The Inflammatory Response to Surgery

Introduction

Tissue damage after surgery triggers a complex inflammatory response termed sterile inflammation characterized by the release of intracellular molecules into the extracellular environment leading to receptor-mediated immune signaling cascades. A key feature of this inflammatory response involves removing necrotic cells and launching a program of tissue repair. Patients may not only respond differently to a similar sterile insult because of genetic differences, but also as a consequence of preexisting disease that can substantially modify the inflammatory phenotype. The presence of comorbid diseases frequently fuels an established dysregulated inflammatory response, which contributes to organ injury and immunosuppression. Postoperative complications, including (subclinical) organ dysfunction and infection, increase morbidity and mortality following surgery, even after discharge from hospital. Immune alterations are not only the result of direct tissue injury but are also influenced by perioperative medications and interventions. This chapter will discuss the broad current understanding of the immune response to tissue damage, the interaction of this response with comorbid diseases, and clinical factors that influence perioperative inflammation.

Defining Acute Systemic Inflammation After Surgery

Although the acute systemic inflammatory response is widely referred to, defining it objectively in the modern perioperative era is rather elusive. Consensus definitions are lacking, in contrast to sepsis. First described by Sir David Cuthbertson, the classic textbook response entails a biphasic immune, inflammatory, and metabolic response to injury. The first ebb phase, as coined by Cuthbertson, involves peripheral vasoconstriction, concomitant hypothermia, and shunting of blood and substrates to vital organs. A transition then occurs (termed flow by Cuthbertson), with a hypermetabolic phase ensuing. In the modern perioperative setting, these classic characteristics are rather less distinct for several reasons. First, many of the cardiometabolic features following trauma/surgery have been derived from critical illness, chiefly because these measurements are more attainable in this patient population. Despite significant morbidity in noncritically ill surgical patients, it is not clear as to whether this classic temporal pattern occurs in other patients—particularly in the modern era of multimorbidity, anesthesia, and surgery. Second, various clinical measures are nonspecific (e.g., heart rate, temperature), and are frequently unhelpful in convincingly differentiating between the systemic inflammatory response syndrome and alternative pathophysiologic/nonpathologic etiologies. Third, the interaction between common (treated) chronic comorbidity and acute systemic inflammation is poorly defined. Fourth, the nonspecificity of various commonly used inflammatory biomarkers cannot distinguish easily between sterile inflammation and alternative triggers of the inflammatory response. Table 2.1 summarizes common clinically used physiologic and biochemical markers for systemic inflammation after surgery.

Table 2.1

Clinical and biochemical measures of systemic inflammation after surgery.

Type	Marker	Description	Associations	References
Clinical	Systemic inflammatory response syndrome (SIRS)	SIRS diagnosed if 2 + criteria are met without evidence of an infectious source: Temperature < 36°C (96.8°F) or > 38°C (100.4°F); Heart rate > 90 min −1 ; Respiratory rate > 20 min −1 or P a CO 2 < 4.3 kPa; White cell count < 4 × 10 9 L −1 or > 12 × 10 9 L −1 or > 10% immature neutrophilic bands.	Length of duration of SIRS associated with increased mortality and complication rate after gastrointestinal and vascular surgery and trauma.	Haga et al. Shepherd et al.
	Sequential Organ Failure Assessment (SOFA)	Combined total of scores (0-4) in each of six organ systems (nervous, respiratory, cardiovascular, hepatic, renal, and coagulation).	Increasing score associated with increased mortality after elective gastrointestinal and cardiac surgery.	Bota et al.
Biochemical	Neutrophil-lymphocyte ratio (NLR)	The ratio of neutrophils to lymphocytes in blood.	Increased ratio associated with adverse events in cardiac, vascular, gastrointestinal, and orthopedic surgery.	Malietzis et al.
	C-reactive protein	Acute phase protein synthesized in the liver and produced largely in response to interleukin-6.	Increased levels correlated with the degree of tissue trauma caused by orthopedic surgery and with anastomotic leak rate after upper gastrointestinal resection.	Rettig et al.
	Albumin	Family of abundant globular proteins representing the majority of protein present in plasma.	Hypoalbuminemia associated with increased rates of wound infection, need for further surgery, and respiratory complications.	Neumayer et al.

Key references pertaining to the perioperative/trauma population are cited.

Where It All Starts: Cellular Origins of Surgical Inflammation

The activation of the host response to sterile inflammation is, unsurprisingly, triggered directly by cellular injury as a result of surgery. Surgical tissue injury shares many similarities with the immune response to infectious pathogens. Upon tissue injury, loss of plasma membrane integrity and cell death (necrosis) leads to the release of danger-associated molecular patterns (DAMPs) into the extracellular environment ( Fig. 2.1 ). Pattern recognition receptors (PRRs), including highly conserved Toll-like receptors (TLRs), are expressed on a wide range of immune and nonimmune (epithelial, endothelial and fibroblasts) cells. PRRs recognize both pathogen-associated molecular patterns (PAMPs) and DAMPs (also known as alarmins) following tissue injury. Thus host innate immune surveillance monitors endogenous (self) markers of tissue damage as well as nonself antigens, such as bacterial infection—a process known as the “danger hypothesis.” Receptors and downstream signaling pathways common to both sterile and pathogenic stimuli, such as nuclear factor-ĸβ and mitogen-activated protein kinase, lead to similar patterns of cytokine release and cellular activation. A diverse array of stimuli synonymous with surgical tissue trauma activate the ubiquitous NLRP3 inflammasome, including multiple microbial products, endogenous molecules, and particulate matter. The biochemical function of inflammasomes is to activate caspase-1, which leads to the maturation and release of interleukin 1β (IL-1β) and IL-18, and induction of pyroptosis (a form of cell death) fueling the release of other inflammatory mediators. Human monocytes (unlike tissue resident macrophages) can release mature IL-1β in response to TLR ligands alone, but most microbial stimuli appear to prime the NLRP3 inflammasome for activation. Clinically, sterile and pathogenic inflammatory responses are frequently indistinguishable. DAMPs implicated in generating inflammation and organ dysfunction after surgery ( Table 2.2 ) include mitochondrial DNA, which activate innate inflammation via TRLs.

Table 2.2

Damage-associated molecular patterns with potential roles in organ dysfunction after surgery.

Molecule	Physiologic function	Location	Receptor	Reference
HMGB1	Chromatin regulation	Nucleus of immune cells	TLR4	Andersson et al.
Histones	Nucleosome structure	Nucleus	TLR2/4/9 and NLRP3	Silk et al.
Mitochondrial DNA	Mitochondrial genome	Mitochondria	TLR9 / NLRP3	Zhang et al.
ATP	Cellular energy source	Mitochondria	P2RX7 / NLRP3	Gombault et al.
Uric acid	Byproduct of purine metabolism	Cytoplasm	NLRP3	Hughes and O’Neill

ATP, Adenosine triphosphate; HMGB1, high-mobility group box 1 protein; NLRP3, NACHT, LRR and PYD domains containing protein 3 inflammasome; P2RX7, P2X purinoreceptor 7 ; TLR , Toll-like receptor.