Nebulised Ketamine

Background

Pain relief is a top priority for patients and clinicians, and yet we know that we are not always as effective as we should be in relieving it. This week, we will look at a paper on the use of nebulized ketamine as opposed to intravenous sub-dissociative dose ketamine for treating acute painful conditions in the emergency department. The paper is in Academic Emergency Medicine by Nguyen et al. 1. Traditionally, we generally use opioids for significant pain relief. Still, these have side effects and the potential for addiction if used long-term (not an issue in acute pain management usually). As readers of the blog will know, Ketamine, an NMDA receptor antagonist, can be used as an alternative medication or as an adjunct to other analgesic drugs (including opiates) in the ED. We have looked at intramuscular, intravenous, and oral administration routes in the past, but what about nebulised ketamine? Would that work, and would it work well. This week, we have a paper looking at exactly that. The abstract is below, but please read the full paper yourself.

The Abstract¹ – Nebulised Ketamine for moderate to severe pain

Study objective: We aimed to assess and compare the analgesic efficacy and adverse effects of intravenous subdissociative dose ketamine to nebulized ketamine in emergency department (ED) patients with acute painful conditions.
Methods: We conducted a prospective, randomized, double-blind, double-dummy clinical trial in adult patients (ages 18 and older) with a numerical rating scale pain score of >5. We randomized subjects to receive either a single dose of 0.3 mg/kg of intravenous (IV) ketamine or 0.75 mg/kg of nebulized ketamine through a breath-actuated nebulizer. Primary outcome was the difference in pain scores on the numerical rating scale between groups at 30 minutes postmedication administration. The secondary outcomes included the need for rescue analgesia, occurrences of adverse events in each group, and the difference in pain scores at 15, 30, 60, 90, and 120 minutes. We calculated a 95% confidence interval (CI) for a mean difference at 30 minutes, with a minimum clinically important difference set at 1.3 points.
Results: We enrolled 150 subjects (75 per group). Mean pain scores through numerical rating scale were 8.2 for both groups at baseline, which decreased to 3.6 and 3.8 at 30 minutes, yielding a mean difference of 0.23 (95% CI -1.32 to 0.857). We observed no clinically concerning changes in vital signs. No serious adverse events occurred in any of the groups throughout the study period.
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.
Nguyen, A., et al. (2024). Comparison of Nebulized Ketamine to Intravenous Subdissociative Dose Ketamine for Treating Acute Painful Conditions in the Emergency Department. Annals of Emergency Medicine.

What kind of paper is this?

This paper is a double-blind, randomized, clinical trial. This type of study is considered the gold standard in clinical research because it minimises bias and allows for a direct comparison between interventions. It’s an. appropriate design for this question.

Tell me about the patients

The trial involved 150 adult patients who presented to the ED with acute pain. To qualify for the study, patients needed to have a numerical rating scale (NRS) pain score of 5 or higher (on an 11-point scale), indicating moderate to severe pain. The patient cohort was reasonably diverse, reflecting a wide range of demographics and underlying conditions. Importantly, the inclusion criteria were designed to capture individuals experiencing significant pain that necessitated intervention, thereby ensuring the relevance of the findings to real-world clinical settings. There were quite a lot of exclusions including those requiring immediate management or cardiovascular instability.

Tell me about the interventions

The study compared two interventions: intravenous sub-dissociative dose ketamine (IV-SDK) and nebulized ketamine via a breath-actuated nebuliser (K-BAN). Participants were randomized into two groups. One group received 0.3 mg/kg of IV ketamine and a placebo nebuliser, while the other group received 0.75 mg/kg of nebulised ketamine and a placebo IV saline solution. The dosages were selected based on prior studies indicating their effectiveness and safety at sub-dissociative levels .

I’ve not encountered a breath-actuated nebuliser before, but in essence, it only delivers the drug as the patient breathes in, which is probably a good idea, as we don’t really want ketamine being nebulised into the main room atmosphere.

What are the main findings?

The primary outcome measured was the change in pain scores at 30 minutes post-administration. Both intravenous and nebulized ketamine significantly reduced pain scores from a baseline of 8.2. The intravenous group’s scores dropped to 3.6, while the nebulized group’s scores decreased to 3.8. The mean difference of 0.23 points between the two groups was not statistically significant, indicating that both methods are equally effective in reducing acute pain within the initial 30 minutes. The confidence intervals were fairly close (95% CI 1.32 to 0.857)

Secondary outcomes included the need for rescue analgesia, adverse events, and pain score differences at multiple time points (15, 30, 60, 90, and 120 minutes). No serious adverse events were reported in either group, and vital signs remained stable throughout the study period.

It’s worth noting that a large number of patients (21 in the nebuliser group, 10 in the IV group) required rescue analgesia, but only 12 of those had the rescue analgesia (morphine/ketoralac/tramadol/paracetamol) according to the protocol. To look at this the authors looked at just those patients who did not have rescue analgesia and still found no difference. However, the fact that over twice as many patients in the nebuliser group needed rescue analgesia is clinically important. I can’t see this analysed in the paper but I’ve calculated a Chi squared test on these propotions that comes out with a p-value of 0.027 which is also statistically significant.

The authors looked at side effects and found more side effects of elements such as dizziness, restlessness, and unreality in the intravenous group.

Is the design robust?

While the study’s design is robust, several critical appraisal points need consideration. Firstly, the sample size is relatively small, and a larger sample could enhance the power of the study or even be redeveloped into a non-inferiority design. It’s worth noting the difference in rescue analgesia between the two groups. Secondly, the study was conducted at a single medical center, which may limit the generalisability of the results to other settings with different patient populations or resources. Furthermore, the reliance on patient-reported pain scores, while a standard practice, introduces subjective bias that could affect the outcomes. Future studies might benefit from incorporating objective measures of analgesia, such as physiological markers of pain.

Another concern is the follow-up duration. While the study effectively measures pain relief up to 120 minutes, it does not address the long-term outcomes or potential delayed adverse effects of ketamine use. Extended follow-up periods could provide more comprehensive data on the safety and efficacy of these interventions over time. We do know that ketamine may produce other effects in patients, such as significant dreams over days to weeks and it would be interesting to see these reported.

Does this change our practice?

The study suggests that both IV and nebulized ketamine are viable options for managing acute pain in the ED. When would we use this option though? I do see some patients in whom it is really challenging to get IV access, which is my preferred route for analgesia, but with ultrasound guidance, it is usually possible in a timely manner. However, in some patients I can see it as a potential option, although it would need us to purchase different nebuliser devices (not an option at the moment).

I’m also a little unsure about the rescue analgesia question, with more in the nebuliser group and also protocol violations.

Lastly, I think that the lack of usual care with alternative agents such as opiates is a weakness in this trial in terms of changing practice. The inclusion criteria were that the attending physician believed that the patient may benefit from ketamine analgesia. I’m a little unclear whether that practice is the same as my own where ketamine is probably not used at this stage of a patient’s care (as other analgesics may not have been tried). This is commonly an issues with single centre trials where inclusion criteria are based on clinician opinion. It injects subjectivity into the selection and makes it more difficult to understand whether the practice at this centre is similar to my own.

Conclusion

This study suggests that both intravenous and nebulized ketamine may be effective for treating acute pain in the ED. This is potentially a useful addition to our analgesic options, although I am unsure in how many patients this would be an option for in my practice. I’d like to see the results reproduced and in a bigger study before I am certain of this.

References

1.
Nguyen T, Mai M, Choudhary A, 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 Emergency Medicine. Published online May 2024. doi:10.1016/j.annemergmed.2024.03.024