Anaesthesia and the immune response

4 Anaesthesia and the immune response LESLIE G U N Z E N H A E U S E R GIRISH C. M O U G D I L ALIX M A T H I E U

It has been long suspected that surgery and anaesthesia may render an individual prone to infection in the perioperative period. Although a wide variety of factors may contribute towards the pathogenesis of perioperative infection, in the final analysis it is a depression of the immune response that allows an invading organism to become established. Therefore, it is important to assess the influence of different anaesthetic agents on various aspects of the immune response. A clearer understanding of anaesthesia-induced suppression of the immune response should facilitate a further decrease in morbidity and mortality from perioperative infection, tumour growth and dispersal of malignant cells.

THE IMMUNE RESPONSE The ability of the host to recognize, specifically memorize and subsequently defend against any 'foreign molecules', 'antigens' or the 'non-self' forms the basis of the immune response. This ability to protect the host against 'non-self' involves both the 'non-specific' and the 'specific' components of the cellular and the humoral.immunity.

Non-specific immunity The 'non-specific' or 'innate' immunity is genetically determined and each individual is born with it. It forms the first line of defence against infection, and does not require a prior memory of exposure to the offending organism, antigen or foreign molecule. Upon appropriate antigenic stimulation, granulocytes and macrophages exhibit enhanced chemotactic migration as well as avid phagocytic and bactericidal activities. Additionally the activation of the properdin and complement systems along with the liberation of enzymes such as lysozymes results in a quick demise of the invading organisms. The enhanced capillary permeability, migration of monocytes and macrophages, phagocytosis and liberation of bactericidal enzymes result in the establishment of an inflammatory reaction. Bailli~re's Clinical Anaesthesiology--

Vol. 5, No. 1, June 1991 ISBN0-7020-1524-5

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Specific immunity The 'specific' or 'acquired' immunity is an adaptive response requiring an earlier memory of exposure to the foreign substance or the antigen. Following phagocytosis, digestion and processing by macrophages the information concerning the antigen is presented to the small lymphocytes, cells that play a key role in the immune response. On an anatomical and functional basis lymphocytes are subclassified into thymus-dependent or T lymphocytes, and bursa-dependent or B lymphocytes (Roitt, 1980).

B lymphocytes B lymphocytes are concerned with the synthesis of circulating antibody and are fundamental to the humoral component of the immune response. Following antigenic stimulation, the B cells are activated and transformed into plasma cells capable of producing various types of immunoglobulins against the circulating antigen. These circulating antibodies can confer humoral immunity that may be passively transferred from the mother to the offspring. B-cell recognition of the antigen in blood, lymph or on the surfaces of the infected cells also results in rapid lymphoproliferation and production of an enlarged clone of B cells, all bearing antibody molecules on the cell membranes that act as specific receptors for the antigen. Other longer-lived B cells carry an antigen-specific memory and forestall recurrence of infections by mounting a swift response when challenged by the antigen again.

T lymphocytes T lymphocytes are thus called because they are processed by (or are in some way dependent upon) the thymus gland for their maturation. These cells do not produce antibody and are responsible only for the cell-mediated immune response. Furthermore, most T cells cannot recognize free antigen circulating in the blood or the lymph. They may respond to the antigen on a cell surface only if the foreign substance is displayed in conjunction with one of the host cell's own proteins, i.e. molecules coded for by the segment of DNA making up the major histocompatibility complex (MHC). Therefore, for the induction of the cell-mediated immune response the T cells must simultaneously recognize the antigen and the MHC protein. On stimulation by appropriate antigens, T cells transform into lymphoblasts, undergo proliferation, and perform functions that depend upon their subclass. An antigen or its equivalent upon entry into the body sets in motion a series of events in which the antigen is processed by monocytes and macrophages and presented to the T lymphocytes (Cantor, 1984). The monocytes secrete interleukin 1, which serves to activate the T cells and also induces the expression of receptors for the T cell-derived lymphokine interleukin 2 (Dinarello, 1984). T cells secrete interleukin 2 which serves an autocrine function and an immunoregulatory function for other cell types. Under the influence of interleukin 2, T lymphocytes proliferate and differentiate into

