.1 mg/kg IV) + fentanyl (0.5 microgram/kg), and one used fentanyl 1.5 microgram/kg

One trial used morphine (0.1 mg/kg IV + 0.1 mg/kg every 4 hours), one used morphine + placebo, one used midazolam (0.1 mg/kg IV) + fentanyl (0.5 microgram/kg), and one used fentanyl 1.5 microgram/kg Outcome: Primary Outcome: Difference in pain scores. Secondary Outcomes: Incidence of adverse events and reduction in adjuvant opioids.



Authors’ Conclusions: “The data failed to provide convincing evidence to either support or refute the use of subdissociative-dose ketamine for management of acute pain in the ED. The decision to initiate subdissociative-dose ketamine should be based on assessments of potential risks and benefits of therapy on a case-by-case basis”.

Quality Checklist for Therapeutic Systematic Reviews:

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

Key Results: Four randomized controlled trials totaling 428 patients were identified and met inclusion criteria.

Using the GRADE Criteria, the authors noted that the overall quality of evidence was low to moderate with potential biases including small sample sizes, lack of (or compromised) blinding, and lack of randomization.

In addition, the various trials used various doses of ketamine and comparator opioid analgesics, as well as different pain scales.

For the primary outcome, two studies (Messenger 2008 and Galinski 2007) demonstrated no detectable differences in pain scores.

One study (Gurnani 2007) reported, “significantly lower pain scores” but systematic review authors do not provide absolute values or number needed to treat estimates.

The only paediatric paper (Kennedy 1998) reported reduction in Observational Scale of Behavioral Distress (OSBD) scale scores in ketamine compared to fentanyl.

For the secondary outcome of adverse effects, Kennedy et al. reported higher incidence of post-treatment pediatric vomiting in ketamine vs. midazolam (NNT 17, 95% CI 10 to infinity), but Gurnani reported no vomiting in adults.

Gurnani reported significantly increased use of rescue therapy (which is undefined in the systematic review) with morphine (18/20) compared with ketamine (0/20), equating to a NNT approaching 1.

Across all 4 studies only one case of emergency phenomenon was reported and all reported adverse events were transient without requiring prolonged evaluation or hospitalization.

For the secondary outcome assessing the amount of adjuvant opioids consumed, both Galinski and Gurnani reported a significant reduction in the amount of morphine consumed or requested.

Listen to podcast to hear Billy respond to our questions.

Only searched two electronic databases (MEDLINE and EMBASE). No search of the grey literature (research abstracts and experts in the field). Did not explicitly follow the PRISMA Guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Used the GRADE instrument to assess quality as opposed to the Cochrane instrument designed for systematic reviews of randomized controlled trials. Did not include observational studies and conduct pre-planned sub-study analyses of randomized control trials and observational trials to broaden readers’ understanding of the published literature on this topic. We would have like to have seen more specific recommendations for future investigators in this field. One of the studies included was by Dr. Bo Kennedy who noted that the dose of ketamine used for sub-dissociative purposes is still uncertain. Dr. Sri Chinta has an in-press manuscript at Annals EM that finally tests the appropriate paediatric ketamine dose (answer ED 50 = 0.5-0.7 mg/kg and ED 95 = 0.7 mg/kg). Dr. Kennedy also raised the concern that none of the studies controlled how fast the ketamine was given (pushed or titrated to effect). Dr. Kennedy also hypothesized that ketamine’s effectiveness might depend on the type of pain based being studied. Dr. Bill Dribben researches NMDA receptors. He believes that low dose ketamine such as that used in subdissociative doses, can produce schizophrenia-like symptoms in some patients.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: Agree that published randomized control trial data neither supports or refutes the emergency department effectiveness or safety of subdissociative-dose ketamine to manage acute pain in children or adults.

SGEM Bottom Line: High-quality published evidence to support the use of subdissociative-dose ketamine to quickly reduce acute pain in emergency department settings is lacking, but lower quality studies inconsistently demonstrate effectiveness with uniformly low risk of adverse effects.

Case Resolution: You discuss the issue of subdissociateve-dose ketamine with the patient. She agrees to give it a try to see if it will help her back pain.

Clinically Application: The current published evidence should neither encourage nor dissuade use of subdissociative-dose ketamine as an adjunct to acute pain control in emergency department patients, but keep in mind that the absence of evidence is not evidence of absence.

What Do I Tell My Patient? Many options exist to alleviate your pain in the emergency department today. One choice is intravenous ketamine, which several small and potentially flawed studies indicate may quickly reduce your pain, while reducing the amount of other pain medications that you require today. In children, 1 in 17 may vomit as a result of ketamine who otherwise would not have vomited, but few other significant side effects have been reported.

Keener Kontest: Last weeks winner was Jay Taylor from my Western University. Jay knew that Captopril was the first ACE-Inhibitor approved by the FDA.

Listen to the podcast for this weeks question. The first correct email sent to TheSGEM@gmail.com with “gunner” in the subject line will win a cool skeptical prize.