Paper: Nguyen T et al. Comparison of Nebulized Ketamine to Intravenous Subdissociative Dose Ketamine for Treating Acute Painful Conditions in the Emergency Department: A Prospective, Randomized, Double-Blind, Double-Dummy Controlled Trial. Ann Emerg Med 2024. [AHEAD OF PRINT]
Clinical Question: Which ketamine regimen is superior for treating moderate to severe acute pain: 0.75mg/kg nebulized or 0.3mg/kg IV?
What They Did:
- Single-center, prospective, randomized, double-blind, double-dummy, superiority clinical trial
- Adult patients (≥18 years of age) with a numerical rating scale pain score of ≥5
- Patients randomized to:
- IV Ketamine: 0.3mg/kg + Placebo nebulizer
- Nebulized Ketamine (K-BAN): 0.75mg/kg + Placebo IV solution
- Clinically important difference set for 1.3 points for the primary outcome
- K-BAN Preparation
- 50mg/mL concentration at a dose of 0.75mg/kg
- Standardized volume at 5mL by adding NS solution to nebulizer
- Run for 5 to 15min
- IV Ketamine Preparation
- 10mg/mL concentration at 0.3mg/kg in a 100mL NS bag
- Run for 15min
- Placebo Preparation
- 100mL NS solution bag
- Breath-actuated nebulizer with normal saline solution
- Rescue Analgesia
- 0.1mg/kg IV morphine
Outcomes:
- Primary: Difference in pain scores on the numerical rating scale between groups at 30 minutes post medication
- Secondary:
- Need for rescue analgesia
- Occurrences of adverse events
- Difference in pain scores at 15, 30, 60, 90, and 120min
Inclusion:
- Adults (≥18 years of age)
- Presenting to the ED
- Acute painful condition (Including: abdominal pain, flank pain, back pain, musculoskeletal pain, and headache)
- Initial pain score of ≥5 (On a standard 11 point – 0 to 10 numeric rating scale)
- Patients had to be awake, alert, and oriented to person , place, and time
- Give informed consent
- Ability to verbalize nature of any adverse effects
Exclusion:
- Painful conditions requiring immediate intervention by treating physician
- Altered mental status
- Unstable vital signs
- SBP <90 or >180mmHg
- Pulse <50 or >150BPM
- RR <10 or > 30BPM
- Acute intoxication
- Allergy to ketamine
- Actual body weight >150kg
- Unable to provide consent
- PMH of EtOH or drug abuse
- Pregnant or breast feeding women
Results:
- 150 patients enrolled (75 per group)
- Mean pain scores using numerical rating scale was 8.2 for both groups at baseline
- Mean age ≈46
- Almost 50/50 split men & women
- Most common complaints
- Abdominal pain ≈46%
- Musculoskeletal pain ≈ 26%
- Flank pain ≈22%
- Pain scores on NRS at 30min
- IV Ketamine: 3.6
- Nebulized Ketamine: 3.8
- Mean difference 0.23; 95% CI -1.32 to 0.857
- There was no change in mean pain reduction at 60 and 120 minutes
- Rescue Analgesia:
- IV Ketamine: 10 patients
- Nebulized Ketamine: 21 patients
- Slightly more sedation, restlessness, dizziness , and feelings of unreality up to 30minutes in the IV ketamine group compared to the nebulized ketamine group
- No clinically concerning changes in vital signs
- No serious adverse events occurred in any of the groups throughout the study period
Strengths:
- 1st RCT comparing IV to nebulized ketamine for analgesia in the ED
- The primary outcome is patient oriented
- Physicians, nurses, study investigators, and patients were blinded to the treatment
- Baseline characteristics related to age, sex, vital signs, and initial pain scores were similar between groups
- Groups were relatively similar with respect to chief complaints and final diagnoses (One exception: IV ketamine group had slightly more subjects with nontraumatic musculoskeletal pain)
- Asks a clinically important question that could spare patients from the need of getting an IV or IM medication
Limitations:
- Convenience sample which can cause a selection bias (Only enrolled patients Monday through Friday between 8am and 8pm when ED pharmacist was available)
- Small sample size and short duration of study are inadequate to assess the full extent of safety and analgesic effect of the two regimens beyond 120min
- No standardized inhalation time (Range 5 to 15min) which could have led to variability in onset of analgesia among subjects receiving nebulized ketamine
- Unblinding may have occurred because of quicker onset of nystagmus in the IV ketamine group
- 1 of 3 patients who were eligible for enrollment refused
- Selection bias: Treating physician had to determine if ketamine was the right agent for the patient before entry to the trial
- Large number of rescue analgesics were given outside study protocol, which could dilute treatment effect (Although this was not seen with additional sensitivity analysis excluding these patients)
- There was a large difference in the administration of rescue analgesia noted between groups with IV ketamine groups receiving less rescue analgesia compared with the nebulized ketamine group. This could be explained by the fact that standardized inhalation time could vary both the onset/duration of analgesia and the full dose of ketamine not being given with the nebulizer (Authors did not measure the residual amount of ketamine remaining the int breath-actuated nebulizer)
Discussion:
- Both routes of administration led to significant and clinically important reduction in pain throughout the study
- IV ketamine was not superior to nebulized ketamine for short-term pain relief in the ED with both routes resulting in similar changes in pain scores at 30min up to 120min post medication
- Both routes decreased pain score by nearly 4.5 points in each group from baseline to 30 min and mean change in pain score of nearly 5 points from baseline to 120 min
- Out of 31 patients receiving rescue analgesia, 12 patients received an opioid rescue with only 4 of these being in the IV ketamine group
- Nebulized ketamine required more rescue analgesia than IV ketamine (I have not used this in my practice, but one thing to keep in mind is patients may require rescue analgesia with this route)
- IV ketamine resulted in more feelings of unreality than nebulized ketamine (Anecdotally, one strategy to reduce might be to slow the infusion down from 15minutes to 30minutes)
Author Conclusion: “We found no difference between the administration of IV and nebulized ketamine for the short-term treatment of moderate to severe acute pain in the ED, with both treatments providing a clinically meaningful reduction in pain scores at 30 minutes.”
Clinical Take Home Point: Although the trial has some limitations, it appears both subdissociative IV and nebulized ketamine work similarly to reduce short-term pain in the ED. Both are a nice opioid sparing option in the armamentarium of treating acute pain.
References:
- Nguyen T et al. Comparison of Nebulized Ketamine to Intravenous Subdissociative Dose Ketamine for Treating Acute Painful Conditions in the Emergency Department: A Prospective, Randomized, Double-Blind, Double-Dummy Controlled Trial. Ann Emerg Med 2024. [AHEAD OF PRINT]
For More Thoughts On This Topic Checkout:
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter/X: @EMSwami)
