Immunopharmacological considerations of general anaesthetics for surgical procedures in the times of COVID-19: Correspondence

Dear Editor, Since its discovery in December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 6.88million deaths andmore than 676million cases of coronavirus disease 2019 (COVID-19) worldwide as of 10 March 2023. Face masks, hand washing, proper sanitation, contact tracing, lockdowns, early confirmatory testing, and fortified medical facilities have all helped to curb the rapid spread of SARS-CoV-2. Despite a worldwide vaccination drive meant to protect communities and promote herd immunity, the virus has not been contained yet. This is mostly attributed to the recurring introduction of novel variants and mutations of SARSCoV-2, which has caused multiple waves, and the current rapid increase in COVID-19 cases, which represents the fourth wave and is primarily attributable to the recently developed Omicron variant. Recent global healthcare systems have been severely impacted by the emergence of COVID-19. The variety of disease severity, prolonged infectious periods, and common clinical symptoms and causation contribute to the difficulty of diagnosis, treatment, and resource allocation. Furthermore, COVID-19 outbreaks have led to significant restrictions on surgical practice and education. In the 12 weeks following the first pandemic surge, more than 28 million surgical procedures were cancelled due to COVID-19 infections, with millions of people awaiting surgical treatment. There is new study that indicates an increased risk of mortality for surgical patients who become infected with COVID-19 within the first six weeks after their operation. The American Society of Anaesthesiologists and the Anaesthesia Patient Safety Foundation have come together to issue a joint recommendation based on the data that is currently available. This recommendation is to delay surgery for 4–12weeks after a diagnosis has been made, with the variable timeline depending on the severity of COVID-19 and vaccination status. COVID-19 primarily not only affects the pulmonary system, but it is also known to cause endothelial dysfunction, vascular inflammation, and sweeping changes in the coagulation cascade. It is believed that all these things contribute to an increase in the risk of developing deep vein thrombosis, pulmonary embolus, and cerebrovascular accident. Moreover, pulmonary problems, cardiac injury, and acute renal injury have been related with cytokine release and localized inflammation. Collectively, these relationships create a substantial potential mortality risk for postoperative patients who have higher inflammatory activation due to surgery. This risk may raise the morbidity and mortality rate among surgery patients. There is evidence that suggests a 30-day mortality rate of 19.1% in elective surgical patients and a 30-day mortality rate of 26.0% in emergency surgical patients. Furthermore, approximately half of patients who underwent surgery while infected with SARSCoV-2 experienced postoperative pulmonary complications. In addition, given the scope of the pandemic, perioperative outcomes following a previous SARS-CoV-2 infection are a major concern, as a considerable number of patients who have been previously infected would require surgery. Infection with SARS-CoV-2 during surgery is associated with a 10-fold increase in short-term mortality. Therefore, it is crucial to minimize the danger of patients entering the hospital while incubating SARS-CoV-2 or contracting the virus in the hospital. This is especially critical for individuals at high risk of severe disease and mortality from COVID-19 including comorbidities. Concurrently, emerging SARS-CoV-2 mutations and subvariants have resulted in the reinstatement of hygienic measures and limitations in several countries all over the world. In addition, having surgery during or close to the time of an active SARS-CoV-2 infection is linked to an increased risk of developing postoperative complications, such as postoperative aDepartment of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, bPRTPP, National Research and Innovation Agency (BRIN), Yogyakarta, cDepartment of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, dMedical Research Unit, eDepartment of Microbiology, fTropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia, gDepartment of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore, hDivision of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India, iMolecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, jCollege of Medicine, Alfaisal University, Riyadh, Saudi Arabia, kDepartment of Public Health and Nutrition, The University of Haripur, Haripur, Pakistan, lDepartment of Pharmacy, BGC Trust University Bangladesh, Chittagong and mDepartment of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh

treatment, and resource allocation [7] . Furthermore, COVID-19 outbreaks have led to significant restrictions on surgical practice and education [8] . In the 12 weeks following the first pandemic surge, more than 28 million surgical procedures were cancelled due to COVID-19 infections [9] , with millions of people awaiting surgical treatment [10] . There is new study that indicates an increased risk of mortality for surgical patients who become infected with COVID-19 within the first six weeks after their operation [10] . The American Society of Anaesthesiologists and the Anaesthesia Patient Safety Foundation have come together to issue a joint recommendation based on the data that is currently available. This recommendation is to delay surgery for 4-12weeks after a diagnosis has been made, with the variable timeline depending on the severity of COVID-19 and vaccination status [11,12] .
