Is Ketorolac Safe to Use in Plastic Surgery? A Critical Review

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1 Research Is Ketorolac Safe to Use in Plastic Surgery? A Critical Review Aesthetic Surgery Journal 2015, Vol 35(4) The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com DOI: /asj/sjv005 Diana M. Stephens, MD; Bryson G. Richards, MD; William F. Schleicher, MD; James E. Zins, MD, FACS; and Howard N. Langstein, MD, FACS Abstract Background: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that provides postoperative pain control and reduces narcotic requirements. However, concerns regarding postoperative hematoma have limited its use in plastic surgery. Objectives: Our goal is to critically review the risk of bleeding with ketorolac in plastic surgery patients, with a focus on aesthetic surgery. Methods: A PubMed/Medline literature search of clinical trials using the keywords surgery and NSAID yielded 2574 results. Of these results, 1036 included ketorolac and twelve involved plastic surgery patients. Six studies reported postoperative hematoma rates: three prospective randomized trials, two retrospective reviews, and one case series. These were subjected to statistical analysis to determine if an association existed between ketorolac and postoperative hematomas. Results: Six papers reported 981 cases. Ketorolac use resulted in similar hematoma rates when compared to control groups, 2.5% (12 of 483) versus 2.4% (12 of 498), respectively (P =.79). There were no reported hematomas associated with ketorolac in over 115 patients undergoing aesthetic facial procedures. rates of those undergoing aesthetic breast surgery, including reduction and augmentation mammoplasties, were 4.3% (11 of 257) in the ketorolac group versus 2.2% (6 of 277) in controls (P =.59). Reduction in postoperative narcotic use and improved pain scores was also reported. Conclusions: Our literature review did not find a significant association between hematoma formation and ketorolac use in a variety of plastic surgery procedures. These findings are similar to those in other surgical subspecialties. Level of Evidence: 3 Accepted for publication January 5, 2015; online publish-ahead-of-print March 30, Plastic surgeons have become increasingly aware that postoperative pain control is a critical part of the patient experience. Recently a wide variety of pharmaceutical agents, longer acting local anesthetics, and pain pumps have entered the scene. The resulting concept of multimodal therapy has gained credibility as a means of maximizing postoperative pain control. Ketorolac tromethamine (Toradol, F. Hoffman - La Roche Ltd, Nutley, NJ, USA), a powerful short-term analgesic, is one of the agents specifically aimed at reducing the need for postoperative narcotics. 1,2 Ketorolac nonspecifically blocks the cyclooxygenase enzyme, inhibiting the synthesis of prostaglandins, prostacyclins, and thromboxane A2, 3 while having no effect on Risk the coagulation profile (protime, partial thromboplastin time, and bleeding time) in a randomized, double-blind study. 4 In spite of ketorolac s documented efficacy, plastic surgeons have been hesitant to adopt it for use as a standard Dr Stephens is a Resident and Dr Langstein is the Chairman, Division of Plastic Surgery, University of Rochester Medical Center, Rochester, New York. Drs Richards and Schleicher are Aesthetic Fellows, and Dr Zins is the Chairman, Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio. Corresponding Author: Dr Diana M. Stephens, University of Rochester, Division of Plastic Surgery, 601 Elmwood Avenue, Box 661, Rochester, NY 14642, USA. diana_stephens@urmc.rochester.edu

2 Stephens et al 463 postoperative method of pain control because of the possibility for postoperative bleeding. However, other surgical fields including otolaryngology, 5 orthopedic surgery, 6 urology, 7 cardiac, 8 neurosurgery, 9 and general surgery 10 have evaluated the use of ketorolac and found it to be safe and effective without an undue increase in postoperative hematoma. In this report, we critically review the use of ketorolac in plastic surgery in an attempt to answer the question, Is it safe? METHODS A thorough review in PubMed/Medline databases was performed in February 2013 using the keywords surgery and NSAID. From this search, 2574 results were found. These results were then refined to include only those articles mentioning Toradol or ketorolac, yielding 1036 results. The abstracts were reviewed, resulting in 12 papers related to the use of ketorolac in plastic surgery. The authors excluded studies