Immune Modulatory Effects of Nonsteroidal Anti-inflammatory Drugs in the Perioperative Period and Their Consequence on Postoperative Outcome

Dirk J. Bosch, M.D., Ph.D.; Gertrude J. Nieuwenhuijs-Moeke, M.D., Ph.D.; Matijs van Meurs, M.D., Ph.D.; Wayel H. Abdulahad, Ph.D.; Michel M. R. F. Struys, M.D., Ph.D., F.R.C.A.

Disclosures

Anesthesiology. 2022;136(5):843-860. 

In This Article

Unfavorable Immune-modulating Effects of Nsaids

Wound, Anastomotic, and Bone Healing

Wound Healing. NSAIDs might have immune-modifying properties that are detrimental in the process of normal wound healing. There are a number of crucial steps in the process of normal wound healing, including the acute phase response, proliferation, and remodeling of tissue. The acute phase is characterized by homeostasis and inflammation. Neutrophils are involved at an early stage and stimulate the migration of fibroblasts, epithelial cells, and vascular endothelial cells.[134] In a later stage, macrophages become the predominant cells and form an important barrier against bacteria.[134] In response to cytokines, released upon (surgical) injury, nitric oxide is produced, which is essential for angiogenesis and mediation of inflammation.[135] In an animal study in which nitric oxide was bound to ibuprofen, wound contraction increased, and epithelialization improved; the authors concluded that the results indicated that the esterification of ibuprofen with nitric oxide reverses the healing-suppressant effect of ibuprofen.[136] During the proliferation step, fibroblasts are the most important cells and are involved in wound contraction, collagen synthesis, and angiogenesis.[137] NSAIDs might impair the acute and proliferation phase of wound healing by their inhibitory effects on PGE2.[138–140] Inhibition of PGE2 is related to impaired wound healing; therefore, the use of NSAIDs in the proliferative phase of wound healing may result in increased scar formation.[140] PGE2 has shown to be essential for neutrophil removal via the promotion of reverse migration.[141] Although the negative effects of NSAIDs on wound healing are well documented in animal studies, large clinical trials describing the effects of NSAIDs in wound healing are lacking. During a phase 3 randomized, placebo-controlled trial to evaluate the safety of intravenous meloxicam (30 mg) after major surgery, no differences were observed regarding wound healing.[70] The authors, however, pointed out the relatively healthy study population, in which patients with a history of cardiovascular, renal, hepatic, and bleeding events were excluded.

Anastomotic Healing. The hypothesis of impaired wound healing also applies to an intraabdominal bowel anastomosis, in which NSAIDs may increase the risk of anastomotic leakage. COX-2 is essential for gastrointestinal homeostasis, and the subsequent prostaglandin PGE2 is involved in mucosal repair.[142,143] Moreover, anastomotic healing benefits from a proinflammatory response, leading to proliferation, angiogenesis, and granulation.[144] Reduced prostaglandin expression has been shown to reduce measured hydroxyproline levels and collagen repair in fresh anastomosis.[145] However, no information has been provided about the subtype of collagen, and therefore, the quality of the collagen cannot be determined.[144] An association between the perioperative use of NSAIDs and an increased risk of anastomotic leakage is demonstrated in various animal experiments and human clinical trials.[143,146] A randomized controlled trial in 24 rats assessed the effect of parecoxib on abdominal wound healing, both clinically and histologically.[71] There were no differences in clinical outcome; however, histological differences, on which the study was powered, were observed, such as decreased epithelization and increased necrosis in the parecoxib group.[71] The results, however, are not generalizable to humans, as the authors chose an intraperitoneal route of administration. Interestingly, the risk of anastomotic leakage caused by NSAIDs seemed to be location-dependent, with a higher risk in small bowel anastomosis compared to colon anastomosis.[147–149] Three meta-analyses, one published in 2018, 2019, and 2020, all concluded that caution must be taken when prescribing NSAIDs after gastrointestinal anastomosis.[72–74] A subgroup analysis in the meta-analysis of Jamjittrong et al.[72] showed that nonselective NSAIDs, but not selective COX-2 inhibitors, were significantly associated with anastomotic leakage. However, according to the authors, the safety of selective COX-2 inhibitors was inconclusive. In another subgroup analysis of randomized controlled trials by the same authors, no significant association was observed.[72] Finally, a fourth meta-analysis has recently been published, in which the authors pointed to important methodologic concerns regarding the previous meta-analyses, such as the inclusion of different types of gastrointestinal anastomoses and the underlying surgical pathology.[75] In this latest meta-analysis, only patients with colorectal cancer were included (N = 10,868). The authors concluded that perioperative NSAID administration does not increase the overall anastomotic leakage rate and that these findings were consistent throughout subgroup analyses for low anterior resections and both NSAID classes. Nevertheless, this latest meta-analysis also has important methodologic limitations: like most studies, there are no data on dosage and duration of administration. In addition, it is unclear when administration was started, as later dosing during the postoperative phase is associated with a lower risk of anastomotic leakage. There are currently no registered studies (accessed January 2, 2021, clinicaltrials.gov) examining the effects of NSAIDs on anastomotic leakage.