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subsets of cells which have direct helper, suppressor, suppressor-inducer and cytotoxic functions. T cells also secrete other lymphokines such as interferon gamma, which activates monocytes and macrophages to undertake tumoricidal and microbicidal functions (Griffin, 1982). In addition, interferon gamma also activates cytotoxic T cells and antibody-producing B cells (Lethi and Fauci, 1986). Interleukin 2 may also directly induce natural killer (NK) cells to exhibit cytotoxic function. Only the cytotoxic T cells, which destroy infected, foreign or malignant cells, actively defend the body. The other subclasses of T cells modulate the immune response by secreting messenger proteins or by direct contact with other cells. On the basis of function, four subsets of T cells have been recognized; however, on the basis of biochemical markers on their surfaces there are only two main kinds: T4 cells that have helper and inducer roles, and T8 cells that possess cytotoxic and suppressor inducer roles. T4 helper cells. These cells facilitate the activities of other T and B cells and bear the T4 biochemical markers on their surfaces. They respond to antigen in association with class II MHC proteins, which are primarily found on the surface of antigen presenting cells. Following recognition of a specific antigen, these cells enable T-cell cytotoxic activity and B-cell antibody production. They also help release lymphokines and a mounting of the delayed hypersensitivity response. T4 inducer cells. Inducer T cells trigger the maturation of T lymphocytes from their precursor forms into functionally distinct and competent cells. T8 cytotoxic T cells. These cells actively defend the body and possess specific cytotoxic ability that can lyse foreign cells, infected and malignant cells. These cells bear the T8 surface markers and recognize the antigen in conjunction with only ctass I MHC proteins. T8 suppressor cells. These cells fine-tune the immune response by dampening the T and B antibody synthesis by B cells, and also exert a suppressor effect on the T-cell cytotoxicity. In addition to T and B lymphocytes, other major factors in the immune response are: Killer cells

Killer or K cells are lymphocytes that do not bear either T or B cell surface markers but have a great affinity for, and will lyse target cells coated with specific antibodies. Natural killer cells

Natural killer (NK) cells also do not have specific surface markers and represent only a peripheral arm of the immune system. However, they possess the ability to kill virus-infected cells and tumour cells without interacting with lymphocytes or recognizing antigens. These cells are

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probably regulated by suppressor cells and they do not attack normal cells. Although the T and B lymphocytes specifically participate in either the cellular or the humoral components of the immune response, their activities are always interrelated with each other and other cell types which allow amplification and regulation of the various components of the host defence systems. ANAESTHESIA AND THE IMMUNE RESPONSE

The concept that anaesthesia may alter the course of an infection by modifying the immune response has been under consideration for almost a century. As early as 1903, Snell reported that ether, chloroform and chloral hydrate increased the mortality from anthrax in guinea-pigs (Snell, 1903). Rubin (1904) made similar observations in rabbits infected with streptococci and exposed to ether or chloroform. The evidence reviewed in more recent literature also supports the concept that anaesthesia can adversely affect different components of the cellular and humoral immune response (Moudgil and Wade, 1976; Ryhanen, 1977; Walton, 1978; Duncan et al, 1982; Kehlet et al, 1982). Anaesthesia and leucocyte chemotactic migration

The mobilization of granulocytes, macrophages and other phagocytic cell towards the inflamed and injured tissues is one of the earliest events in the body's defence against infection. Any depression of this directional locomotion is likely to allow the invading organisms to become established in the tissues and thereby enhance the incidence of infection. Therefore several workers have investigated the effects of different anaesthetic agents on leucocyte migration. Initially, a reversible dose-dependent inhibition of random locomotion of Tetrahymena pyriformis and human lymphocytes following exposure to halothane was observed by Nunn et al (1968, 1970). By using modified Boyden's chambers (where the directional migration of the cells across a micropore filter was measured), Moudgil et al (1977) reported a dose-dependent depression of chemotactic migration by local, intravenous and inhalational anaesthetic agents. This depression also occurred at clinical concentrations of the anaesthetic agents; it was short-lived and reversible. A similar inhibition of leucocyte locomotion under the influence of intravenous anaesthetic agents has also been observed in vitro by others more recently (Mathieu et al, 1979). Additionally, Mathieu also reported a significant depression of leucocyte migration with 1.4% halothane only, while enflurane appeared to have either no effect or enhanced migration (Mathieu and Mathieu, 1980). Likewise, an inhibition of leucocyte migration in the postoperative period was reported by Stanley et al (1976) and subsequently confirmed by Moudgil et al (1981) in patients having surgery under general anaesthesia. In contrast, in vitro studies by Duncan and Cullen (1977) and Nunn et al (1979) failed to reveal a depression of chemotactic migration by thiopentone or halothane. In order to clarify these

