Background

Sub-dissociative dose ketamine in the ED for treatment of pain is gaining recognition as an adjunct or alternative to opioid analgesics.  Previous research from this group and others have demonstrated a role of low dose ketamine (0.1-0.3 mg/kg IV) as opioid sparing analgesic.The major issue with wider ketamine use is its adverse effects; the feeling of unreality, nausea, vomiting and emergence reactions.  Both anecdotal observation and research data has shown a correlation between low dose ketamine rates of infusion and adverse effects.  The intent of this study was to show if a prolonged infusion could mitigate some of the commonly seen side effect of ketamine without affecting analgesic effect

Clinical Question

Is there a difference in the rate of adverse effect and analgesia efficacy between Low Dose Ketamine (LDK) intravenous push and LDK short infusion?

Population

Adults ages 18-65 years of age who presented to single urban ED primarily for management of acute abdominal, flank, back, traumatic chest or musculoskeletal pain with an intensity of 5 or greater on standard 0-10 Numeric Pain Rating Scale (NRS). Patients had to be awake, alert, and oriented, able to demonstrate understanding of any adverse effects they might experience

Intervention

LDK short infusion (SI), defined as 0.3 mg/kg in 100 mL normal saline given over 15 minutes

Control

LDK defined as 0.3 mg/kg intravenous push over 3-5 minutes

Outcomes

Primary: Rates of adverse events based on Side Effects Rating Scale of Dissociative Anesthetics (SERSDA) at time 5, 15, 30, 60, 90, and 120 post LDK administration. In addition, degree of sedation was measured using Richmond Agitation-Sedation Scale (RASS).
Secondary: Analgesic efficacy as measured by change in NRS, changes in vital signs, and need for rescue analgesia

Design

Prospective, randomized, double-blind, double dummy controlled single center study.

Excluded

Pregnant and breastfeeding women were excluded from trial. In addition, patients with altered mental status, allergy to ketamine, weight less than 46 kg or greater than 115 kg. Patient with unstable vital signs, defined as SBP < 90 or > 180 mmHg, heart rate < 50 or > 150 bpm, and respiratory rate < 10 or > 30 bpm. Medical history of acute head or eye injury, seizure, and intracranial hypertension. Renal and hepatic insufficiency patients were also excluded. Last, patients with history of alcohol or drug abuse, psychiatric illness and analgesic use 4 hours prior were also excluded.

Primary Results

  • 48 patients enrolled
    • n = 24 in LDK IVP
    • n = 24 in LDK SI
  • No statistically significant difference in baseline pain reported between groups
    • Mean baseline pain in both groups was > 8

Critical Results

  • Overall rates of adverse effects (primary outcome)
    • Similar between two arms for all adverse effects (headache, fatigue, dizziness, hearing/vision/mood change, halluciation) with exception of feeling of unreality
    • Feeling of unreality (measured on SERDSA)
      • IVP 91.7% vs SI 54.2%
      • Absolute difference: 37.5% NNH: 2.67
  • Median severity of feeling of unreality on SERDSA at 5 minutes
    • IVP 3.0 vs SI 0.0 (p = 0.001)
  • Median RASS scale at 5 minutes lower in the IVP group (- 2 vs. 0)

Secondary Outcomes:

  • Similar decreases in mean pain at 15 minutes
  • No statistically significant difference in vital signs
  • No statistically significant difference in need for rescue analgesia

Strengths

  • Study asks a clinically relevant, patient centered question
  • Providers, patient, and data collection team blinded to medication route via double dummy design
  • Dummy short infusion and IV push given simultaneously to maintain blinding
  • No difference in baseline pain

Limitations

  • Convenience Sample: Patients not enrolled consecutively (Only Monday – Friday 8a – 8p)
  • Single center study decreases external validity
  • Study is small and differences may be exaggerated (particularly in terms of the absolute difference in the primary outcome)
  • Excluded patients with increased ICP, despite previous studies demonstrating the irrelevance of ketamine in this clinical scenario
  • No data on distribution of pain presentations or if chronic vs acute pain

Author's Conclusions

"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.”

Our Conclusions

Low dose ketamine (0.1 mg/kg – 0.3 mg/kg) as a short infusion (15 minutes) for treatment of pain in the emergency department has less adverse effects without change in analgesic effect than low dose ketamine intravenous push (over 5 minutes).

Potential Impact To Current Practice

Providers should consider giving LDK for analgesia as a short infusion as opposed to IV push to minimize adverse effects and increase patient comfort.

Bottom Line

Low dose ketamine given as a short infusion over 15 minutes has lower rate of feeling of unreality and sedation than as intravenous push over 5 minutes without affecting analgesic effects.

Read More

REBEL EM: Low-Dose Ketamine for Acute Pain in the ED: IV Push vs Short Infusion

The PharmERToxGuy: How to Administer Low-Dose IV Ketamine for Pain in the ED

Comments from Experts:

I’ve been using sub dissociative doses of ketamine for a while with good results.
As Sergey noted, there better results with slow infusion vs Ivp.
Interestingly, tisch has already developed a protocol for ketamine for pain control, but mandates it be given over 10 minutes, where as Sergey’s study infused over 15.
Along the lines of non narcotic pain control, I’ve been using Iv lidocaine  (1.5 mg/kg over 20 minutes )  for renal colic with good results.
This is a very apropos discussion given the current opioid epidemic.
Ashika Jain, MD