Abstract and Introduction
Nonsteroidal anti-inflammatory drugs are among the most commonly administered drugs in the perioperative period due to their prominent role in pain management. However, they potentially have perioperative consequences due to immune-modulating effects through the inhibition of prostanoid synthesis, thereby affecting the levels of various cytokines. These effects may have a direct impact on the postoperative outcome of patients since the immune system aims to restore homeostasis and plays an indispensable role in regeneration and repair. By affecting the immune response, consequences can be expected on various organ systems. This narrative review aims to highlight these potential immune system–related consequences, which include systemic inflammatory response syndrome, acute respiratory distress syndrome, immediate and persistent postoperative pain, effects on oncological and neurologic outcome, and wound, anastomotic, and bone healing.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and are known for their analgesic, antipyretic, and immune-modulating properties. Their mechanism of action is though inhibition of cyclooxygenase, also known as prostaglandin–endoperoxide synthase, the key enzyme involved in prostaglandin synthesis. Cyclooxygenases (COX-1 and COX-2) catalyze the formation of prostaglandin (PS) H2 (PGH2) from arachidonic acid, upon which PGH2 is metabolized by tissue-specific isomerases to other prostanoids such as prostaglandins (PGD2, PGE2, PGF2α), prostacycline (PGI2), and thromboxane. Prostanoids are a subgroup of eicosanoids with distinct functions in health and disease. Their most important general and immunologic effects are summarized in Table 1 and shown in Figure 1.
Effects of the most important immune active prostanoids: prostaglandin (PG) I2, PGE2, and PGD2. PGI2 increases the level of anti-inflammatory cytokines, while the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and interleukin 12 decrease in vitro. Depending on the stage of inflammation, PGE2 has a profound effect on the production of cytokines by T cells. Particularly at later stages of immune responses, PGE2 has immune suppressive properties, resulting in the inhibition of T helper (Th) 1 cell cytokines (interferon γ [IFN-γ] and IL-2), which results in the suppression of Th1 cell–dependent antimetastatic immunity. Furthermore, PGE2 is a potent inhibitor of the cytolytic effector function of natural killer cells and therefore reduces target cell lysis. In contrast, PGE2 promotes the production of cytokines produced by Th2 (IL-4, IL-5, IL-10, and IL-13), although these cytokines can also be mediated indirectly by PGE2 through cyclic adenosine monophosphate (cAMP). Thus, PGE2 promotes Th2 cell differentiation and shifts the balance away from a cellular Th1 cell to a humeral Th2 cell response, with a decreased Th1/Th2 ratio. PGD2 is a prostaglandin produced mainly by mast cells but also by other leukocytes, including dendritic cells and Th2 cells. Production of PGD2 by mast cells is an important initiator of immunoglobulin E (IgE) mediated type 1 acute allergic reactions. PGD2 has anti-inflammatory effects through inhibition of the production of inducible nitric oxide synthase (iNOS), TNF-α, and IL-1β by mouse and human macrophages.
Both cyclooxygenase isoenzymes have a similar molecular weight, a 65% amino acid sequence homology, and nearly identical catalytic sites, but differ in function, pattern, and location of expression. COX-1 has predominantly homeostatic functions, such as maintaining normal gastric mucosa, regulating renal blood flow, and regulating coagulation by abetting platelet aggregation. It is present in most cells and is constitutively expressed, and various studies have shown that its messenger RNA and protein expression does not change upon inflammation. In contrast, COX-2 is less widely expressed, but its expression is induced upon activation by proinflammatory mediators, like interleukin 1, tumor necrosis factor α, lipopolysaccharides, and tumor promotors. Although it is generally stated that COX-1 is not involved upon immune activation, its role in inflammation should not be underestimated. Studies in animal models have shown that COX-1 serves an important role in the development of inflammatory sequelae like edema.[20,21] Nevertheless, COX-2–derived metabolites are considered to be responsible for mediating pain and inflammation. To minimize side effects, while maintaining their function, selective COX-2 inhibitors were developed and have been available since 2000 (Figure 2).
Cyclooxygenase (COX) 1/2 selectivity of different nonsteroidal anti-inflammatory drugs ordered from mainly COX-1 selectivity to mainly COX-2 selectivity.
A specific category of NSAIDs, aspirin, not only inhibits cyclooxygenase but also stimulates the production of anti-inflammatory and proresolving mediators. These mediators are endogenous bioactive metabolites that are involved in the regulation and resolution of an effective innate immune response. Proresolving mediators stop the recruitment of leukocytes in inflamed tissue and increase the removal of apoptotic polymorphonuclear neutrophils. Polymorphonuclear neutrophils enhance microbial killing and clearance and are considered organ-protective. This unique feature of aspirin involves acetylation rather than inhibition of the active site of COX-2 in endothelial or epithelial cells, which results in the conversion of arachidonic acid to proresolving mediators. Examples of proresolving mediators activated by aspirin, termed aspirin-triggered specialized proresolving mediators, are aspirin-triggered resolvins and lipoxins. Lipoxins are known to regulate leukocyte traffic, interfere with the chemokine-cytokine axis, reduce edema, and block pain signals.
The immune-modulatory consequences of NSAIDs are considered to be relevant in the perioperative period, since surgical injury elicits an inflammatory response associated with postoperative outcome. Several reviews and meta-analyses have focused on the adverse effects of NSAIDs on multiple organ systems like the kidney and heart, which are beyond the scope of this review, whereas the immune-modulating effects of NSAIDs are poorly described.[25–29] Therefore, the aim of this narrative review is to describe the immunologic effects of NSAIDs in the perioperative period and their consequence on different postoperative outcomes. When possible, a distinction will be made between selective and nonselective cyclooxygenase inhibitors.
Anesthesiology. 2022;136(5):843-860. © 2022 American Society of Anesthesiologists | Lippincott Williams & Wilkins