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.

Abstract and Introduction

Abstract

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.

Introduction

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 PGH₂is metabolized by tissue-specific isomerases to other prostanoids such as prostaglandins (PGD

Abstract and Introduction
Beneficial Immune-modulating Effects of Nsaids
Unfavorable Immune-modulating Effects of Nsaids
References

Table 1. Short Outline of General and Immune Effects of Prostanoids
Prostanoids	Receptor	Function	Immunologic Effect
PGD₂	DP_1–2	• Platelet aggregation • Allergic reactions • Contraction of bronchial airway • Sensation of pain • Sleep–wake cycle	• Involved in type 2 immune responses, including T helper 2 cells, type 2 innate lymphoid cells, and eosinophils with a subsequent effect on asthmatic airways inflammation through increased inflammatory cell chemotaxis/cytokines and enhanced immunoglobulin E class switching in B cells.¹ • Elevated level of PGD₂ resulted in a defect in virus-specific T-cell responses due to impaired respiratory dendritic cells migration.² • PGD₂ also has anti-inflammatory effects upon multiple spontaneous dehydrations and conversion into 15-deoxy-Δ-prostaglandin J2, which in turn inhibits the activation of nuclear factor κB system resulting in reduction of interleukins 6, 1β, and 12 and tumor necrosis factor α from macrophages and decreases the production of inducible nitric oxide synthase.³
PGE₂	EP^1–4	• Contraction and relaxation of smooth muscle • Control of blood pressure • Sensation of pain • Proinflammatory response	• Serves as an important proinflammatory mediator, involved in development of all physical signs of inflammation such as rubor, tumor, and dolor. • Also has anti-inflammatory properties that are context-dependent; downregulation of interleukin 2 by T cells and phagocytosis by macrophages.⁴ • Promotes dendritic cells migration and upregulates costimulatory molecule expression to promote T cell activation.⁵ • Promotes T helper 2 cell response by impairing the ability of dendritic cells to produce interleukin 12 and shifts the balance away from a cellular T helper 1 cell to a humoral T helper 2 cell response with a decreased T helper 1/T helper 2 ratio.⁶ • Involved in the activation of the T helper 17 cell responses that characterized by the production of the proinflammatory cytokine interleukin 17.⁷ • Promotes the development and function of regulatory T cells.⁸ • Inhibits the cytolytic function of natural killer cells and therefore reduces target cell lysis.⁹ • Suppresses proliferation and induce apoptosis of immature B cells and enhances immunoglobulin class switching in mature B cells.^10,11
PGI₂	P	• Platelet aggregation • Vasodilatation • Renin release	• Decreases the production of proinflammatory cytokines (tumor necrosis factor α and interleukins 12, 1β, and 6) and chemokines (MIP-1α and MCP-1) and increases the production of the anti-inflammatory cytokine interleukin 10 by bone marrow dendritic cells.¹² • Inhibits the ability of dendritic cells to stimulate antigen-specific T-cell proliferation.¹² • Inhibits T helper 1 cell and T helper 2 cell activation, differentiation, and cytokine production, while enhancing T helper 17 cell immune responses and interleukin 17 production.¹³
PGF₂α	FP_A-B	• Stimulates the contraction of uterine and bronchial smooth muscle • Produces vasoconstriction	• Involved in cellular infiltration and early recruitment of neutrophils.¹⁴
Thromboxane	TPα_-β	• Platelet aggregation • Vasoconstriction • Bronchoconstriction	• Acts as a general suppressor of a low-avidity interaction between dendritic cells and T cells and inhibits T cell activation.^15,16

PG, prostaglandin.

Table 2. Overview of Described Literature and Their Conclusions about the Effect of Nonsteroidal Anti-inflammatory Drugs on Different Postoperative Outcomes
Outcome	Randomized Controlled Trial	(Systemic) Review	Meta-analysis
Immune response
Surgical stress response	• Decreased^33–36
Systemic inflammatory distress syndrome/sepsis	• Improved⁴⁵		• Improved⁴³
	• No effect⁴⁴
Pulmonary effects
ARDS	• No effect⁴⁹	• Unknown⁵⁰	• Improved (animal)⁵¹
Aspirin-exacerbated respiratory disease	• No effect (COX-2)⁵²	• No effect (COX-2)⁵³
Inflammation and pain
Preemptive		• Moderate effect⁵⁴	• Improved (COX-2)^55,56
Perioperative		• Improved⁵⁷	• Improved^58,59
Persistent pain	• No effect^60–63		• No effect⁶⁴
Oncology
Outcome	• Improved⁶⁵	• Unknown⁶⁶	• Improved (animal studies)⁶⁷
Neurology
Postoperative cognitive dysfunction			• Improved⁶⁸
Aneurysmal subarachnoid hemorrhage	• No effect⁶⁹
Healing processes
Wound healing	• No effect⁷⁰
Anastomotic healing	• Impaired (animal study)⁷¹		• Impaired^72–74
			• No effect⁷⁵
Bone healing	• No effect⁷⁶	• No effect⁷⁷	• Impaired⁷⁸
			• No effect in high-quality studies⁷⁹