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contradictory findings, Moudgil et al (1984) investigated the effects of equipotent concentrations of different volatile anaesthetic agents and 70% nitrous oxide on polymorph and monocyte chemotactic migration. These investigations revealed that, after exposure to 1 MAC (minimum alveolar concentration) of various anaesthetic agents, the degree of depression of chemotactic migration varied with different anaesthetic agents. With the exception of nitrous oxide, this severity of depression paralleled the lipid solubility of the anaesthetic agent. Both the neutrophil and the monocyte chemotactic migration were least affected by isoflurane and most affected by methoxyflurane and 70% nitrous oxide. Narcotics, including morphine, fentanyl and pethidine (meperidine), have also been demonstrated to have inhibitory effects on chemotaxis (Mathieu et al, 1979). In addition, the agonist-antagonist narcotic agents nalbuphine and butorphanol have also been incriminated in inhibitory activity (Mathieu et al, 1980). Muscle relaxants have also been studied with regard to chemotaxis; Mathieu and Mathieu (1980) demonstrated that pancuronium and curare inhibit chemotaxis, while gallamine and suxamethonium (succinylcholine) actually increase movement, but these effects were seen at generally higher than clinical concentrations. In summary, although many anaesthetic agents have been shown to interfere with chemotaxis, other studies have disputed these observations. The consensus at present is that anaesthetic agents cause a short-term, reversible depression of chemotactic migration. The mechanisms whereby anaesthetic agents induce an inhibition of chemotactic migration remain yet to be defined and need further exploration. However, any depression of chemotactic migration could be clinically relevant in relation to perioperative infection. Anaesthesia and phagocytosis

In order to combat an infection effectively, an intact phagocytic function is essential. Several human and animal studies have investigated the effects of different anaesthetic agents on the phagocytic activity of neutrophils and macrophages. At the turn of the century it was shown that ether and chloroform produced a dose-dependent inhibition of phagocytosis in animals (Hamburger, 1916). Similarly, a reduction in the number of Salmonella bacteria ingested by peritoneal neutrophils after halothane anaesthesia in mice has been reported (Bruce, 1967). Previous human studies after either halothane or nitrous oxide narcotic anaesthesia without surgery revealed a decrease in phagocytosis of latex particles and nitroblue tetrazolium (NBT) reduction in one instance, but showed only a minimal inhibition in another, after 0.5-2.5% halothane or 80% nitrous oxide (Cullen, 1974). More recently, both halothane and enflurane were shown to depress the 'phagocytic capacity' in a dose-dependent manner both in vivo and in vitro (Lippa et al, 1983). Similarly, the metabolic activity of the phagocytic cells, as assessed by NBT reduction, was depressed postoperatively for several days following surgery under halothane anaesthesia but not with neuroleptanaesthesia or extradural blockade (Bardosi and Tekeres,

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1985). Coronary artery bypass surgery under high-dose fentanyl anaesthesia was also shown to inhibit the oxidative mechanism of phagocytically activated granulocytes as measured by chemiluminescence, suggesting a depression of phagocytosis that lasted up to the fourth postoperative day (Perttila et al, 1986). In addition to the effects of volatile anaesthetic agents, another study investigated the effects of premedicants, intravenous induction and local anaesthetic agents on the human leucocyte phagocytic activity in vitro (Moudgil, 1981). This study revealed a dose-dependent, statistically significant depression of phagocytic activity following exposure in vitro to varying concentrations of intravenous induction agents, narcotics and local anaesthetic agents. These observations were not the result of a non-specific drug concentration effect, since equimolar concentrations of the other non-anaesthetic drugs investigated failed to produce a depression of phagocytosis. Thus, it would appear that several anaesthetic agents may potentially enhance the risk of perioperative infection by reducing the phagocytic activity. This depression may be further compounded by surgical intervention per se, since several other studies have shown leucocyte phagocytic function to be impaired by the stress of surgery and anaesthesia in humans and in animals (Hole, 1984; Bardosi and Tekeres, 1985; Barth et al, 1987). However, contradictory data showing no change in leucocyte functional activities have also been reported (Cullen, 1974; Heberer et al, 1985; Knudsen et al, 1987).

