When adverse outcomes occur postoperatively, anesthesiologists and surgeons often are at odds about the mechanism and may blame each other. If the creatinine changes after cardiac, vascular, or other surgeries, the surgeon may infer that the patient was over- or under-hydrated or there was too much hypotension, while the anesthesia team might state that the surgeon was too slow and the aortic cross-clamp time or pump time was too long. But what if the real problem is an issue inherent to the process itself, along with the patient’s underlying condition, that is exacerbated by the surgical procedure? The role of perioperative inflammatory status is becoming increasingly recognized as a possible predictor of postoperative morbidity (Front Aging Neurosci 2022;14:865244).
Defining the issue
Inflammation is the body’s response to an insult or injury and its subsequent attempt to defend against infection, prevent further damage, and promote healing. It starts with the release of cytokines following cellular damage, triggering DNA transcription and upregulation of inflammatory biomarkers such as interleukins, cytokines, tumor necrosis factor, and oxygen-free radicals.
These biochemical signals lead to a cascade of reactions. A loosening of tight junctions creates a weak endothelium, allowing inflammatory biomarkers to leak across borders, such as from the GI tract to the bloodstream or from the bloodstream to the central nervous system (CNS) (Anesth Analg 2022; 134:419-31). Additionally, increased endothelial adhesion allows activated monocytes and neutrophils to attach to and pass through the endothelium, infiltrating the parenchyma of the brain.
In the CNS, histologic studies have shown that this process leads to prolonged morphologic changes in microglia and astrocytes (Anesth Analg 2019;128:781-8). Neuroimaging using MRI and PET scans have demonstrated hippocampal inflammation following both cardiac and abdominal surgery (Brain Behav Immun 2016;54:178-93). These changes persist even after inflammatory biomarkers have normalized. In some patients, the result may present as postoperative delirium and postoperative cognitive dysfunction (POCD).
Inflammation and surgery
If inflammation is a natural response to injury, then it’s an inevitable reaction to any surgical procedure even if this inflammation is overwhelming and detrimental. For example, postoperative delirium is the most common postoperative complication in the elderly, with an incidence of 10% even months after surgery (Lancet 1998;351:857-61). Although the exact pathophysiologic mechanisms are not fully understood, mounting evidence points to neuroinflammation as the culprit.
Aside from the CNS, there is also evidence connecting elevated levels of inflammatory bio markers to dysfunction of multiple organ systems. During kidney transplantation, the inflammatory molecule NLRP3 (nucleotide-binding domain-like receptor protein 3) is associated with ischemia-reperfusion injury, which increases the risk of delayed graft function, acute rejection, and need for dialysis (Can J Anaesth 2022;69:448-59).
Patients on cardiopulmonary bypass undergo extensive cellular injury from surgery and activation of the complement system when blood contacts the CPB circuit. This leads to an overwhelming inflammatory response that is detrimental to the patient’s recovery. Even nonsurgical interventions, such as mechanical ventilation in the ICU, result in an increase in inflammatory markers that signal the onset of ventilator-induced lung injury (VILI).
Anesthesia and inflammation
With few exceptions, most anesthetic techniques and agents do not seem to induce an inflammatory reaction. In fact, one study involving anesthesia without surgery found no cytokine response after two hours of inhalational anesthesia (Br J Anaesth 2020;125:282-90). Nonetheless, the type of anesthesia and specific anesthetic agents can modulate inflammatory responses.
The inhaled anesthetics sevoflurane, isoflurane, and desflurane have demonstrated protective effects in several organ systems, including the heart, kidneys, and CNS. Sevoflurane has been shown to reduce inflammatory markers from VILI (Br J Anaesth 2020;125:282-90).
TIVA with propofol is even more impressive. In a study comparing propofol TIVA to sevoflurane, all inflammatory markers were significantly lower, and renal function was much better for the propofol group. Propofol achieves this by scavenging oxygen-free radicals (OFRs), since its chemical structure is similar to vitamin E (a powerful antioxidant), directly inhibiting inducible nitric oxide synthase (iNOS) mRNA transcription. In addition, propofol’s intralipid solution acts as a free radical scavenger. The result is fewer pro-inflammatory cytokines, less neutrophil activation, and decreased OFR production (Anesth Analg 2008; 106:371-8).
Local and regional anesthesia disrupts nociceptive impulses so that fewer prostaglandins, interleukins, or pronociceptive peptides, such as substance P and neurokinins, are produced from afferent fibers, which should decrease neurogenic inflammation. Local anesthetics (LAs) also interact with macrophages and fibroblasts recruited to the site, in addition to keratinocytes, which are local to the site. LAs impair the inflammatory response without diminishing the host response to tissue injury.
In an animal model, thoracic epidural with bupivacaine is associated with lower levels of TNF and IL-1 beta but not the other cytokines. In this same study of mesenteric ischemia, gut inflammation was decreased. The sympathetic control of neuraxial analgesia allows increased parasympathetic activity, which plays a role in central neuromodulation of inflammation (Anesth Analg 2011;113:1226-32).
LAs can modulate inflammatory pathways and reduce the pro-inflammatory cytokines NF-kB, TNF alpha, IL-1, IL-2, and IL-8. Consequently, LA infusions can reduce neutrophil adhesion to the endothelium by blocking TNF-alpha in endothelial cells. In fact, lidocaine has been shown to reduce CNS inflammation by decreasing inflammatory cytokines in the microglial cells (Minerva Anestesiol 2015;81:1001-9).
