Should Ketamine be Used for Trauma Analgesia?

Case Description:

A 21-year-old male presents to your emergency department via EMS after suffering a motorcycle accident.  He was travelling at approximately 80 km/h when he lost control of his vehicle and slid into a median.  He has an open fracture of his left tibia and fibula, but bleeding is controlled, and his left foot is neurovascularly intact.  Despite receiving 10mg of intravenous morphine given by paramedics, he is screaming in pain and you are unable to perform your trauma assessment.  Vital signs are: BP 90/50, HR 125, RR 28, O2 99%, T 36.6C, glucose 8.8, GCS 15.  The orthopaedic surgery team has assessed the patient but will not have an operating theatre for 30 minutes.  How will you control his pain?

Research Question:

For emergency department trauma patients, is ketamine a safe and effective option for analgesia when compared to current standard practice?

Search Strategy:

2 databases were searched, published data after December 31, 2018 was not reviewed.

Ovid MEDLINE: Keyword search ketamine and analgesia and trauma limit to full text English last 5 years (16 results).  The literature search was not further narrowed down with advanced features because of the limited amount of published data on the topic.

EMBASE: Keyword search ketamine and analgesia or trauma limit to full text English last 10 years.

Background:

Trauma is a pervasive and often painful disease, affecting people of all ages across the country^​1​. Early and effective analgesia in the trauma bay is important not only for acute symptom control, but it has also been associated with decreased chronic pain, as well as a shorter period of recovery^​2–5​.  Several factors contribute to the selection of analgesic medications, and adequate pain control is often incomplete^​6–8​ or difficult to achieve. Opioid medications are often appropriate first-line analgesics for acute pain but come with hemodynamic and respiratory depression, as well as concerns surrounding the ongoing opioid crisis.  Ketamine is a dissociative and analgesic medication that can be used alone or in tandem with other analgesics.  Away from the emergency department, research has been performed to examine the safety and efficacy of ketamine for trauma patients, showing that ICU patients with a sub-dissociative ketamine infusion used less opioid analgesics and had preferable hemodynamics^​9​.  Ketamine’s analgesic effect has also been studied for procedural sedation, where it has demonstrated both equivalent and inferior analgesia (when combined with a sedative) to opioids^​10,11​.  Here we present the current literature surrounding the safety and efficacy of ketamine in the trauma bay in order to establish its utility for these patients.  

Importance:

Early and effective analgesia in trauma patients improves outcomes and limits disability, but pain is often overlooked in the unstable patient, or hemodynamically depressing medications are foregone for fear of losing stability.  In the right patient and when coupled with other analgesics, ketamine may limit hemodynamic depression while effectively treating pain.  This review was undertaken to gain a deeper understanding of the safety and efficacy of this medication and, if supported, to encourage emergency physicians to consider low-dose ketamine for analgesia in trauma patients.

Summary of Evidence:

The Efficacy of Ketamine for Analgesia

There is diverse evidence demonstrating the efficacy of ketamine as an analgesic for trauma patients: 

• In 2017 Haske and colleagues^​12​ completed a comprehensive systematic review/meta-analysis of 41 studies over a 10-year period, comparing ketamine, morphine, fentanyl or any combination of these, for analgesia in pre-hospital or emergency department trauma patients.  The results showed that ketamine could offer similar analgesia as other commonly used medications but did not demonstrate clear superiority [compared to pain scale reductions with morphine alone, ketamine alone (mean increased reduction of 1.27/10 versus morphine p=0.31) and ketamine + morphine (mean increased reduction of 1.23/10 versus morphine p=0.02)].^​12​
• Similarly, in 2018, Karlow and colleagues published a systematic review/meta-analysis examining the efficacy of low-dose IV ketamine (=/< 0.5mg/kg IV push or short infusion) to IV opioids for pain control in emergency department patients (not necessarily trauma patients)^​13​.  This study included three randomized controlled trials (RCTs) and the authors also found that low-dose ketamine was as effective as standard of care for analgesia in emergency patients [compared to pain scale reduction with morphine, ketamine was not inferior (relative reduction =0.42 95% CI = -0.70 to 1.54)].^​13​
• In 2012, Jennings and colleagues compared ketamine and morphine to morphine alone in an RCT of prehospital trauma patients^​14​.  Trauma patients were treated with 5mg IV morphine, then, if still with pain of 5/10 or greater, were randomized to receive either ketamine or further doses of morphine, until pain was relieved.  A total of 135 patients were included, and the study was open label.  There was a clear superiority in pain control in the ketamine group, with a mean reduction in pain score of -5.6 (95% CI -6.2 to -5.0) compared to -3.2 (95% CI -3.7 to -2.7) in the morphine alone group [difference in mean pain score change = -2.4 (95% CI -3.2 to -1.6)].^​14​
• In 2017, Benov and colleagues published a review of 17 years’ worth of all case data from the prehospital military trauma registry of the Israeli Defence Forces^​15​.  This included data from 141 patients, primarily young (median age 21) men, who had received ketamine for pain control, with the most common reason being explosion.  While a statistical analysis was not done, the review made a relatively conclusive statement: “Ketamine in subanesthetic doses is almost an ideal analgesic exhibited through its profound pain relief, its margin of safety, and its role in potentiation of opioids and prevention of opioid hyperalgesia.”^​15​ 
• Use of ketamine to prevent opioid hyperalgesia is also mentioned in the literature review published by Sullivan and colleagues in 2016, which explored multi-modal and opioid sparing techniques for pain control in trauma patients^​16​.  The authors indicate that ketamine has a diverse utility for pain control in trauma patients, citing its ability to provide analgesia in the opiate-dependent population, or for those who are a risk for opiate addiction, facts which are acutely relevant with the ongoing opiate crisis in Canada^​16​.

