The risk of hematoma formation after exposure to ketorolac was 2.4 [odds ratio (OR), 2.4; 95% confidence interval (CI), 0.8–7.4; P = 0.114), after controlling for the differences in BMI and age between cases and controls. The 2.4 OR indicates that a breast reduction patient is 2.4 times more likely to develop a postoperative hematoma after being exposed to ketorolac than a patient who is not exposed. The OR of 2.4 is associated with a wide CI (0.8–7.4) and was not statistically significant indicating an inconclusive result.
The association between perioperative ketorolac exposure and breast hematoma received attention shortly after its approval in 1989, when an anecdotal case series reported 4 hematomas within 10 days, occurring after the initiation of ketorolac use at the author’s institution.17 Allegedly, the hematoma rate returned to baseline after cessation of use. However, the small sample size and lack of follow-up limited the validity of this study. Subsequent to the above case series, 2 other retrospective cohort studies have identified a positive correlation between ketorolac exposure and postoperative hematomas after reduction mammaplasty.11,12
The first, by Blomqvist et al.12, featured a retrospective cohort of 293 consecutive reduction mammaplasty patients. Among patients who received ketorolac, 60% developed a hematoma (3 of 5), which was significantly higher than the 4.7% rate among patients who did not receive an NSAID (12 of 253; P < 0.05, Fisher’s exact test). Furthermore, patients who received diclofenac developed more hematomas compared with those who did not receive an NSAID, but this was not a statistically significant difference (14.3%; 5 of 35; P > 0.05, Fisher’s exact test). In the study by Blomqvist et al.12, ketorolac was administered as a 30 mg intramuscular dose, and diclofenac a 75 mg intramuscular dose, and these medications were given both intra- and postoperatively. The authors adopted a broad definition of hematoma, including all bleeding managed nonoperatively and operatively. If hematomas managed conservatively were excluded, the incidence of bleeding in the 3 groups changes to 4 of 253 (1.6%), 1 of 5 (20%), and 1 of 35 (2.9%) in the non-NSAID, ketorolac, and diclofenac groups, respectively. The main drawbacks of this study were its small sample size particularly of the ketorolac group and failure to analyze comorbidities that may influence bleeding.
More recently in 2012, in a retrospective review of 379 reduction mammaplasty patients, the authors found that the incidence of hematoma requiring reoperation was 6 of 252 (2.4%) in the non-NSAID cohort, and 11 of 120 (8.7%) in the ketorolac cohort.11 Most (~94%) of the patients in the ketorolac group received 30 mg intravenous ketorolac intraoperatively. The relative risk of hematoma formation requiring reoperation was statistically significant in the ketorolac group (risk ratio = 3.6; 95% CI, 1.4–9.6). There was also a higher proportion of patients with hypertension in the ketorolac group (27 of 127, 21.3%) compared with the nonketorolac group (32 of 252, 12.7%; P < 0.05, chi-square statistic), which may have confounded the results and predisposed the patients exposed to ketorolac to greater bleeding. The authors do report mean arterial pressures, which were measured immediately upon entering and exiting the recovery room, which were not statistically significant between the 2 groups. One may argue that these pressures are discrete points, which do not accurately reflect the flux in blood pressure over time. Similar to our results, this study had a broad CI for their risk ratio.
There is evidence evaluating ketorolac use after other breast procedures as well, although the planes of tissue dissection differ from breast reduction techniques. Dowbak13 anecdotally reported on a cohort of 105 submammary breast augmentations treated with 30 mg of intramuscular ketorolac immediately before completion of the procedure. None of the patients in their series developed a postoperative hematoma. The definition of “prior to completion of procedure” in relation to hemostasis, closure of the incision, or before reversal of general anesthesia was not specified. There was also no report on follow-up.
In another retrospective study of 215 patients undergoing transverse rectus abdominis myocutaneous flap for breast reconstruction, no differences were found in the incidence of hematoma among the groups receiving ketorolac (1 of 65, 1.5%) and those who did not (4 of 150, 2.7%).14 In this study, ketorolac was only administered in the postoperative setting as part of a patient-controlled analgesia pump at a dosage of 30 mg intravenous ketorolac every 8 hours if needed. Patients who were given ketorolac had a shorter duration of use of the patient-controlled analgesia pump and inpatient stay, although this difference was not statistically significant. Hypothetically, administration of ketorolac in the postoperative setting may reduce bleeding diathesis, because primary hemostasis has already been achieved and thus the antiplatelet effect of ketorolac would be negligible. This concept has also been suggested and demonstrated in nonplastic surgery literature.18
Three prospective randomized controlled trials have also evaluated ketorolac’s analgesic properties as a wound irrigant in subpectoral breast augmentation.7,19,20 Collectively, 150 patients were randomized to receive either pocket irrigation with a ketorolac and bupivacaine mixture or normal saline (1 study used no irrigant as a control7). Of the 150 patients, there were no cases of hematoma requiring surgical evacuation. It is difficult, however, to interpret these results, as the route of administration (pocket irrigation versus intramuscular or intravenous injection), and perhaps the clinical effect of ketorolac is different.
