Our article presents the results of the first randomized, double-blinded controlled trial of LDK for the treatment of pain in trauma patients with at least three rib fractures. This trial was pragmatically designed to include not just patients with isolated rib fractures, but the multiple-injured population typically seen in trauma centers. While no difference was noted in NPS or OME within the entire cohort at 12 hours, 24 hours, or 48 hours, LDK significantly reduced OME utilization in severely injured patients (ISS, >15). Interestingly, the OME reduction was not related to admission to the ICU or general trauma ward, which suggests that our findings are related to the patients' cumulative injuries and not simply an effect of where they were cared for. Unfortunately, we could not determine if a specific additional injury (i.e., long bone fracture or abdominal injury) in addition to the rib fractures contributed to this finding.
This study has several limitations. First and foremost, the use of NPS as the primary outcome presents challenges. Pain is subjective and difficult to assess, particularly in patients with multiple injuries. We tried to have “thoracic pain scores” recorded separately from the “global pain score” that a patient reported. However, separating out pain scores was inconsistent despite several study protocol information sessions and, ultimately, we had to use either the thoracic or global “pain score” as recorded by the nursing staff. Additionally, this study allowed the treating provider to use any medications within the multimodal rib fracture pain management order set. Since there was no difference in the medications prescribed within the groups, we do not think this had any impact on the study results but cannot say this definitively. Not standardizing the pain regimen is another potentially confounding variable. Intravenous opioid medications were recommended while the investigational drug was infusing, but a transition to oral narcotics was permitted to prevent increasing length of stay. Oral narcotic doses and frequency are less variable, which could decrease the effect on OME.
Finally, it should be noted that the protocol did not allow for titration of the ketamine infusion. The ketamine infusion was intentionally set at a low fixed dose of 2.5 μg·kg−1·min−1, and underdosing may have led to the lack of differences in OME and NPS between groups. In a Cochrane review analyzing ketamine for acute postoperative pain, dosing of ketamine varied from 2 μg·kg−1·min−1 to 1 mg·kg−1·min−1.22 The heterogeneity of dosing indicates that the optimal dose of adjunct ketamine has not been determined, but interpatient variability in response to ketamine has been reported.24 Ketamine appears to work on several receptors including NMDA, cholinergic, and monoaminergic receptors, any of which may affect a patient's analgesic response to ketamine.25 Future studies using higher doses of ketamine or the ability to titrate a ketamine infusion based on an individual's response to the drug may demonstrate a significant benefit.
The overall project design was performed by N.W.K., T.W.C., and J.S.P. The literature search was a joint effort of all authors included on the trial. Data collection was performed by N.W.K. and T.W.C. Sample size calculation, statistical methodology, and data analysis was performed by A.S. and Z.Y. Data interpretation was performed by all listed authors on the study. Writing of the article and critical revision of the article was performed by all the listed authors.
None of the authors have any financial and personal relationships with other people or organizations that could potentially and inappropriately influence their work and conclusions on this topic.
The authors have no conflicts of interest.
Source of Funding: This trial was funded through institutional grant funding (Research Affairs Committee grant 3307034).
Financial Disclosures: T.W.C. and N.W.K. are paid consultants for InnoVital Systems Inc. The remaining authors have no financial disclosures.
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Dr. David A. Spain (Stanford, California): Thank you, Drs. Rotondo and Reilly and the Program Committee for the privilege of discussing this outstanding work.
I hope you noticed that Dr. Kugler was up here at the ready as the prior discussion was closing. It's like having short turnover time in the OR – doesn't always happen, but it's beautiful when you get it. I had the privilege of hearing Dr. Kugler present this work at the Wisconsin State COT Chapter Meeting a few months ago, and he did an excellent job today as well.
The group from Medical College of Wisconsin are to be congratulated for doing what few of us have: conducting a prospective, randomized, blinded trial. The amount of work required to pull this off is incredible, and they are really to be commended. And I would like to thank Dr. Kugler for his excellent presentation. I have just a few quick questions for you, Dr. Kugler:
1. At our hospital, the pain scores by convention are recorded by the nurses with the patient at rest; if you're in bed, not doing a whole lot, you may not have a lot of pain. Do you have any data on the activity level of your patients in these two groups? Were patients on ketamine more likely to be up and walking around?
2. Did you look at respiratory function in these patients? We have been using inspiratory volumes with an incentive spirometer to determine if we have good pain control, and it seem to correlate. Do you have any experience with this?
3. You mentioned that this is a low to medium dose of ketamine. Will your group continue these efforts, maybe with a dose escalation protocol?
4. And then, finally, rib fractures are very challenging and may take a long time for patients to recover their projected normal activities. You have gone through all this effort to set up a mechanism to study these patients and shown you can conduct prospective randomized trials; so what's next on your research agenda for these patients?
With both the nationwide opioid crisis and the opioid shortage, non-narcotic alternatives to pain control are becoming increasingly important. The group from the Medical College of Wisconsin are to be congratulated for tackling such a difficult problem and I look forward to their continued efforts in this area. Thank you very much.
Dr. Kimberley A. Davis (New Haven, Connecticut): This was a beautifully presented study. I have a quick question for you. Have you adjusted your pain regimen or standardized your protocols, particularly in the more severely injured patients?
