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Date: October 7, 2024

Reference: Nguyen 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. Annals of EM 2024.

Guest Skeptic: Dr. Brendan Freeman is an emergency medicine physician, assistant professor of emergency medicine, and medical education fellow at Staten Island University Hospital. He completed his residency training at New York Presbyterian Brooklyn Methodist after graduating from medical school at Touro University College of Osteopathic Medicine in California.

Case: You’re working your usual day shift in the emergency department (ED) from 9 am to 5 pm on a Tuesday. The next patient you pick up is a 38-year-old male with a history of kidney stones, presenting with severe flank pain radiating to the groin. He has a history of difficult intravenous (IV) access, is hemodynamically stable, and has no signs of infection. His allergies to acetaminophen, non-steroidal anti-inflammatories (NSAIDs), and opioids limit your pain management options. A bedside sonogram shows no significant hydronephrosis. You’re considering ketamine for pain relief but wonder if you should choose IV sub-dissociative ketamine or nebulized ketamine?

Background: Ketamine has long been recognized as a versatile drug in emergency medicine, particularly for its role in analgesia and procedural sedation. Initially developed as an anesthetic in the 1960s, ketamine’s unique pharmacological profile makes it particularly suitable for acute care settings. It is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, which induces dissociative anesthesia, meaning patients experience analgesia and amnesia without the loss of consciousness typically associated with other anesthetics​​.

In recent years, ketamine has gained popularity in the ED, particularly for treating acute pain. It is used at lower doses than those required for anesthesia (0.1–0.3 mg/kg IV) and is called “low-dose” or sub-dissociative ketamine (SDK). These lower doses of ketamine effectively manage pain without producing full dissociation, reducing the likelihood of severe adverse effects​​. This ability to provide analgesia with minimal respiratory depression and hypotension makes ketamine an attractive alternative to opioids, particularly in patients for whom opioid use is problematic​​.

Ketamine’s administration is flexible, with several routes available including IV, intranasal (IN), and more recently, nebulized forms. Each method has its advantages, and ongoing research continues to refine the efficacy and safety of these delivery methods in acute pain management in the ED​​.

Prior research by this same group has shown ketamine breath-actuated nebulizer (K-BAN) has effective analgesic properties at three different doses 0.75 mg/kg, 1 mg/kg, and 1.5 mg/kg up to 120 minutes. However, no one has compared K-BAN analgesic efficacy to IV-SDK though.

Clinical Question: Which ketamine regimen is superior for treating moderate to severe acute pain in the emergency department, 0.75 mg/kg nebulized or 0.3 mg/kg intravenously?

Reference: Nguyen 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. Annals of EM 2024.

  • Population: Adults aged 18 and older presenting to the ED with acute pain numerical rating scale (NRS) pain score of ≥5​
    • Exclusions: Patients with altered mental status, respiratory distress, hypotension, or known allergy to ketamine​.
  • Intervention: Nebulized ketamine at 0.75 mg/kg via breath-actuated nebulizer (K-BAN) plus IV saline infusion
  • Comparison: IV sub-dissociative dose ketamine (IV-SDK) at 0.3 mg/kg plus nebulized saline
  • Outcome:
    • Primary Outcome: Reduction in pain scores on the NRS at 30 minutes post-administration​
    • Secondary Outcomes: The need for rescue analgesia, adverse events, and pain reduction at additional time points (15, 60, 90, and 120 minutes)
  • Type of Study: Prospective, randomized, double-masked, double-dummy controlled trial

Authors’ Conclusions: “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”​.

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors). Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. No
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes
  12. Financial conflicts of interest. “The study received grant support from the New York State Empire Clinical Research Investigator Program (ECRIP) and the Maimonides Research and Development Foundation. The authors report no independent disclosures or conflicts of interest.”

Results: They recruited 150 ED patients into the study (75 in each group) with 147 patients available at 30 minutes and 127 patients at 120 minutes for data analyses. The mean age was 46 years, close to equal male-female split, with most patients presenting with abdominal pain (46%), flank pain (22%) and non-traumatic musculoskeletal pain (16%). The mean pain score was 8.2 on the numerical rating scale from 0 to 10.

Key Result: Both ketamine routes of administration decreased pain but there was no significant difference between the two at 30 minutes in reducing pain scores​.

