BACKGROUND
In the wake of the opioid crisis, clinicians are pursuing alternative and combination options for pain control (Kaye et al., 2020). Nonsteroidal anti-inflammatory drugs (NSAIDs) are a nonopiate class of pain medications. However, NSAIDs have temporary antiplatelet aggregation effects resulting from inhibition of cyclooxygenase-1 (COX-1) Blaicher et al., 2004; (Catella-Lawson et al., 2001; Pedersen & FitzGerald, 1985; Schafer, 1995). The administration of these medicines in a trauma population whose injuries often lead to life-threatening hemorrhage is a matter of concern, especially with regard to solid organ injury.
Studies evaluating the bleeding risk associated with NSAIDs have shown mixed results, and few have been specific to the trauma population (Neal et al., 2014). Studies examining the risk of perioperative bleeding associated with NSAIDs have had mixed results in varying surgical procedures. Further, elucidating the risk associated with using these medications in various patient populations is of particular interest to trauma providers who are confronted with a substantial need for pain control.
KEY POINTS
* NSAIDs in trauma are controversial given that COX-1 inhibition of platelet aggregation could worsen bleeding.
* We found no increase in need for surgical intervention or angioembolization on solid organ injury in patients given NSAIDs.
* We found no increase in need for or amount of blood transfusions in patients given NSAIDs.
* NSAIDs appear to be a safe adjunct in pain control for trauma patients with solid organ injury.
OBJECTIVE
This study aimed to evaluate the impact of NSAIDs on blunt trauma patients with solid organ injury. The primary outcome of interest was the incidence of surgical interventions on or angioembolization of the affected organ. Secondary outcomes included incidence of packed red blood cell (PRBC) transfusion, changes in creatinine values, and mortality. Additionally, we evaluated the prescribing patterns of NSAIDs throughout the study period.
METHODS
This study was a retrospective cohort study of traumatically injured patients admitted from June 2015 to June 2019 at an urban, Level I adult trauma center in Columbus, OH, approved by the OhioHealth Institutional Review Board (case number 1426495). An initial TraumaBase query data report was generated based on inclusion and exclusion criteria during the study timeframe. Electronic medical records were used for further data collection of the remaining study variables.
We identified all patients 15 years and older evaluated by our Trauma Service between June 1, 2015, and June 30, 2019, with blunt hepatic, splenic, renal, pancreatic, or adrenal injury. Patients were excluded if they had penetrating injures, death within 24 hr of admission, known bleeding or clotting disorder by admission history, were using antiplatelet or anticoagulants prior to arrival, were started on an antiplatelet or anticoagulant as an inpatient (beyond standard venous thromboembolism prophylaxis doses), underwent operative removal or embolization of an affected organ before the institution of NSAIDs, were pregnant, or were prisoners. Additionally, patients were removed from the data pool if significant patient data were missing from the database (Figure 1).
The goal of this study was to evaluate any differences in clinical indicators of bleeding in patients who were given NSAIDs throughout their hospital course compared with those who were never given NSAIDs. Our primary outcome assessed the incidence of angiography with embolization of solid organs or operative intervention for repair or removal of injured solid organs. Secondary outcomes evaluated the number and timing of units of PRBC transfused, changes in creatinine throughout the hospital course indicating renal injury secondary to NSAID use, overall mortality, and prescribing patterns of NSAIDs over the study period.
Statistical Analysis
Descriptive statistics such as mean, median, standard deviation, frequency, and percentage were used to describe numerical data. Odds ratios (ORs) were used to compare groups for the need for operative intervention, angioembolization, and PRBC transfusion delivery. [chi]2 tests were used with p < .05 to compare groups with dichotomous outcomes such as the need for a procedure. A Wilcoxon signed-rank test was used to compare paired data such as ISS. An a priori power analysis was conducted, which determined that the minimum sample size to achieve 80% power was 232 patients who received NSAIDs and 580 who did not. The threshold for statistical significance was set at .05. Statistical analysis was conducted using SAS Version 7 (SAS Institute Cary, NC).
RESULTS
A total of 706 patients were included in the study. Table 1 details the demographic information of patients. The group of patients given NSAIDs had a higher average Injury Severity Score (ISS) than those in the non-NSAID group (p = .017). Of the 28 patients who died, none were given NSAIDS (OR 0.94, 95% confidence interval CI [0.92, 0.96], p < .01).
Of all patients, 206 (29%) were given NSAIDs during their hospital stay. Of the 206 NSAID patients, 131 (64%) were given ketorolac, 68 (33%) were given ibuprofen, and 7 (3%) were given other NSAIDs-celecoxib, indomethacin, and naproxen (see the Supplemental Digital Content, available at: http://links.lww.com/JTN/A68). The NSAID prescribing on the service did not increase significantly over the 6-month intervals (Figure 2).
Regarding the primary outcome, patients who were given NSAIDs were less likely to have an organ-specific operation than the non-NSAID group (OR 0.46, 95% CI [0.25, 0.85], p = .012). NSAIDs were given to 13 (6%) patients who had an operation after NSAID administration (Table 2) compared with 64 (13%) patients who needed an operation who were never given NSAIDs. Interestingly, of patients who had organ-specific operations, the group given NSAIDs had a lower average ISS compared with the non-NSAID group (p < .01) (Table 3). Patients who were given NSAIDs were less likely to undergo organ-specific angioembolization than the non-NSAID group (Table 3). Of those with embolizations, there was no difference in ISS between NSAID-given and non-NSAID-given groups (Table 3).