The Safety of Ketamine

The safety profile of ketamine has also been examined in the literature, specifically:

• Losvik and colleagues published a large retrospective cohort study (n=8176) in 2015, comparing the hemodynamics of Iraqi military members suffering trauma^​17​.  Their protocols call for ketamine analgesia for patients with penetrating trauma or burn injuries, and pentazocine (an opioid) for patients with spinal cord, eye, or blunt injuries.  The ketamine population was associated with higher blood pressures and preferable hemodynamics than the pentazocine group.  In severely injured patients ketamine analgesia was associated with improved blood pressure compared to pentazocine analgesia (p=0.03), although there was also a significant difference in the pre-intervention population given the difference in injury patterns^​17​.  This study found a similar result to Benov et al, and describes ketamine as a hemodynamically safe medication for analgesia in trauma patients^​15,17​.
• In the emergency department, Karlow et al cite a preferable side effect profile for ketamine when compared to IV opioids for ED pain control^​13​. 
• With respect to adverse events, the study by Jennings and colleagues identified ketamine as a more frequent cause of disorientation (morphine group 0%, 95% CI 0 – 5.5; ketamine group 11.4%, 95% CI 5.1 – 21.3), compared to a higher rate of nausea in the morphine subgroup (morphine group 9.2%, 95% CI 3.5 – 19.0%; ketamine group 4.3%, 95% CI 0.9 – 12.0)^​14​.
• In 2008, Messenger and colleagues completed an RCT examining the safety of ketamine and propofol to fentanyl and propofol for emergency department procedural sedation^​18​.  A total of 63 patients were enrolled, and the number of adverse events (hypotension, decreased respiratory rate, etc.) was found to be higher in the fentanyl group (52%) than the ketamine group (22%), suggesting that as an analgesic, this is likely a safe medication to use for trauma patients in the emergency department^​18​.

Ketamine as an analgesic is almost always studied as a medication co-administered with another analgesic or a sedative, confounding bias must be considered whenever interpreting the results from the studies described above.

Unanswered Questions and Challenges:

There are several challenges with studying acute analgesia in trauma patients. Pain is a relative and inherently subjective experience and assigning it a number on a pain scale does not make it truly objective.  Also, many physicians are hesitant to examine a new medication when so many effective options already exist. 

Questions which remain unanswered include (a) what are the best ways to limit adverse effects of analgesics in trauma?; (b) what is the optimal dosing for ketamine as an analgesic in trauma?; and (c) what is the role for ketamine as a stand-alone analgesic in emergency department trauma patients?

Case Conclusion:

You estimate the weight of the patient at 75kg, and deliver 20mg of IV ketamine (0.27mg/kg) to the patient, in addition to a further 5mg of IV morphine and 15mg of IV ketorolac.  His pain rapidly reduces and you are able to safely complete your trauma assessment on a comfortable patient.

Key Points:

• When combined with opioids, sub-dissociative dose ketamine has been shown to be more effective at providing analgesia for trauma patients than opioids alone.
• The hemodynamic properties of sub-dissociative dose ketamine make it a relatively safe choice for analgesia in trauma patients
• Ketamine is being used effectively as first-line analgesia for trauma patients by multiple military organizations.
• The current literature is limited in terms of methodological quality, small sample sizes, and concern for bias (particularly selection and misclassification bias) making it difficult to recommend its’ use on a wide scale.
• A large randomized controlled trial to evaluate the effectiveness of ketamine compared with opioids on pain scores and hemodynamic outcomes is needed.

References:

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Casey Petrie

Dr. Casey Petrie is a 3rd year emergency medicine resident at Queen's University. He has a special interest in pain and the way that we manage it in the emergency department.

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• Should Ketamine be Used for Trauma Analgesia? - December 5, 2019

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Melanie Walker

Dr. Melanie Walker is a Research Scientist and the Resident Research Director in the Department of Emergency Medicine at Queen's University.

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• No beat and ‘roids to treat? Corticosteroids in cardiac arrest outcomes - April 23, 2020
• Should Ketamine be Used for Trauma Analgesia? - December 5, 2019

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Tim Chaplin

Dr. Tim Chaplin is an Emergency Physician and Trauma Team Leader with the Department of Emergency Medicine at Queen’s University. He is also the medical director of the RACE Team at KGH. His academic interests include resuscitation and simulation-based education. Outside of work, Tim enjoys the lake and the odd triathlon.

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• Should Ketamine be Used for Trauma Analgesia? - December 5, 2019