Since the Taiwan Society of Anesthesiologists (TSA) declared anesthesia safety to be a major focus, many types of quality assurance checklists and feedback systems have been put in place in medical institutions. However, quality assurance alone does not provide a plausible explanation or resolution for the rate of delayed postoperative mortality that is much higher than that observed in the first few weeks after operation.¹ This long-term effect seems to be strongly associated with perioperative immune events influenced by anesthesia and surgery such as psychological stress, tissue injury, hypothermia, anesthetics, transfusion and pain. Both inflammation and immune suppression which concurrently emerge perioperatively puzzle many clinical anesthesiologists and need to be delineated in order to minimize the long-term risk.

As traumas or surgical procedures break through the anatomic and physiologic barriers, both tissue injury and infection develop. The acute inflammation derived from innate immunity is first initiated by the tissue residential macrophages, mast cells and dendritic cells, and circulating neutrophils are then recruited for the engagement.² In aseptic tissue injury, the inflammation is initiated by the components released from the broken cells such as cellular and mitochondrial debris, heat shock proteins, and the transcription factor high mobility group I protein (HMGB1).² The severity of inflammation is correlated with the degree of tissue injury and the length of surgery.³ Thus, a patient who undergoes surgery is in a complex situation of high mobilization of catecholamines, inflammation and procoagulation, which may actually dominate the progress of recovery from tissue injury and, to a further extent, the longer-term outcome after surgery. Examples of the relationship between disease progression and severity of inflammation have been demonstrated, such as coronary plaque vulnerability, which is related more to the inflammatory activity inside the plaque than to the size of the plaque per se.⁴ Therefore, the incidence of postoperative plaque rupture may be connected with the quality of perioperative care, principally focused on the control of host responses during anesthesia. Although the causative relationship between related postoperative mortality or morbidity and the quality of anesthesia cannot be firmly established at this moment, this concept no doubt has enlightened anesthesiologists on the seemingly eccentric but innovative theme for study, which needs the devotion of many researchers to accumulate evidence, either from animal or clinical studies, to elucidate the complex events.

The genetic factors seem to obscure the multiple immunological interactions. It has been demonstrated that patients with polymorphisms in
interleukin-6 (-174G/C) and C-reactive protein (3UTR1846C/T) have a three-fold higher incidence of stroke after cardiac surgery.⁵ Furthermore, patients with a polymorphism in tumor necrosis factor-α, which has been shown to enhance the inflammatory response, are subsequently subjected to higher morbidity after cardiopulmonary bypass.⁶ Other geneticvariants have also been suggested to be relevant
to morbidity and severity of inflammation postoperatively, such as CCR5, leukocyte antigens, tolllike receptors (TLR), and mannose-binding lectin.⁷⁻⁹An interesting example is that profound hypercytokinemia and resultant mortality were observed in mice with lipopolysaccharide challenge, the mechanism of which was mediated by TLR4 overactivity enhanced by thermal injury.¹⁰⁻¹² Therefore, immunogenetics and pharmacogenomics are becoming the novel issues that TSA members should pay attention to in the next decade.

Evidently, both surgery and anesthesia share the responsibility of causing immune paralysis perioperatively, and anesthetic procedures play an essential role in these immunosuppressive effects. In brief, volatile anesthetics and the intravenous anesthetic, propofol, may contribute to a decrease in inducible nitric oxide synthase expression and nitric oxide production in macrophages.^13,14 Studies have demonstrated that volatile anesthetics suppressed cytotoxicity in natural killer cells, induced apoptosis or suppressed the normal biological functions and trafficking in lymphocytes.¹⁵⁻¹⁸ These immunosuppressive effects may predispose patients to acute or chronic inflammatory diseases such as arthrosclerosis, diabetes, myocardial infarction, thromboembolic events, stroke, infection, multiorgan failure, cognitive defect and even tumor recurrence or metastasis since the immune system is impaired perioperatively. In this June issue of the Journal, Dr. Li’s study demonstrated that platelets primed with lidocaine decreased P-selectin expression and platelet−leukocyte aggregations.¹⁹ It is clear that P-selectin is released from the granules and expressed on the surface upon platelet activation, and platelet−leukocyte aggregation has also been speculated to be a critical event in several inflammatory diseases such as atherosclerosis. Our laboratory has also demonstrated that levobupivacaine exerts similar suppressive effects on platelets via multiple target sites such as p38 MAPK, protein kinase C (PKC) δ subtype, cytosolic phospholipase A₂ (cPLA₂), and Akt, but not Gαq as suggested previously (submitted manuscript). Therefore, it is intriguing to further investigate how the volatile agents affect platelet functions, the subsequent influence on the immune responses, and the long-term results postoperatively.