Bone Healing. In addition to the potential negative effects on wound and anastomotic healing, the use of NSAIDs perioperative might also affect bone healing, since inflammation is an essential part of the early stage of bone fracture healing. Although the contribution of NSAIDs is controversial with respect to other risk factors (comorbidities, medications, oncology interventions, and lifestyle habits), the inhibition of COX-1 and COX-2 might result in an impaired bone turnover.[150] COX-2 is involved in the differentiation of mesenchymal cells into osteoblasts.[151] In COX-2 knockout animals, bone density was significantly decreased, whereas parathyroid hormone levels were increased, implicating a compensatory mechanism for the lack of COX-2 expression.[152] In a meta-analysis from 2010, the authors reviewed all available evidence regarding the effect of NSAIDs exposure on bone healing.[79] Lower-quality reports showed a significant association between NSAID exposure and nonunion, while this association disappeared when only higher-quality studies were included in the analysis.[79] A more recent meta-analysis from 2019, however, observed a negative effect of NSAIDs on bone healing, which may be dose- and/or duration-dependent, since low dose or short duration was not associated with nonunion.[78] Low dose or short duration was, however, not defined in this study and could only be analyzed in 4 of 16 evaluable studies, of which 2 found no effect and 2 found an increased risk. Moreover, it should be noted that no randomized studies were included in either meta-analysis. A systematic review including 3 randomized controlled trials and 13 retrospective studies concluded that there was no strong evidence that NSAIDs led to an increased rate of nonunion.[77] In all of these analyses, the authors had to deal with heterogeneity and conflicting data among the included studies. Important differences between long bones and vertebral bones, with variation in reported nonunion rates between both, and lifestyle habits, such as smoking, should be taken into account. Furthermore, there was a significant difference in the definition of nonunion between studies, ranging from a radiographic score to the need for reoperation. Finally, these studies also showed a large variation in dosage, type of NSAID, and duration of administration. A recent randomized trial examined the effect of different ibuprofen regimens (3 × 600 mg ibuprofen for 7 days vs. 3 × 600 mg ibuprofen for 4 days vs. placebo) on bone healing in Colles' fracture patients.[76] The authors concluded that there were no differences in bone mineral density, histomorphometric estimations, and changes in bone biomarkers between the treatment groups.[76] Although confounding variables were equally distributed between groups, the start of treatment could differ substantially between patients. According to clinicaltrials.gov, this study was initially registered under NCT01606540, with a power calculation of 192 participants. The final study is registered under NCT01567072, with the same power calculation, but only 95 patients were included. A forthcoming randomized controlled trial (NCT03880981) will study the effect of NSAIDs on the healing of tibia fractures and Achilles tendon ruptures (accessed January 2, 2021).

In conclusion, based on histological and animal studies, there appears to be an association between NSAIDs, in particular COX-2 inhibition, and impaired wound, anastomotic, and bone healing after surgery. However, high-quality clinical trials are lacking, and many questions are unanswered, such as the duration of use, type of NSAID, and, for anastomotic healing, whether underlying pathology and the location of the anastomosis influences the outcome. The potentially negative consequences that have emerged in histological and animal studies have therefore not been sufficiently substantiated in clinical studies. Administration must be individually weighed against the other known risk factors and benefits of NSAIDs (studies are summarized in Table 2).