that failed to mention rate of bleeding or complications. Of these, only six papers reported complication rates, which included hematomas. The primary outcome studied in our report was bleeding or hematoma formation after ketorolac use in plastic surgery procedures. In addition, we recorded the level of evidence, study type, type of surgeries performed, timing of ketorolac use, route of administration, dose, hematoma rates, and country of study for each of the studies included in our review (Table 1). Statistical analysis compared aggregated hematoma rates among groups using a paired t-test to determine any significant association between ketorolac use and postoperative bleeding. Table 1. Literature Summary: Toradol Use in Plastic Surgery Study Level of Evidence Study Type Torgerson 2 Prospective et al. 16 randomized Marin-Bertolin 2 Prospective, et al. 15 double-blind, randomized McCarthy et al Prospective, double-blind, randomized Type of Surgery Facial aesthetic surgery Various Plastic Surgery Procedures Breast augmentation Dowback Commentary Breast augmentation Cawthorn et al Retrospective chart review Sharma et al Retrospective chart review Breast reduction TRAM Flap Breast Reconstruction Timing of use RESULTS The six papers that met inclusion criteria after our query contained data from 981 cases (Table 1). When all 981 cases from the six papers selected for review were combined, ketorolac use resulted in similar hematoma rates when compared to control groups, 2.5% (12 of 483) versus 2.4% (12 of 498) respectively (P =.79, Table 2). In addition, when specific operations from all six papers were combined and analyzed, no statistically significant increase in bleeding was noted in the ketorolac group (Table 3). Specifically, there were no reported hematomas associated with ketorolac in over 115 patients undergoing aesthetic facial procedures requiring significant undermining (facelift, brow lift). The hematoma rate for those undergoing aesthetic breast surgery, including reduction and augmentation mammoplasties, was 4.3% (11 of 257) in the ketorolac group versus 2.2% (6 of 277) in controls, (P =.59, Table 2). When the six papers were analyzed individually, all found a significant reduction in both postoperative pain and narcotic use. Five of the six studies showed no increased risk of bleeding with the use of ketorolac for postoperative pain management. However, one of the six studies analyzing the incidence of bleeding in breast reduction demonstrated a significant association between ketorolac use and hematoma rate, this being the only outlier. DISCUSSION Ketorolac tromethamine is frequently used as a powerful postoperative short-term analgesic agent by a variety of surgical specialties. It is particularly useful in decreasing Route Dose Definition of Rate With Toradol Intraop SQ Local or IM 30 mg N/A SQ: 0/95 IM: 0/ 25 Postop IM 30 mg 1 hematoma in study drained percutaneous in the office Intraop Intraop, near completion Intraop and postop Implant pocket irrigation 30 mg N/A 0/25 (Bupivicaine and Ketorolac implant pocket irrigation) Rate in Control Group (No Toradol) Advocate Toradol Use Country 0/25 (local alone) Yes Canada 1/46 0/46 (Metamizol) Yes Spain 0/25 (no irrigation) Yes USA IM 30 mg N/A 0/105 N/A Yes USA IV 30 mg Return to OR for evacuation 11/127 (8.7%) 6/252 (2.4%) (Narcotic alone) 3 requiring transfusions Postop IV Did not specify Not defined 1/65 4/150 Yes USA No Canada

3 464 Aesthetic Surgery Journal 35(4) Table 2. Cases From All Six Papers Combined Ketorolac No Ketorolac P Value formation all cases 12/483 (2.5%) 12/498 (2.4%).79 formation aesthetic breast surgery 11/257 (4.3%) 6/277 (2.2%).59 Table 3. Rate By Plastic Surgery Procedure Type of Surgery Rate with Study Group (Ketorolac Use) Rate in Control Group Breast reduction 11/127 6/252 (P =.17) Breast reconstruction 1/67 4/154 (P =.58) Breast augmentation 0/130 0/25 (P - N/A) Facial surgery (facelift or forehead lift with or without other surgeries) 0/115 2/25 (P - N/A) Cutaneous oncology 0/12 0/14 (P - N/A) Aesthetic surgery 1/12 0/12 (P - N/A) Head and neck 0/6 0/8 (P - N/A) Congenital anomalies 0/4 0/2 (P - N/A) Tissue expansion 0/4 0/2 (P - N/A) Hand 0/2 0/2 (P - N/A) Post-trauma reconstruction 0/2 0/0 (P - N/A) Trunk reconstruction 0/1 0/1 (P - N/A) Scar revision 0/1 0/1 (P - N/A) narcotic use and the resultant adverse sequelae associated with narcotic analgesia. The reduction or elimination of postoperative narcotics has been shown to reduce nausea, vomiting, 11 recovery room time, and hospital stay. 12 Per manufacturer guidelines, ketorolac use is limited to five days in order to reduce the risk of any untoward effects, including hemorrhage, cardiovascular effects, renal effects, anaphylactic reaction, and skin reactions. 