Dr. Eileen M. Bulger (Seattle, Washington): Just a quick question. I'm concerned about the 43 percent of your patients that declined enrollment in the study. Did you look at that group to see if they are any different than the cohort that you studied?
Dr. Doulas J. E. Schuerer (St. Louis, Missouri): Again, trying to be brief, I was curious about resource utilization. When we use ketamine, it's usually on people who can't get the other type of drips or are narcotic users, but they have to stay in the ICU while on the ketamine drip; as opposed to epidural when they can be on the floor. Does this protocol increase your use of ICUs?
Dr. Krista L. Kaups (Fresno, California): I'm curious to know why you excluded the patients over 65. Sometimes those are the most challenging patients to develop pain regimens for, so it would have made sense to include those patients.
Dr. Walter L. Biffl (San Diego, California): Very nicely done study. Quick question and comment. How did the morphine requirement translate to the post-discharge environment? Did you do follow-up?
And I think a lot of people in this room probably saw a paper published in the last year in the Annals about spin in randomized trials that are negative, and this was a negative trial – you found a difference in a sub-group of a secondary outcome – so, your conclusion in the abstract, which a lot of people will limit their reading to that, I would temper it a little bit. I don't think we've demonstrated it's a useful adjunct yet. Congratulations, again.
Dr. William S. Hoff (Bethlehem, Pennsylvania): Just to take it a step further from my colleagues’ discussions. Two of your exclusions were some of the more challenging patients that we have: the elderly and the chronic opioid abuser. Do you have any plans now that you have these results to perhaps look at those specific populations? Thank you.
Dr. Nathan Kugler (Milwaukee, Wisconsin): Thank you for the wonderful questions. So, should I address these we'll start at the top.
So, pain scores in terms of resting versus dynamic at our institution are certainly a challenge, as I think they are at most institutions. We relied heavily on the nurses in terms of reporting all pain scores.
We were unable to tease out, even in a prospective fashion, whether or not these were all up and ambulating versus sitting down.
I think that's a focus of a future study that we're looking to incorporate, in terms of are patients able to get up and move around easier with this low-dose ketamine component.
Certainly, we know that all of our patients are enrolled with early physical therapy and early ambulation is a part of all of those patients' care throughout the hospital stay, but unfortunately that data, we were unable to look at this separately.
With respect to respiratory function, Incentive Spirometry is certainly one of the things that patients are encouraged to utilize by both the nurses as well as our providers. In this study, however, we utilized vital capacity, which is an indexed measure based off of each patient.
All patients enrolled in the study had chest trauma monitoring protocol, which is a standardized protocol utilized in our institution, that is a respiratory therapist-driven protocol.
What we did find when we looked at the vital capacities between the separate cohorts is that there was no significant difference at the initial onset of vital capacity between the placebo and the ketamine group. And as we followed it through, we did not see any statistically significant difference between the vital capacities achieved while on the infusion.
With respect to the ketamine dosage that was utilized within the trial, we relied on our anesthesia colleagues, which we'll sort of talk about this in a different component, to help guide the study, as they are sort of the masters of ketamine at our institution and the gatekeepers to utilization in the hospital.
The group that we worked with had limited experience with this as an analgesic, particularly in a trauma patient population, so the dose that was fixed was based on a retrospective study that we looked at that appeared to be safe as well as predominantly effective.
Since the sort-of onset of this trial, they've become a lot more comfortable with utilization of ketamine, and thus they've started to increase their doses, even just since this trial was finished.
With respect to the future directions for this, I think that we have isolated a group within our sub-group analysis that suggest that severely injured patients may have a potential benefit to the use of low-does ketamine.
We utilized rib fractures as a proxy to severely injured patients, and it was of our interest due to the complexity of managing rib fracture patients' pain. Certainly moving forward, looking at severely injured patients as a different cohort as a whole, will be a key and a challenge to designing the future trials of this.
With respect to why a patient declined enrollment within the study, so this was difficult to assess, but for the most part, there seemed to be a large portion of patients who were unfamiliar with the drug or had concerns given the drug.
Patients were approached in the Emergency Department in an attempt to enroll them early within a 12-hour time frame to start the drug, which may have been a limiting factor, given, sort of, they just experienced a trauma, and now they're being approached about a research study.
With respect to ketamine and ICU utilization, so, when we looked at our disposition from the Emergency Department, we found there was no significant difference between ICU and floor dispositions between the placebo versus the ketamine group.
Our institution does allow the utilization of a ketamine infusion at a fixed dose on the floor, so we did not require ICU admission for all of these patients, unless they needed ICU admission for other injury-related purposes.
With respect to the question of why to exclude patients over the age of 65, at our institution, we have two separate chest trauma monitoring and thoracic management protocols based on age.
Age of 65 or greater has a different pain medication regimen as well as some different adjuncts; thus, we felt that it was important to separate these two out so that we had a consistent study group.
We did, in fact, perform the same exact trial within the cohort at 65 years or older, which that trial has now concluded at the same time as this, but that data is still being analyzed, so hopefully we'll have that to follow.
With respect to transition to post-discharge and whether or not this affected the overall requirements for patients and follow-up, we chose not to look at how much patients were discharged on due to the fact that this is somewhat provider-dependent; however, we have a subsequent, an additional trial that's going on to look at the quality of life as well as their overall outcomes.
Thank you, and I'd be happy to take any questions after.