Original Contribution
A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of  pain in the ED

https://doi.org/10.1016/j.ajem.2017.03.004Get rights and content

Abstract

Study objective

Compare adverse effects and analgesic efficacy of low-dose ketamine for acute pain in the ED administered either by single intravenous push (IVP) or short infusion (SI).

Methods

Patients 18–65, presenting to ED with acute abdominal, flank, or musculoskeletal pain with initial pain score  5, were randomized to ketamine 0.3 mg/kg by either IVP or SI with placebo double-dummy. Adverse effects were evaluated by Side Effects Rating Scale for Dissociative Anesthetics (SERSDA) and Richmond Agitation-Sedation Scale (RASS) at 5, 15, 30, 60, 90, and 120 min post-administration; analgesic efficacy was evaluated by Numerical Rating Scale (NRS).

Results

48 patients enrolled in the study. IVP group had higher overall rates of feeling of unreality on SERSDA scale: 92% versus 54% (difference 37.5%; p = 0.008; 95% CI 9.3–59.5%). At 5 min median severity of feeling of unreality was 3.0 for IVP versus 0.0 for SI (p = 0.001). IVP also showed greater rates of sedation on RASS scale at 5 min: median RASS − 2.0 versus 0.0 (p = 0.01). Decrease in mean pain scores from baseline to 15 min was similar across groups: 5.2 ± 3.53 (95% CI 3.7–6.7) for IVP; 5.75 ± 3.48 (95% CI 4.3–7.2) for SI. There were no statistically significant differences with respect to changes in vital signs and need for rescue medication.

Conclusion

Low-dose ketamine given as a short infusion is associated with significantly lower rates of feeling of unreality and sedation with no difference in analgesic efficacy in comparison to intravenous push.

Introduction

Ketamine's role as a safe and effective modality for treating pain in the emergency department (ED) has recently been expanding [1]. Ketamine possesses potent analgesic, amnestic, and anesthetic properties. It is a non-competitive N-methyl-d-aspartate (NMDA1) and glutamate receptor antagonist that decreases central sensitization and “wind-up” phenomenon at the level of the spinal cord (dorsal ganglion) and central nervous system and provides anti-hyperalgesia, anti-allodynia, and anti-tolerance [2]. The NMDA receptor blockade leads to decreases in acute pain, opioid tolerance, opioid-induced hyperalgesia, as well as decreases in persistent chronic (allodynia) and neuropathic pain [2], [3]. Ketamine given intravenously in low (sub-dissociative, analgesic) doses (0.1–0.3 mg/kg) provides effective analgesia with minimal effects on hemodynamics, cognition or consciousness [3].

A growing body of evidence from clinical trials conducted in the ED and pre-hospital settings supports the use of low-dose ketamine (LDK2) when administered as either an adjunct or single agent for a variety of acute and chronic painful conditions. These trials demonstrate significant opioid–sparing and analgesic efficacy that is comparable to opioids [4], [5], [6], [7], [8]. However, these studies also show significant rates (14%–80%) of bothersome adverse effects that include feeling of unreality, sedation, nausea, vomiting, and dizziness. These adverse effects are apparent in the first several minutes after intravenous push (IVP3) administration and are typically short-lived. For that reason, at our institution, we modified our protocol for the administration of LDK from an IVP over 3 to 5 min to a short infusion (SI4) over 10 to 15 min in order to mitigate these effects. To date, no trial has directly compared intravenous push dose to short infusion of LDK.

The goal of our study was to evaluate the rates of adverse effects and the analgesic efficacy of intravenous push (IVP) dose of LDK in comparison to short infusion (SI) for adult patients presenting to the ED with a variety of acute painful conditions. We hypothesized that administration of LDK by SI would be associated with decreased rates of adverse effects and would have similar analgesic efficacy when compared to IVP dose.

Section snippets

Study design and setting

Our study was a prospective, randomized, double-blind, double-dummy trial comparing safety and analgesic efficacy of intravenous LDK given as a push dose (over 5 min) versus given as a short infusion (over 15 min). The study was conducted at a 711-bed urban community teaching hospital with an annual ED census of > 120 000 visits. Patient screening, enrollment, and data collection were performed by study investigators (SM, CF, JD, MM, MY, and IP).

This study was approved by the Maimonides Medical

Results

We enrolled 48 subjects (24 in the IVP group and 24 in the SI group) into our study (Fig. 1). The groups were similar in terms of demographic characteristics (Table 1). Mean ages were 42.2, 43.6 years old, respectively with 37.5% and 50.0% males, also respectively. Mean baseline NRS pain scores in the two groups were both > 8.0 and not significantly different from each other. The first dropout occurred at 60 min in the IVP group; 21 participants in each group were still observable at 120 min.

Limitations

This was a single center study in which subjects were enrolled as a convenience sample based on availability of members of both the ED research and pharmacy teams. This may have led to selection bias or under-representation of patients who may present to the ED late at night. Our stringent exclusion criteria and sample size of 48 subjects were inadequate to assess variance in safety of the two different administration routes of study medication.

Discussion

Sub-dissociative dose ketamine analgesia in the ED is gaining recognition as a viable adjunct and alternative to opioid analgesics for managing a variety of acute and chronic painful conditions. To date, the high incidence of unpleasant (bothersome) adverse effects associated with ketamine administration has proven to be a significant barrier to the promotion of more widespread and well-tolerated utilization of this analgesic modality. It has remained unclear if the rate of intravenous

Additional contributions

John Marshall, MD for his support and guidance; Maryam Zaeem, PharmD, Russell Bardsley, PharmD, and Nechama Rothberger, PharmD for medication administration to study patients, and all the volunteers for their assistance. Authors acknowledge and thank all the ED nurses for their tireless help and support of this project.

Meetings

The study was accepted for oral presentation at the May 2017 Society for Academic Emergency Medicine Conference in Orlando, Florida.

Grant support

None.

Conflicts of interest

All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors have no independent disclosures or conflicts of interest.

Author contributions

A. Likourezos and P. Homel had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Motov, Fromm.

Acquisition, analysis, or interpretation of data: All authors.

Statistical analysis: Likourezos, Homel.

Drafting of the manuscript: Drapkin.

Critical revision of the manuscript for important intellectual content: Motov, Homel, Fromm.

Obtained funding: Fromm.

Study supervision: Motov, Fromm.

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