13 While documentation of the safety and efficacy of ketorolac in numerous surgical subspecialties is compelling, its safety and efficacy in plastic surgery is perhaps less so. 2,6-8 A recent multispecialty meta-analysis of double-blinded, randomized, controlled trials of ketorolac by Gobble et al 14 concluded that ketorolac does not increase perioperative bleeding. Their study included all surgical specialties and had very strict inclusion criteria: only double-blind, randomized, controlled trials. Of the 27 studies cited by Gobble et al, however, only one 15 included plastic surgery patients. Since a number of plastic surgery procedures require significant undermining with the potential for the increased likelihood of bleeding, the plastic surgery community might be more convinced of the safety of ketorolac if an analysis was limited to plastic surgery operations only, hence, the reason for our study. In our review of the plastic surgery literature, five authors supported the use of ketorolac, whereas one did not. All authors agreed that ketorolac administration significantly reduced postoperative narcotic use and significantly improved the patient s postoperative recovery experience. Only one of the six papers found an increased incidence of hematoma after breast reduction surgery. However, when all cases from all six studies were combined and when we subcategorized patients by operation, no significant increase in postoperative hematoma was noted. Ketorolac use in facial aesthetic surgery and in head/neck plastic surgery procedures was evaluated in two studies. Torgerson et al (Level II Evidence) 16 prospectively randomized 140 consecutive patients undergoing facelift or brow lift surgery. The groups treated with ketorolac either intramuscularly or by local injection required significantly less morphine at each postoperative interval studied (P <.001 at each interval). Two patients in the control (non-ketorolac) group developed a hematoma requiring surgical evacuation, while none of the 115 patients in the ketorolac group developed a hematoma. Torgerson et al 16 concluded that the use of local ketorolac is a safe and effective way to reduce the need for postoperative narcotics in facial aesthetic procedures. Marín-Bertolín et al (Level II Evidence) 15 performed a randomized, double-blind study comparing intramuscular ketorolac and metamizol for postoperative pain control in 100 patients undergoing a variety of plastic surgery procedures. Head and neck and aesthetic cases represented 38% of the participants. No bleeding events were noted in patients undergoing facial aesthetic or head and neck surgery. Only one patient in the study group required percutaneous outpatient drainage of a hematoma after an abdominoplasty. They concludedthatketorolacwasassafeandeffectiveasmetamizol and did not significantly raise hematoma risk. However, caution was suggested in procedures in which postoperative hematoma is of specific concern. Two studies documented ketorolac use after aesthetic breast augmentation surgery, and both advocated for ketorolac use as a safe means of improving pain control without increased risk of bleeding. McCarthy et al (Level II Evidence) 17 performed a double-blinded, randomized trial of 50 patients undergoing primary subpectoral breast augmentation. Half were treated with pocket irrigation with bupivacaine and ketorolac infused with a wound catheter into the implant pocket after implant placement. The other half received no pocket irrigation. Ketorolac has a 100% systemic absorption and bioavailability rate when injected into muscle or subcutaneous tissue. 18 No patients experienced hematoma, seroma, or infection. Further, the study group demonstrated significantly improved pain control at