In a theoretical scenario, a randomized controlled trial, with a narrow CI, evaluating the cause-and-effect relationship between ketorolac and bleeding after reduction mammaplasty would provide us with the best evidence if ethical considerations were not an issue. The study with the closest design to a randomized controlled trial thus far has been by Marín-Bertolín et al.21, who examined a prospective cohort of 92 patients undergoing various plastic surgery procedures who were randomized to either ketorolac or metamizole groups. Their primary outcomes were pain scores and complication rates. In their study, 2 patients bled after receiving ketorolac, whereas none of the patients who received metamizole had a bleed, leading the authors to conclude that ketorolac is safe among individuals without baseline high bleeding risk. However, only 6 of the 92 randomized patients had a breast procedure, which were reconstructive in nature. The study by Marín-Bertolín et al.21 was also included as part of a meta-analysis of 27 randomized controlled trials evaluating bleeding risk after ketorolac use across many procedures.22 It was the only study examining plastic surgery procedures. Notably, there were no significant differences in bleeding between ketorolac-exposed and nonexposed patients.
There are 2 main barriers to conducting a randomized controlled trial concerning this topic. First, it is unethical to randomize a patient into a group where they might incur potential harm. Second, because the baseline rate of postoperative hematoma is low (2.4% after reduction mammaplasty11), a randomized controlled trial would require a large sample size, long recruitment time, and significant resources. A case-control study design is therefore a feasible method that overcomes the low incidence of hematoma and the ethical concerns.
In our study, our primary aim was to compare the frequency of ketorolac exposure among patients who developed a hematoma after a breast reduction mammaplasty and patients who did not. Ketorolac exposure did not predict hematoma formation in our sample statistically as the P value did not meet our significance threshold of 0.05 (OR, 2.4; 95% CI, 0.8–7.4; P = 0.114). The OR of 2.4 is clinically important however. It can be interpreted that it is 2.4 times as likely for a postoperative breast reduction patient who has been exposed to ketorolac to have hematoma formation than a patient who has not been exposed. As both clinical significance and statistical significance must be established to render the results conclusive, this study remains inconclusive.
The fact that BMI was statistically different between cases and controls indicates a that the matching protocol did not work as expected. When the difference in BMIs between cases and controls was not considered in our statistical model, ketorolac exposure reached statistical significance with regard to hematoma formation. However, this significance disappeared when we accounted for the BMI difference statistically. From a clinical perspective, the OR of 2.4 suggests that patients who receive ketorolac are almost 2.4 times more likely to develop a hematoma. If this was the “truth,” most surgeons would not expose their patients to ketorolac. Our CI, however, is quite broad (0.8–7.4) indicating a lack of precision, even though our study was adequately powered based on our sample size calculation. We cannot dismiss these findings, however, as there is more weight to the right of the value OR = 1 on the CI scale, which means that there may be a clinically important association even if our study has not shown it (Fig. 1).
Among cases, the hematomas occurred with approximately the same frequencies on each side (55% left, 42.5% right), which seems to indicate that the level of training may not be related to hematoma development (in general, at our institution the resident operates on one side and the staff surgeon on the other). Anecdotally, bleeding from ketorolac has been described as “generalized ooze” and we were interested to see if staff surgeons were more likely to describe the bleeding in this way among cases exposed to ketorolac. Interestingly, their descriptions did not differ.
The primary limitation to our study is the retrospective design, which precludes cause-and-effect associations. There was also no control over the perioperative prescription patterns of ketorolac. We therefore cannot make any suggestions regarding ketorolac dosing, route, and timing (preoperative, intraoperative, or postoperative) on the risk of hematoma formation.
Last, journal editors and reviewers have traditionally accepted articles with positive results. Thankfully, this is changing, as this practice introduces bias to the scientific evidence as the results of all studies need to be published. Publishing results of all studies facilitates the pooling of results in systematic reviews and meta-analyses with more “truthful” conclusions. Although this study was inconclusive, it provides useful evidence for investigators to use in future meta-analyses. Alternatively, a larger, multi-site, case-control study can be used to provide further evidence of the association observed and its strength. Future studies could also examine the impact of ketorolac timing (preoperative, intraoperative, or postoperative administration) or dose on the risk of hematoma after reduction mammaplasty.
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Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.
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