Anaesthesia and bactericidal activity The ability of anaesthetic agents to impair neutrophil microbicidal activity both in vitro and in vivo has been reviewed recently (Welch, 1986). Earlier studies utilized NBT reduction as an index of microbicidal activity. More recently, utilizing the technique of chemiluminescence, a highly sensitive indicator of neutrophil oxidative microbicidal activity (Welch, 1980), where the light emission by the highly reactive and excited oxygen radical is evaluated, it was shown that only enflurane (not isoflurane) inhibited the bactericidal activity (Welch and Zaccari, 1981). Similar observations of inhibition were also made following exposure to halothane (Welch, 1981). The production of H2Oz which is necessary for microbicidal activity, was also reported to have decreased following monocyte exposure to halothane (Stevenson et al, 1987), while concomitant exposure to interferon alpha had a protective effect. Nakagawara et al (1986) have conclusively shown a reversible inhibition of OF production by human neutrophils following exposure to halothane, and to a lesser extent enflurane, while isoflurane had the minimal effect at clinically relevant concentrations. These authors further demonstrated that neutrophils exposed to halothane, enflurane and isoflurane have a decreased entry of Ca 2+ from an extracellular milieu with a resultant decrease in intraceUular Ca 2+ levels, thus causing an anaestheticinduced inhibition of neutrophil OF production (Nakagawara et al, 1986). By measuring the superoxide-produced chemiluminescence, a dosedependent depression of bactericidal activity was also reported with

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thiopentone and Althesin however, methohexitone, morphine, diazepam and lignocaine (lidocaine) failed to produce similar effects (White et al, 1983). All these investigations suggest that the impairment of neutrophil oxidative function or failure of granule phagosome fusion by volatile and other anaesthetic agents may compromise host resistance during surgery. Therefore, patients requiring prolonged periods of surgical anaesthesia and who are already immunocompromised before surgery may require extra prophylaxis and care during such operations in order to decrease the incidence of perioperative infections.

Anaesthesia and lymphocyte function

The ability of the peripheral blood lymphocytes to proliferate in response to a mitogen such as phytohaemagglutinin (PHA) or an alloantigen is a recognized correlate of cell-mediated immunity. Similarly, lymphocyte cytotoxicity and T helper/suppressor (T4/T8) cell ratios are utilized to assess the immunocompetence of cell-mediated immunity. Additionally, the NK lymphocytes, because of their ability to recognize and kill tumour cells without processing the tumour-specific antigens, are thought to form a primary immune defence mechanism against the development of tumours. Several studies have shown that the combination of surgery and anaesthesia can depress the lymphocyte function (Riddle, 1967; Walton, 1978), and the severity of depression of lymphocyte function can be further correlated with the degree of surgical stress (Cullen et al, 1976). In concert with the known effects of stress on the immune response, various psychoneural factors have also been shown to have an adverse effect on the immune system (Udelman and Utdeman, 1983). In a recent study it was shown that endogenous opiates ~-endorphin, dynorphin and methionine-enkephalin caused a reduction in vitro of NK cell activity as well as antigen-specific cytolysis (Prete et al, 1986). Likewise, the splenic NK cell activity of rats was suppressed following a foot shock stress that caused an activation of opioid mechanisms. A similar suppression of NK cell activity could also be induced by high doses of morphine. This opioid-induced suppression could be blocked by the antagonist naltrexone (Shavit et al, 1984). These immunosuppressive effects of morphine would appear to be mediated by opiate receptors in the brain, since NK cell activity was unaffected by administration of n-methylmorphine (codeine), a morphine analogue that does not cross the blood-brain barrier (Shavit et al, 1986). These direct effects of opiates on the cytolytic T cell and NK cell function may provide a link between stress and disease susceptibility. Since opiates and their analogues are widely used as premedicants, there is an inherent danger of inducing immunosuppression following the use of these agents. With regard to the effects of inhalational anaesthetic agents on the lymphocyte function, experimental evidence is not entirely conclusive. Lymphocyte exposure to halothane produced a decrease in mitogeninduced lymphoproliferation in vitro at concentrations found during clinical anaesthesia; however, a prolonged exposure was required to observe this