4 Stephens et al 465 six hours versus controls. Dowbak (Level V Evidence) 19 briefly discussed his experience with ketorolac use in 105 consecutive aesthetic breast augmentations, all receiving postoperative ketorolac. He stated that there were no hematomas in his patient series. No specific demographics or further details were described by the author in this small series presented by his brief discussion of the topic. The author advocated the safe use of ketorolac. Since breast augmentation does not require the development of large flaps, it is perhaps not surprising that the above studies found little to no hematoma risk with ketorolac. Cawthorn et al (Level III Evidence) 20 specifically evaluated ketorolac use after breast reduction surgery. This was the only report documenting an increased risk of bleeding. In this study of 379 consecutive patients retrospectively reviewed, ketorolac use was associated with a significantly greater risk of a hematoma requiring operative evacuation; 11 of 127 (8.7%) in the treatment group versus 6 of 252 (2.4%) in the control group (P <.05) developed a significant hematoma. Three patients in the ketorolac group required blood transfusions, compared to none of the controls. An important finding was that the group that received ketorolac had a significantly higher rate of hypertension preoperatively (P =.04). This may possibly have confounded their findings. Given their results, the authors do not support the use of ketorolac in breast reduction surgery. Finally, breast reconstruction and ketorolac use was studied by Sharma et al (Level III Evidence) 21. They performed a retrospective review of 215 patients undergoing autologous breast reconstruction with either unilateral or bilateral TRAM flaps. Sixty-five patients received intravenous ketorolac along with IV morphine for pain control, while 150 received IV morphine alone. There was no difference in hematoma rates with 1.5% in ketorolac group versus 2.7% in the control group. The transfusion rate was similar between the study and control groups as well: 10.8% and 11.3% respectively. The ketorolac group used significantly less IV morphine than did the control group (P =.02). Therefore, the authors supported the use of ketorolac as a safe adjunct for postoperative pain control in autologous breast reconstruction. In the final analysis, there is uniform consensus across surgical specialties regarding the efficacy of ketorolac in reducing postoperative pain and narcotic use. Our review confirms this and extends the findings by specifically including plastic surgery operations. Less clear, however, is the issue of postoperative bleeding. Since plastic surgery procedures often require significant undermining, bleeding concerns are well founded. When plastic surgery operations from all six studies were combined we found no difference in hematoma rate. However, the diversity of operations reviewed may have masked significant differences in bleeding tendencies with a given procedure. We therefore categorized the procedures by type, again finding no difference in postoperative bleeding. However, the relatively small number of cases in each category may, again, have masked significant differences in bleeding between the two groups. In addition, the route of ketorolac administration was varied and this, too, may have affected our results. Our study is not without its limitations. Although we were able to capture all of the published outcomes involving ketorolac use and postoperative bleeding in plastic surgery patients, this resulted in only six publications included for critical review. Of these six, only three were prospectively performed. Of those three, only one was double-blinded. The paucity of prospective, double-blinded studies definitely limits the strength of our analysis. Four of the six papers included patients that had procedures done where significant flaps were raised, whereas two did not. We acknowledge the limitations of our study arising from the lack of available multiple double-blinded, prospective, randomized trials evaluating ketorolac use in plastic surgery patients. We hope that our review and analysis will encourage such a study. CONCLUSION In conclusion, the documented beneficial effects of ketorolac on postoperative pain and the potential that the drug may have no adverse effect on bleeding may be reasons enough for the plastic surgery community to consider a prospective multicenter study. The efficacy of ketorolac in postoperative pain reduction and in the reduction of postoperative narcotic use is confirmed for a wide variety of plastic surgery procedures. The relative risk of postoperative bleeding is less clear, however. The promising results found in a small number of plastic surgery studies make a prospective randomized study advisable. Disclosures The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Practice guidelines for acute pain management in the perioperative setting: An updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2): Cepeda MS, Carr DB, Miranda N, Diaz A, Silva C, Morales O. Comparison of morphine, Ketorolac, and their combination for postoperative pain: results from a large,

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