Aspirin-exacerbated Respiratory Disease

The pulmonary effects of NSAIDs in the perioperative period are considered to be minimal. Nevertheless, the administration of NSAIDs should be carefully considered in specific circumstances, and detrimental effects may occur in patients with a history of asthma. In 2% of patients with mild asthma up to 25% of patients with severe asthma, the inhibition of COX-1 may trigger aspirin-exacerbated respiratory disease, a condition characterized by eosinophilic rhinosinusitis with humoral T helper 2 cell inflammation, bronchospasm, and acute asthma exacerbation.[153] Bronchospasm can be severe and life-threatening, developing within 1 to 3 h of administration.[153] The underlying pathophysiologic mechanism is related to inhibition of the cyclooxygenase pathway, resulting in activated lipoxygenase, which leads to increased leukotriene synthesis. Leukotriene provokes the constriction of smooth muscle and the stimulation of airway mucus production.[154] The prostanoids PGD2 and PGE2 also have pulmonary effects, but their role in the development of aspirin-exacerbated respiratory disease is not fully understood. PGE2 causes bronchodilation, while PGD2 causes bronchoconstriction.[155] It is generally assumed that all nonselective cyclooxygenase inhibitors pose a risk for patients with a history of asthma and that highly selective COX-2 inhibitors are safe. This assumption is based on previous data suggesting that the release of both prostanoids (PGD2 and PGE2) is only COX-1–dependent. Although two cases of aspirin-exacerbated respiratory disease were described in a case report after administration of a highly selective COX-2 inhibitor, this observation was not supported by a randomized crossover study in which 16 subjects with mild asthma received etoricoxib, and none developed pulmonary symptoms.[52,156] These results are consistent with a meta-analysis performed by Morales et al.,[53] who concluded that acute exposure to COX-2 inhibitors is safe in patients with stable mild-to-moderate asthma with aspirin-exacerbated respiratory disease. In conclusion, nonselective NSAIDs should be avoided during the perioperative period in patients with a history of asthma. Highly selective COX-2 inhibitors are most likely safe.

Conclusions

In this narrative review, we have summarized the immune-modulating effects of NSAIDs in the perioperative period and their effect on various postoperative outcomes. The body's response to surgical injury, and the accompanying release of subsequent cytokines, chemokines, and prostanoids, affects the postoperative course in various organ systems and regeneration processes. NSAIDs interfere with this response through the inhibition of cyclooxygenase, leading to a reduction in the synthesis of several of the prostanoids involved. Aspirin also stimulates the production of anti-inflammatory and proresolving mediators, but the consequences of this additional effect, to date, are unclear in clinical practice.

NSAIDs have been shown to have immune modulatory effects in cellular and animal models and significantly affect various outcome in these models. In randomized clinical studies, however, the immune-modulatory effects are much less evident, potentially due to a high degree of heterogeneity, genetic variances among patients, the use of various comedications, and the presence of several comorbidities. The risks and benefits of NSAID administration should be weighed individually, taking into account that the dosage and duration of administration often play important roles. To date, there is insufficient or inconclusive evidence from high-quality clinical studies to support the administration of NSAIDs to control the surgical stress response or sepsis, to prevent or improve ARDS, to improve postoperative neurologic outcome, or to minimize the risk of metastatic disease after oncological surgery. On the other hand, there is also insufficient evidence that NSAIDs are related to an impaired wound healing, increased risk of anastomotic leakage, and impaired bone regeneration. Their role in the multimodal treatment of acute pain has been sufficiently demonstrated and is associated with an opioid-sparing effect. It is not yet sufficiently clear whether preemptive administration of NSAIDs also has beneficial effects on postoperative pain perception. There does not, however, appear to be a beneficial effect on the development of chronic pain after surgery.

Search Strategy

We searched PubMed, Google, and clinical guidelines and screened the reference lists of studies retrieved by the searches. Most up-to-date studies and/or those with high impact were selected. Thereafter, a selection was made based on randomized controlled trials, reviews, and systematic reviews, or meta-analyses. We used the following terms: "nonsteroidal anti-inflammatory drugs" OR "NSAID" OR "aspirin" AND:

  • "surgical stress response" OR "cytokine" OR "SIRS" OR "sepsis"

  • "ARDS" OR "acute respiratory distress syndrome"

  • "AERD" OR "aspirin-exacerbated respiratory disease"

  • "surgery" AND "preemptive" OR "preoperative"

  • "surgery" AND "perioperative"

  • "surgery" AND "chronic pain" OR "persistent pain"

  • "surgery" AND "oncology"

  • "surgery AND "postoperative cognitive dysfunction" OR "POCD"

  • "aneurysmal subarachnoid hemorrhage" OR "aSAH"

  • "surgery" AND "wound healing" OR "tissue healing"

  • "surgery" AND "anastomotic leakage" OR "anastomotic dehiscence"

  • "surgery" AND "bone healing" OR "nonunion"

Research Support

Support was provided solely from institutional and/or departmental sources.

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