COVID-19 primarily not only affects the pulmonary system, but it is also known to cause endothelial dysfunction [13] , vascular inflammation [14] , and sweeping changes in the coagulation cascade [15] . It is believed that all these things contribute to an increase in the risk of developing deep vein thrombosis [16] , pulmonary embolus [17] , and cerebrovascular accident [18][19][20] . Moreover, pulmonary problems, cardiac injury, and acute renal injury have been related with cytokine release and localized inflammation [21,22] . Collectively, these relationships create a substantial potential mortality risk for postoperative patients who have higher inflammatory activation due to surgery. This risk may raise the morbidity and mortality rate among surgery patients. There is evidence that suggests a 30-day mortality rate of 19.1% in elective surgical patients and a 30-day mortality rate of 26.0% in emergency surgical patients [9] . Furthermore, approximately half of patients who underwent surgery while infected with SARS-CoV-2 experienced postoperative pulmonary complications [9] . In addition, given the scope of the pandemic, perioperative outcomes following a previous SARS-CoV-2 infection are a major concern, as a considerable number of patients who have been previously infected would require surgery [10] . Infection with SARS-CoV-2 during surgery is associated with a 10-fold increase in short-term mortality [23] . Therefore, it is crucial to minimize the danger of patients entering the hospital while incubating SARS-CoV-2 or contracting the virus in the hospital. This is especially critical for individuals at high risk of severe disease and mortality from COVID-19 including comorbidities. Concurrently, emerging SARS-CoV-2 mutations and subvariants have resulted in the reinstatement of hygienic measures and limitations in several countries all over the world [24] .
In addition, having surgery during or close to the time of an active SARS-CoV-2 infection is linked to an increased risk of developing postoperative complications, such as postoperative pneumonia [25] , respiratory failure [26] , pulmonary embolism [17] , and sepsis [27] , arrhythmia [28] , renal failure [29] , urinary tract infection [30,31] , and deep vein thrombosis [32] . Surgery conducted between 4 and 8 weeks after a confirmed case of SARS-CoV-2 infection is still associated with an increased risk of the patient acquiring postoperative pneumonia [30] . However, there is no increased risk of developing postoperative problems linked with surgery carried out 8 weeks or later after a confirmed SARS-CoV-2 infection [9] . After a waiting period of 8 weeks from the initial date of confirmed SARS-Cov-2 infection, the patient could have surgery (or the time that likely has less SARS-CoV-2 antibodies in the blood).
Several pharmaceutical preparations are subject for use during surgical procedures. One of those is general anaesthetics. General anaesthetics is a reversible drug-induced sleep-like state, that can generate unconsciousness, amnesia, antinociception, and immobility of the patients, while maintaining their physiological stability [33] . The typically employed general anaesthesia are intravenous and inhaled drugs [34] . The most often used intravenous anaesthetics include propofol, thiopental, ketamine, and etomidate [35] which induce anaesthesia by increasing the efficacy of signalling through the inhibitory gamma-aminobutyric acid A (GABA A ) receptors [36] .
Propofol, a strong intravenous hypnotic/sedative drug, is used as a first-line medicine for the sedation of critically ill patients undergoing intensive care, permitting potentially life-saving invasive interventions such as mechanical ventilation [37] . It exhibits rapid and smooth induction with almost no excitation phenomena, a relatively short context-sensitive time, a rapid terminal half-life, and a low incidence of postoperative nausea and vomiting, making it a highly versatile hypnotic agent. It is utilized for sedation and anaesthesia for nearly all types of surgery but is particularly well-suited for anaesthesia in patients having ambulatory surgery [38] and neurosurgery, where rapid psychomotor recovery is of paramount importance. Its efficacy and utility have also been proven for the sedation of patients in the intensive care unit [39] and conscious sedation of patients undergoing diagnostic or invasive procedures [40] .