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effect (Bruce, 1976). Similarly, cell-mediated cytotoxicity, an important defence against malignant cells, was also inhibited following exposure in vitro to 1% or 2.5% halothane (Cullen et al, 1976). Addition of several anaesthetic agents to the lymphocyte cultures simultaneously produced additive effects; 1% halothane and thiopentone (14txg/ml) inhibited cytotoxicity reaction by 20-21% separately, but when added simultaneously to the cultures caused a 45% inhibition (Duncan et al, 1977). A dosedependent, reversible inhibition in vitro of human NK cell cytotoxicity under the influence of halothane, enflurane and nitrous oxide has also been reported in one study (Woods and Griffith, 1986) and the finding corroborated in another (Griffith and Kamath, 1986). The intravenous induction agent thiopentone was also seen to inhibit lymphocytotoxicity reaction at peak concentrations found during the induction of anaesthesia, as well as to decrease PHA-induced lymphoproliferation at higher concentrations of the agent (Park et al, 1971). Ketamine, droperidol or lignocaine did not affect lymphocyte transformation at clinical concentrations, but were able to cause a depression at much higher concentrations (Watkins and Matti, 1982). Thus, it is clear that anaesthetic agents in vitro cause a depression of mitogenic lymphoproliferation, as well as lymphocyte and NK cell cytotoxicity. This depression, however, appears to be short-lived and reversible. The studies of the effects of clinical anaesthesia on human lymphocytes have yielded differing opinions. While halothane and enfturane anaesthesia for 5-7 hours duration, in healthy volunteers, had no effect on the PHA-induced lymphoproliferation in one study, a significant decrease in mitogen and alloantigen-induced lymphoproliferation after anaesthesia with halothane, nitrous oxide and oxygen for only 3 hours was observed in another (Doenicke et al, 1981). In contrast to the depression observed with halothane, balanced anaesthesia using a narcotic/relaxant technique failed to produce a depression of PHAinduced lymphocyte responses (Salo, 1977, 1978). In a recent unpublished study of surgical patients by Moudgil and Singal it was observed that halothane but not isoflurane anaesthesia inhibited PHA-induced lymphoproliferation in the postoperative period. The effects of regional versus general anaesthesia on the immune response have also been investigated. A significant reduction of lymphoproliferation in response to mitogens and histocompatibility alloantigens in mixed lymphocyte cultures was observed in patients having transurethral prostatic resection under general anaesthesia, whereas only minimal changes were seen when surgery was performed under spinal anaesthesia (Whelan and Morris, 1982). Similarly, NK cell activity was significantly depressed in women undergoing caesarean section under general anaesthesia compared with those receiving epidural anaesthesia (Ryhanen et al, 1985). A depression of monocyte-mediated cytolysis and mitogen-induced lymphoproliferation by sera obtained from patients having general anaesthesia but not epidural anaesthesia has also been reported (Hole, 1984). These and other studies would indicate that in comparison with general anaesthesia, surgery under regional anaesthesia does not produce a suppression of cell-mediated immunity.

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Anaesthesia and humoral antibody production