Recent published data have confirmed that platelets are not only members of the coagulation system but they also play a pivotal role in promoting immune responses and initiating inflammation.^20,21 The immunological properties of platelets considered to be proinflammatory are based on two major events. The first well known function is to release the stored biological active mediators from their granules to promote inflammation, such as the CD40- dependent release of RANTES, which conjugates endothelium surface and recruits T lymphocytes to the site of inflammation.²² Other striking findings were receptor-mediated cross-talk between platelets and different immunocytes, including platelet− neutrophil aggregation in reperfusion injury,^23,24 rosette formation of platelet−macrophage/monocyte in atherosclerosis,^25,26 and platelet−T lymphocyte in other inflammation models. Several pathways have been suggested to be involved in platelet−leukocyte cross-talk, such as P-selectin-PSGL/CD15,^27,28 CD40-CD40L,²² GPIb-CD11b,²⁹ GPIIb/IIIa-CD11/CD18²⁷ and CD36-thrombospondin.²⁶ Moreover, it has been found that CD4⁺ T cells^30,31 are essential to the reperfusion-induced inflammation and natural killer T cells³² could be the most important lineage to initiate the early event of reperfusion-induced inflammation. Thus, the CD40-mediated RANTES release and platelet−T cell cross-talk could be a novel pathway for amplification and turn the initial trivial proinflammatory signals to create subsequent full development of inflammation. Therefore, we believe that platelets are a critical proinflammatory lineage in initiating inflammation by cross-talk with CD4⁺ T lymphocytes. Our laboratory is also devoted to investigating the role of each receptor-mediated platelet−T lymphocyte cross-talk in the early event of inflammation by a handful of genetic rendered mouse models. In addition, the soluble factors generated during the inflammatory process will further augment the stress responses and activate the coagulation system perioperatively³³ and thus may have a prominent influence on patients’ long-term outcome.

Taken together, it is highly possible that the quality of anesthesia and surgery has an impact on the delayed mortality and morbidity rates. Although suitable animal models and a large number of studies are still needed to elucidate this causative relationship, the present evidence indicates that it would be prudent to be alert to the complicated multiple immunological interactions during operation. We should make great efforts in our daily clinical service to control the host immune responses and subsequently improve the overall quality of surgical therapy. To achieve the goal of controlling and minimizing both the acute inflammations and host responses, it is important to integrate the knowledge of modern molecular immunology and anesthesiology with the molecular mechanisms of diseases. In addition, we should improve the risk of stratification of disorders preoperatively such as glucose and blood pressure control, perioperative opioids, beta-blockers and clonidine preemptive therapies, and reduce the stress responses during the perioperative period with evidence-based risk-reducing therapies, minimize the variation in metabolic and physiologic parameters during operation, and ensure that all patients enjoy well-qualified postoperative pain control. While these points are well-known to TSA members in theory, they are not often applied in actual practice. It is therefore important to reemphasize that the quality of anesthetic management is relevant not only to immediate postoperative morbidity but also to the long-term outcome. A high standard of anesthesia practice should be defined for anesthesiologists under the patronage of the TSA, and we should continue to search for better ways to improve the quality of our patients’ lives.

Yuan-Ji Day, MD, PhD

Physician Scientist Program

Transgenic & Molecular Immunogenetics Laboratory

Associate Professor, Department of Anesthesiology,

Chang Gung Memorial Hospital

Associate Professor, Institute of Clinical Medical Science,

Chang Gung University

Associate Editor, Acta Anaesthesiologica Taiwanica