Thiopental, the most commonly used barbiturate [35] , is another intravenous anaesthetic administered to intensive care patients, typically for treating patients with refractory status epilepticus or intracranial hypertension [37] . Another intravenous anaesthetic is ketamine hydrochloride, a nonbarbiturate dissociative anaesthetic that swiftly acts and generates profound anaesthesia and analgesia [41][42][43] . Ketamine is an excellent medication for short-term medical treatments that do not require the relaxation of skeletal muscles. It is used for general anaesthesia induction as a pre-anaesthetic to other general anaesthetic drugs [44][45][46] . Etomidate, a nonbarbiturate hypnotic with a very short half-life, is commonly used to induce anaesthesia in intensive care unit patients due to its acceptable hemodynamic profile and quick onset. The advantage of etomidate is that it reduces the risk of induction hypotension, which can lead to coronary hypoperfusion, dysrhythmia, and cardiac arrest. Etomidate, on the other hand, lowers adrenocortical activity by inhibiting 11hydroxylase [47] . Even though etomidate has some adverse side effects (such as adrenal cortex inhibition, hiccup, myoclonus, injection pain, nausea, and vomiting), it is still a good choice for critically ill patients because of its positive properties (such as its rapid onset, short duration, stable cardiovascular profile, minimal respiratory depression, improved endotracheal intubation conditions, lack of histamine release, and rarity of allergic reactions) [48][49][50][51][52] .
Inhaled anaesthetics or volatile anaesthetics can be used to administer general anaesthesia to a patient undergoing surgery [53,54] . In addition, volatile anaesthetics produce their effects rapidly. The majority of individuals who are sedated by these medicines recover swiftly and easily. Using contemporary equipment, their concentrations can be precisely checked, and their application is quite simple. In clinical practice, volatile anaesthetics have been widely utilized for these reasons [54] . In the United States, modern volatile anaesthetics include isoflurane, sevoflurane, and desflurane [54] . Halothane was used in clinical settings for more than 40 years, but it was replaced by newer volatile anaesthetics in the 1990s [55] . Inhalation anaesthetics are used to initiate and maintain general anaesthesia in the operating room. The volatile anaesthetics (halothane, isoflurane, desflurane, and sevoflurane) are liquids at room temperature and must be administered using vaporizers. All inhalational anaesthetics cause amnesia and immobility, except for nitrous oxide, which also relieves pain. Inhaled anaesthetics are often used along with intravenous anaesthetics. In the intensive care unit, inhaled anaesthetics are mostly used for sedation, refractory bronchospasm, and control of status epilepticus that is unresponsive to anticonvulsant medicines [56] . To execute anaesthetic effects, volatile anaesthetics target certain central nervous system receptors, such as the neuronal GABA A receptor, N-methyl-D-aspartate (NMDA) receptor, and glutamate receptor subtypes [57] . Anaesthetic drugs have been reported able to modify immune function, which has the potential for considerable implications on perioperative infections and surgical outcomes [58] . Several studies have shown the immunosuppressive effect of anaesthetic drugs. For instance, propofol has a mixed effect on innate immune system cells, particularly macrophages and natural killer (NK) cells. Propofol inhibits mouse macrophage chemotaxis and oxidative capacity, as well as the synthesis of ATP and interferonγ [59] . There is evidence that it may be less toxic to NK cells, which is significant for cancer patients undergoing anaesthesia because NK cells are known to have antiviral and anticancer properties [60,61] . In a rat model, unlike halothane and ketamine, propofol did not inhibit NK cells or promote metastases [60] . Further research on a human cell model revealed that propofol does not reduce the cytotoxicity caused by NK cells (like sevoflurane and isoflurane did by inhibiting LFA-1) [61] . This indicates that while propofol suppresses macrophage activity, its influence on NK cells may be advantageous in the perioperative treatment of viral and neoplastic conditions. Another general anaesthetics, etomidate, can suppress cellmediated innate immunity by inhibiting the chemotaxis of eosinophils in vitro [62] . Etomidate may potentially have a negative impact on the adaptive immune system. In rats with sepsis treated with etomidate, there was an increase in lymphocyte apoptosis [63] . In addition, in-vitro measurements of phytohaemagglutinin-stimulated lymphocyte proliferation revealed that typical clinical plasma concentrations of etomidate depressed total T-lymphocyte populations [64] . Ketamine possesses anti-inflammatory and immunosuppressive effects, which are mediated by the innate and adaptive immune systems. In rats and humans, ketamine inhibited neutrophil chemotaxis by decreasing the expression of endothelium adhesion molecules. The generation of superoxide free-radical was blocked through decreased phosphorylation of the NADPH oxidase enzyme complex [65] . Ketamine was found to inhibit the differentiation of monocytes into immature dendritic cells (DCs) via an NMDA-dependent and transforming growth factor beta (TGF)-dependent mechanism. DCs are members of the innate immune system and play a critical role in antigen presentation for adaptive T-cell function [65] . At therapeutically relevant doses, dexmedetomidine had no effect on neutrophil chemotaxis, phagocytosis, or superoxide generation [66] .