There was no significant difference in the number of patients given PRBC (95% CI [0.91, 1.99], p = .13) (Table 3). However, of those patients given PRBCs, the NSAID group required fewer total units of PRBC (p = .052) (Table 3). We utilized a delta creatinine (difference between the highest and lowest measured creatinine levels during admission) as a surrogate for renal injury using NSAIDs (a greater delta indicating possible renal injury). There was no difference between groups in the average delta creatinine (p = .72) (Table 3).
DISCUSSION
Our study showed blunt trauma patients with solid organ injury who were given NSAIDS were less likely to need an operation, less likely to need an embolization, had a similar risk for PRBC transfusions, had no difference in serum creatinine values, and had lower mortality rates compared with those never given NSAIDs. Our findings indicate that prescribing NSAIDs as an adjunct to opiates to patients with solid organ injuries has no adverse effect on outcomes. Although this affirms the finding of many studies, this is in direct contrast to numerous others.
Abou Zeid et al. (2019) showed no significant increase in postoperative complications, with better analgesia and shorter postanesthesia care unit length of stay after bariatric surgery when patients were given NSAIDs, and Kelley et al. (2016) showed no increase in bleeding risk in patients who used ibuprofen after plastic surgery soft tissue procedures. However, other research has shown an increased risk of postoperative hemorrhage in patients given ketorolac during laparoscopic gastric bypass, a threefold increase in requirement for surgical hematoma evacuation in patients given ketorolac in reduction mammoplasty, and increased perioperative blood loss and transfusion requirement in patients given NSAIDs during total hip arthroplasties (Cawthorn et al., 2012; Klein et al., 2012; Robinson et al., 1993).
Our study is the only one we are aware of to evaluate the risk of NSAIDs in blunt trauma patients. In our study, those patients receiving NSAIDs had a higher average ISS but had a decreased likelihood of receiving an organ-specific operation, which indicates that, despite a higher degree of injury, NSAID use did not worsen bleeding that would lead to surgery or angioembolization.
We found that NSAIDs were not associated with a difference between the need for having a PRBC transfusion and the total number of units given when the transfusion was necessary. This finding stands in contrast to studies that have shown an increased perioperative blood loss need for transfusions after reconstructive and orthopedic surgery when given NSAIDs (Cawthorn et al., 2012; Robinson et al., 1993). Although it is possible that our providers withheld NSAID administration from patients receiving blood products, within real-world practice this study represents, the use of NSAIDs did not increase the need for transfusion. Concern for renal injury with NSAIDs can often limit their prescription. Our data showed no significant difference in a change in creatinine values between groups, showing that in our population NSAID use did not lead to changes in renal function.
We believe the main strength of our study is its uniqueness in evaluating the use of NSAIDs, specifically in blunt trauma. Previously, we have had to infer the effects of NSAID use on trauma patients from other surgical literature. We have also used a pragmatic primary outcome in the form of organ-specific interventions. Although mortality improved overall in the group given NSAIDs, this is a complex outcome with many influencing factors, and we do not interpret this finding to mean that NSAIDs are a lifesaving intervention. Although it is tempting to ascribe this difference to selection bias (with those patients more likely to do well receiving NSAIDs), the statistically significant difference in ISS between groups indicates that this is not necessarily the case.
Limitations
The limitations of this study are largely due to its retrospective nature and the inability to account for all other confounding factors. The sample size was relatively small, with only 206 patients receiving NSAIDs, and we did not reach the 232 patients required to achieve our targeted power. Many patients had multiple injuries contributing to their clinical state, and we were not able to look specifically at organ injury severity using the Abbreviated Injury Scale, nor were we able to adjust our results to control for variations in this indicator. We did exclude those patients undergoing an organ-specific procedure prior to receiving NSAIDs. We utilized a pragmatic set of exclusion criteria, and it is more likely in a real-world setting that a patient in extremis would not receive NSAIDs and would undergo any necessary procedures first. However, this prevents some analysis of the effect of NSAIDs on more significantly injured patients. Additionally, we did not gather and report the specific doses of NSAIDs or their administration duration. The cumulative effects of NSAID administration could be relevant and informative in future studies.
Future studies are needed to evaluate further the variables associated with bleeding risk. We believe prospectively evaluating this risk with a larger sample size would better advise clinicians. To our knowledge, our efforts to evaluate the bleeding risk associated with NSAID use in solid organ injury trauma patients are novel. As the need for additional pain control options continues to rise, the further research should continue.
CONCLUSION
In this retrospective cohort study of 706 blunt abdominal solid organ injuries, of whom 206 received NSAIDs, we found that patients who were given NSAIDS were less likely to need an operation, were less likely to need an embolization, had a similar risk for PRBC transfusions, yet had no difference in serum creatinine values, and had lower mortality rates compared with those never given NSAIDs. We conclude that NSAIDs appear to be a safe addition to a pain control regimen with no significant effect on solid organ injury.
Acknowledgments
We would like to acknowledge Josh Burton, RN, MSN, for assisting in study planning; statistician Mike Lieber, MS, for statistical planning and analysis, Jim Tsai for data organization and cleaning, and Monica Rozzell along with the trauma registry staff for initial data pulls.
REFERENCES