Although ketamine infusions failed to reduce numerical pain scores or opioid use in the overall cohort, a decrease in opioid use among patients with Injury Severity Scores (Iss) greater than 15 was observed. According to researchers, further studies are necessary to expand on these results, but ketamine infusions appear to be a useful adjunct in severely injured trauma patients.

“Unfortunately, we saw no statistically significant benefit to the utilization of low-dose ketamine infusion for the management of acute pain or in opioid reductions in the overall cohort,” said Nathan Kugler, MD, a general surgery resident at the Medical College of Wisconsin, in Milwaukee. “However, it appears based on these data that utilization of adjunct infusions does have an opioid-sparing effect among severely injured patients, particularly with appropriate pain control.”

As Dr. Kugler reported, rib fractures contribute to a significant portion of the morbidity and mortality associated with polytrauma patients. Although management strategies have evolved over the years with an increasing focus on multimodal pain management strategies, including the use of regional therapies such as rib blocks and/or epidurals, opioid-based therapies have remained the cornerstone of rib fracture management.

“Concerns around opioids have fostered interest in alternative analgesics,” said Dr. Kugler, “but evidence to support the use of ketamine within the trauma population is lacking. Ketamine has been historically utilized at our institution after failure of maximal medical therapy and as a regional adjunct.”

To test the hypothesis that ketamine provides substantial acute pain management benefits within this population, Dr. Kugler and his colleagues designed a prospective, randomized, double-blind, placebo-controlled trial focused on adult patients with at least three rib fractures admitted to a Level I trauma center. The researchers excluded patients over 64 years of age, with Glasgow Coma Scale scores less than 13, and with a history of chronic opioid use.

Patients who met all inclusion and exclusion criteria were approached by an independent study staff member for enrollment and consent. After enrollment, randomization was performed in a blinded fashion by the investigational drug services department at the Medical College of Wisconsin. All patients were then treated in accordance with the acute thoracic pain management protocol, which includes a standardized pain medication regimen, with all patients offered regional therapies, including rib blocks and epidural catheters as necessary. Patients randomly assigned to the experimental arm received a ketamine infusion at a rate of 2.5 mcg/kg per minute within 12 hours of arrival, whereas the placebo cohort received an equivalent rate of normal saline. All infusions were continued for 48 hours.

The primary outcome of the study was reduction in numerical pain score in the first 24 hours after infusion initiation. Secondary outcomes included oral morphine equivalent utilization, ICU and overall length of stay, epidural placement rate, pulmonary complications and adverse events related to ketamine.

As Dr. Kugler reported at the 2018 annual meeting of the American Association for the Surgery of Trauma, 91 patients were enrolled in the study, with 45 (49%) randomly assigned to the experimental arm. With a median Iss of 14 and a median age of 49 years, experimental and placebo groups were well balanced, said Dr. Kugler, adding that motor vehicle collision was the most common (45.7%) cause of injury. According to the data, however, ketamine infusion was not associated with a significant reduction in 24-hour numerical pain score or oral morphine equivalent totals.

“Analysis of numeric pain scoring, utilizing the area under the curve model, demonstrated no significant differences between the interventional and placebo cohorts within the first 24 or 48 hours,” Dr. Kugler said. “After performing an isolated rib fracture analysis, we again found no significant difference in the numeric pain scores at the 24- or the 48-hour mark.”

Low-dose ketamine infusions also did not demonstrate opioid-sparing effects. Researchers observed no significant reduction in opioid requirements at 24 or 48 hours or throughout the entire hospitalization, and this finding was again seen within the isolated rib fracture population. As Dr. Kugler reported, no significant differences were seen in epidural placement, length of stay, respiratory events, sedation or unplanned ICU transfers.

“The side effect of hallucination is a major obstacle to ketamine’s utilization, so it’s important to note that no differences were seen between groups with respect to Confusion Assessment Method–positive events or incidence of hallucination and disturbing dreams,” Dr. Kugler noted.

A separate subgroup analysis of 45 severely injured patients (Iss>15), however, demonstrated a significant benefit with the utilization of low-dose ketamine infusion. Ketamine infusion was associated with a significant reduction in oral morphine equivalent use during the first 24 hours (35.7 vs. 68; P=0.03) and 24 to 48 hours (64.2 vs. 96; P=0.03). Moreover, this trend was preserved and continued for the duration of the patients’ hospitalization despite cessation of the infusion at 48 hours (152.1 vs. 198; P=0.048).

“Although we saw no significant decrease in the area under the curve numeric pain scoring between cohorts, we did note that similar pain control was achieved with significantly less opioid utilization,” Dr. Kugler observed.

David A. Spain, MD, a professor and the chief of acute care surgery at Stanford University Medical Center, in California, underscored the importance of studying non-narcotic alternatives to pain control given the nationwide opioid crisis and opioid shortage.

“The research group at the Medical College of Wisconsin should be congratulated for tackling such a difficult problem, and I look forward to your future efforts in this area,” Dr. Spain said. “Will your group continue with a dose-escalation protocol?”

“The group that we worked with had limited experiences with ketamine as an analgesic, particularly in a trauma patient population, so the dose was fixed based on retrospective [data] that appeared to be safe as well as predominantly effective,” Dr. Kugler responded. “Since the completion of this trial, however, they have become a lot more comfortable with utilization of ketamine and have started to increase their doses.”

“Rib fractures are very challenging and may take a long time for patients to recover in terms of returning to normal activities,” Dr. Spain said. “You’ve gone through all this effort to set up a mechanism to study these patients. … What’s next on your research agenda?”

“With respect to our subgroup analysis, I think we have isolated a group that may benefit from the use of low-dose ketamine,” Dr. Kugler said. “We utilized rib fractures as a proxy to severely injured patients, and it was in our interest due to the complexity of managing rib fracture patients’ pain. Moving forward, however, we intend to design future trials that focus on severely injured patients.”