The majority of volatile anaesthetics bind to the receptors located in the central nervous system ("canonical targets") in order to generate anaesthesia. These receptors include γ-aminobutyric acid type A (GABAA) receptor, NMDA receptor and twopore-domain K + (K2P) channel [67] . In addition to canonical target molecules, volatile anaesthetics also target TLR2, TLR4, LFA-1, Mac-1, and Rap1 ("non-canonical targets") on immune cells, which may suppress the functions of neutrophils, monocytes, and macrophages [68] . Neutrophils and macrophages both generate a variety of cytokines. A broad range of neutrophil receptors, including GPCRs, FcRs, Mac-1, and TLRs, induce cytokine production [69] . Among them, Mac-1, TLR2, and TLR4 are targets of volatile anaesthetics [68] . Volatile anaesthetics influence blood cytokine levels and reduce proinflammatory cytokine concentrations [70] . Extended isoflurane exposure was related to poor neutrophil recruitment and bacterial phagocytosis via the reduced activity of leucocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), which are important adhesion molecules on leucocytes [71] . The usage of volatile anaesthetics has been directly connected to decreased phagocytic activity and chemotaxis. For instance, isoflurane decreases the ability of phagocytes to ingest opsonized and non-opsonized particles in a time-dependent manner [72] . Via dose-dependent actions, sevoflurane and desflurane promote apoptosis of thymus T cells, and desflurane induces apoptosis of B lymphocytes by activating IP3 (inositol triphosphate) [67,72] , which may contribute to immunological suppression after surgical procedures.
Opioids, with morphine being the most thoroughly researched, can yield immunosuppressive effects. Opioids inhibit NK cell cytotoxicity, reduce macrophage-mediated and neutrophilmediated phagocytosis, inhibit the generation of reactive oxygen species by neutrophil, and downregulate cytokine synthesis [73,74] . Additional opioids-induced phenotypical characteristics such as less production of chemokine by neutrophils, reduced antigen presentation by DCs, and increased permeability of the intestinal barrier have also been reported [73,75] . Regarding the adaptive immunity, it has been demonstrated that opioids induce apoptosis, impede immune cell proliferation, and inhibit T-cell-mediated adaptive responses [73,74] . Moreover, B lymphocyte effector response is diminished and Th1 cell death and Th2 differentiation are increased, which further impaired host ability in the pathogen clearance [73,75] . Overall, the inhibition of the immune system by anaesthetic medications may facilitate perioperative infections and may significantly affect post-surgical outcomes.
In conclusion, relevant evidence indicated that certain general anaesthetics may exert suppressive effects on the innate and adaptive immune responses, leaving patients vulnerable to SARS-CoV-2 infection during surgery. In light of such evidence, highest level of precaution shall be taken to prevent exacerbations of infection during and after the application of general anaesthetics. This is important to achieve the best outcome in the medical-surgical interventions amid the absence of alternative medications with better pharmacological properties but less immunosuppressive side effects.

Ethical approval
The authors declare no involvement of animal studies or human participants in the study as it is a correspondence article.

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This research did not receive any specific grant from funding agencies.

Conflicts of interest disclosure
All authors declare that there is no exist of commercial or financial relationship that could, in any way, lead to a potential conflict of interest.