Several anesthetic adjuvants such as dexmedetomidine and clonidine have both anti-inflammatory and antioxidant properties. They reduce pro-inflammatory cytokines via alpha-2 receptors on macrophages and leucocytes (Minerva Anestesiol 2015;81:1001-9). Dexmedetomidine can also help maintain the integrity of the endothelium of several organ systems. After gastrointestinal ischemia, this can prevent translocation of bacteria from the gut to the portal blood, preventing hepatic injury (Anesth Analg 2022; 134:419-31). After a subarachnoid hemorrhage, dexmedetomidine, theoretically, can protect the brain by maintaining the blood-brain barrier and reducing cerebral metabolic rate via decreased sympathetic tone (J Neurosurg Anesthesiol 2022;34:176-82).
Opioids, despite their analgesic properties, induce a pro-inflammatory and immunosuppressive response in the CNS (Minerva Anestesiol 2015;81:1001-9). In this light, regional anesthesia and multimodal analgesia have opioid-sparing capabilities that further increase their anti-inflammatory properties without significant immunosuppressive effects.
Both regional and neuraxial anesthesia can decrease inflammatory biomarkers, but the evidence is mixed. In a randomized trial, Wongyingsinn and associates demonstrated no significant difference in inflammatory markers when local, spinal, or general anesthesia were utilized for inguinal hernia repair (PLoS One 2020;15:e0242925). They measured levels of IL-6, IL-10, and IL-1beta preoperatively and at eight and 24 hours postoperatively. The levels of all three interleukins increased but there was no difference between the three groups (PLoS One 2020;15:e0242925). This report, again, underplays the role of anesthetics in the inflammatory response.
Peripheral nerve blocks compared with morphine PCA after TKA did show a reduction in pain levels, but measures of IL-1, IL-6, IL-10, and TNF alpha were not different between the groups (Anesthesiology 2008;109:484-90). The use of alpha-2 agonists as adjuvants may decrease cytokine production. Preoperative clonidine along with epidural infusions containing clonidine attenuated the increases in IL-1(RA), IL-6, and IL-8 postoperatively, but IL-1 beta and TNF-alpha were unchanged (Anesth Analg 2004;99:502-9).
There are multiple reasons why these data have not translated to a widespread and uniform clinical interpretation. For one, the inflammatory response is immensely complicated. Advances in understanding inflammatory response of one organ system often do not spell an advance in another system. Inflammatory biochemical pathways are typically organ-specific. For example, cardiac and abdominal surgery can both induce inflammation in the hippocampus, but this inflammation seems to be the result of separate pathways (Anaesthesia 2012;67:280-93). An intervention in one of these pathways may not yield benefits in the other.
Identifying which patients are prone to the debilitating effects of inflammation is a critical part of the discussion. In a meta-analysis of postoperative neurologic dysfunction comparing propofol TIVA to sevoflurane, four of the five studies favored propofol in patients over age 65. The remaining study, which showed no benefit, involved patients between the ages of 37 and 39 years (Anesth Analg 2022;134:69-81).
Likewise, animal models have shown that even minor surgeries can trigger neuroinflammation in older, frail adults, but these same changes were not seen in their younger, more resilient counterparts (Anesth Analg 2019;128:781-8). Of course, some patients bring their own inflammation into the OR in the form of underlying comorbidities such as asthma, auto-immune disease, atherosclerosis, dementia, diabetes, and cancer.
Regional anesthesia modulates both local and systemic inflammatory reactions by various mechanisms. Unfortunately, despite the benefit of postoperative pain relief, there seems to be little influence on major clinical outcomes such as POCD (Minerva Anestesiol 2015;81:1001-9, Anesthesiology 2000;93:858-75).
Even with all the biochemical data in human and animal studies, the impact of anesthesia on the inflammatory response to surgery remains unclear. One study went so far as to conclude that the perioperative inflammatory response depends more on the characteristics of the patient and surgical procedure than the type of anesthesia (Anesth Analg 2022;134:69-81).
But this ignores an important factor: the questionable utility of any intervention limited to the OR. Surgery, along with certain cofactors including age, represents the initiation of inflammation and quite possibly an exacerbation of ongoing inflammatory processes associated with the existing comorbidities. A better definition and description of inflammatory markers and individualized patient management, especially in the situation of auto-immune disease, may aid in the understanding of the inflammatory process associated with both surgery and anesthesia (Minerva Anestesiol 2015;81:1001-9).
Inflammation is a complicated, highly regulated but poorly understood response to injury. It is associated with many comorbidities and may contribute to several postoperative complications. Clinical tools that are available today include frailty scores to identify vulnerable patients, possibly initiating prehabilitation programs, use of ERAS protocols, and opioid-sparing regimens that can improve outcomes (Anesth Analg 2020;130:1524-33).
Inflammation is an ongoing process, and extending postoperative regimens through ICU and hospital stay, as well as weeks to months after surgery, are sorely needed. Given current knowledge, recommendations such as opioid-sparing anesthesia, regional/neuraxial anesthesia, and multimodal anesthesia protocols for the most vulnerable patients are certainly warranted. Further research is needed to understand the biochemistry of inflammation and identify specific interventions that will yield clinical benefits.