  • Primary Outcome: Pain reduction at 30 min was from 8.2 to 3.8 in the K-BAN group and from 8.2 to 3.6 in the IV-SDK group
    • The difference in pain scores between the two ketamine groups at 30 minutes was minimal (0.23 points), with a 95% CI ranging from -1.32 to 0.857, indicating no statistically significant difference.
  • Secondary Outcomes: The need for rescue analgesia was higher in the nebulized ketamine group. There were no statistical differences in adverse events between the groups

1. Study Size: The authors performed a power calculation to determine the necessary sample size. They assumed a clinically significant improvement in pain score of 1.3 points in the IV ketamine group compared to the nebulized ketamine group, with a standard deviation of 3.0 points in both groups. To achieve 80% power and maintain an alpha of 0.0465 for a one-sided z-test, they calculated that they would need to enroll 67 subjects per group (total = 134 participants). To account for possible attrition, such as subjects withdrawing early or being discharged before study completion, they increased the sample size to 150 participants (75 per group)​​. There were 147 patients to analyze for the primary outcome of pain reduction at 30 minutes. As in most superiority trials powered for efficacy, the sample size may not have been large enough to detect smaller or less frequent differences in secondary outcomes, such as adverse events or the need for rescue analgesia. Studies with small sample sizes are more prone to type II errors—failing to detect a difference when one exists​​. Larger studies would be required to establish safety and capture rare adverse events​​.

2. Double-Dummy Masking: A double-dummy methodology was used in this trial to try to ensure masking for both patient and clinician despite the different routes of administration (intravenous and nebulized). This technique is often used in trials where two interventions cannot be made to look identical, as is the case when comparing nebulized ketamine to intravenous ketamine. However, clinicians weren’t blinded to nystagmus. Nystagmus is a distinct reaction commonly associated with ketamine administration. This reaction, particularly noticeable after IV administration, could have had the potential to unmask the clinicians during the study. The patients may also have been aware of this phenomenon. One way to measure the effect of masking would have been to ask the patients and clinicians which group they thought they had been allocated.

3. Single Centre: This trial was conducted at a single medical center, which raises concerns about external validity, meaning that the results may not apply to other EDs with different patient demographics, staffing levels, or clinical practices​​. Single-center studies often reflect the practice patterns, resources, and patient characteristics specific to that location. There is evidence in the critical care literature that single-center RCTs typically do not replicate when a multi-center RCT is conducted [1].  A multi-center trial could help confirm if these findings hold across different settings, including rural, urban, or academic hospitals​​.

4. Measurement Bias: The primary outcome in this trial was pain. The Numerical Rating Scale (NRS)​ is a validated tool for assessing pain. However, patient-reported subjective outcomes can introduce measurement bias because individual pain tolerance and perception vary widely among patients​​. Factors like emotional state, previous pain experiences, and expectations of the treatment might have influenced the patients’ self-reported pain scores. Although they did try to mask group allocation, reducing the likelihood of observer bias, the inherent variability of subjective pain assessment remains a potential limitation​​. It would have also been interesting to have a true placebo group. While this would likely be unethical, it would have quantified the placebo effect in this trial.

5. Patient Preference: It would be interesting to know if patients had a preference for ketamine administration. Would they prefer the K-BAN over the IV-SDK? More subjects in the IV-SDK group experienced sedation, restlessness, dizziness, and feelings of unreality up to 30 minutes post-medication administration. If this trial is tested in a multi-centred trial, they could use sunglasses to mask nystagmus, ask patients and clinicians to guess group allocation, gather more information about the patient’s emotional state, previous pain experiences and expectations, and see if they had a preference for ketamine administration.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusion.

SGEM Bottom Line: K-Ban and IV-SDK probably have similar analgesic efficacy at 30 minutes, but need more prospective, multi-center data to confirm and information about patient preference.

Case Resolution: You decide to go with the K-BAN and after 30 minutes, your patient is pain-free and ready for discharge home.

Clinical Application: It is a reasonable option to try K-BAN on a patient for pain relief if you have the resources.

What Do I Tell the Patient? I can see you are in severe pain. Ketamine is a safe and effective analgesic that can help reduce your pain. We can give it to you by an IV or nebulized to breathe in using a mask. Which treatment would you prefer?

Keener Kontest: Last week’s winner was Scott Luce. He knew the real story behind naming the AI in the movie 2001 Space Odyssey. It is not IBM minus one letter to make HAL but rather Heuristic ALgorithmic.

Previous SGEM Episodes Discussing Ketamine:

  • SGEM#93: Ketamine, A Bad Reputation?
  • SGEM#111: Comfortably Numb – Low dose Ketamine as Adjunct for ED Pain Control
  • SGEM#114: Ketofol – Does It Take Two to Make a Procedure Go Right?
  • SGEM#130: Low Dose Ketamine for Acute Pain Control in the Emergency Department
  • SGEM#198: Better Slow Down – Push vs. Short Infusion of Low Dose Ketamine for Pain in the Emergency Department
  • SGEM#233: Larry in the Den with Kiwis (LDK) – Low Dose Ketamine vs. Opioids for Acute Pain
  • SGEM#356: Drugs are Gonna Knock You Out – Etomidate vs. Ketamine for Emergency Endotracheal Intubation

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

Reference:

  1. Kotani Y, Turi S, Ortalda A, Baiardo Redaelli M, Marchetti C, Landoni G, Bellomo R. Positive single-center randomized trials and subsequent multicenter randomized trials in critically ill patients: a systematic review. Crit Care. 2023 Nov 28;27(1):465. doi: 10.1186/s13054-023-04755-5. PMID: 38017475; PMCID: PMC10685543.