Reports on the effects of anaesthesia on humoral immunity in humans are meagre, with inconclusive results. Although a slight decrease of immunoglobulin concentrations in the postoperative period has been reported (Cohnen, 1972), there is no firm evidence that anaesthesia alters the production, functional activity or levels of immunoglobulin in the perioperative period. The postoperative slight decrease in immunoglobulin levels is predominantly due to protein loss from the intravascular space and not to anaesthesia p e r se. Since the half-life of serum immunoglobulins is long, i.e. 2.4 days (IgE) to 21 days (IgG), transitory disturbances in immunoglobulin production are unlikely to be reflected in serum concentrations. However, a decrease of immunoglobulin plaque-forming cells has been reported following open heart surgery (Salo et al, 1981; Eskola et al, 1984). Stevenson and colleagues (1986) found no significant change from controls with in vitro studies of halothane exposure and B-lymphocyte humoral function. When evaluating the effect of anaesthetic agents on humoral immunity, the effect of surgical stress on immunoglobulin production must again be considered. Cohnen (1972) and Eskola et al (1984) concluded that suppression of antibody production correlated with the severity of surgical trauma, and found IgG to be particularly depressed, while IgM levels increased. Ferrero and colleagues looked at the effect of halothane on lymphocytes, finding reduced capping of surface immunoglobulins after the lymphocytes were exposed to a 1% concentration of the volatile gas (Ferrero et al, 1986). The capping phenomenon is a cell surface antigen-antibody reaction, believed to be the initial step in lymphocytic activation. Stevenson and his colleagues, however, found no difference from controls in the proliferative response to halothane-exposed lymphocytes (Stevenson et al, 1986). A number of studies in vivo have shown decreased numbers of circulatory B lymphocytes and decreases in B-cell mitogen responses with surgery (Kehlet et al, 1977; Kurtz et al, 1983; Mollitt et al, 1984; Purl et al, 1984). However, few studies have attempted to differentiate between the effect of anaesthesia and that of the surgery itself on this depression. On the basis of animal experiments and measurements made after battle injuries, it would appear that antibody production remains unaltered after surgery and anaesthesia. Anaesthesia and infection

It is difficult to ascertain the precise role of anaesthesia in the pathogenesis of perioperative infection since several factors contribute towards it. However, several animal studies have shown that anaesthetic intervention alone may alter the course of an infection. Halothane anaesthesia has been shown to increase the mortality from salmonella infection in mice in one study (Moudgil et al, 1981), and double the mortality from faecal peritonitis in another (Duncan et al, 1976). Halothane anaesthesia for 2 hours was also reported to have increased mortality from murine hepatitis virus (MHV3)

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infection in newly weaned mice (Moudgil, 1973). The mortality was significantly increased when anaesthesia was given immediately before and up to 24 hours after infection (Moudgil, 1973). A more recent study using caecal ligation and puncture sepsis model revealed that the intravenous agents ketamine and pentobarbitone, and the inhalational agents halothane, enflurane and isofturane, produced a significantly enhanced mortality from sepsis in mice (Hansbrough et al, 1985). All the agents were shown to significantly depress the helper/suppressor lymphocyte ratio, an effect which persisted for 72 hours following anaesthetic intervention. In addition to inhalational anaesthetic agents, morphine has also been shown to decrease resistance to infection in mice by drastically reducing the reticuloendothelial system activity, phagocyte count, phagocytic index and superoxide anion production in polymorphonuclear leucocytes and macrophages. Similar depression of alveolar macrophage counts, phagocytosis and bactericidal activities were observed in rabbits, thus suggesting a lack of species specificity (Tubaro et al, 1983). These and other studies suggest that anaesthesia may enhance the morbidity and mortality from infection by modifying the host defences. Anaesthesia and malignancy In studies of cell-mediated immunity against tumour cells in humans, the presence of tumour-associated antigens has been confirmed by several laboratories. It appears that the neoplastic cell is antigenic and that cellmediated immune responses of the host tend to inhibit tumour growth. Studies of effects of anaesthesia on 'tumour takes' are contradictory. Both enhanced pulmonary metastasis (Agostino and Clifton, 1964) and an absence of significant effect by anaesthesia (Schatten and Kramer, 1958) have been reported. Besides general tests of overall immunity, tumourspecific responses have also been evaluated in the perioperative period. The ability of the host leucocytes to kill turnout cells (tumour specific leucocytotoxicity) was depressed up to 7 days following mastectomy under halothane anaesthesia for carcinoma of the breast (Vose and Moudgil, 1975) and Wilms' tumour (Kumar and Taylor, 1974). Tumour cell killing by cytotoxic leucocytes was also inhibited by local anaesthetics (Kemp and Berke, 1973), barbitone (Lee et al, 1975) and halothane in vitro (Cullen et al, 1976). Although it is difficult to assess the anaesthetic effects in isolation from surgical intervention, from the above studies it would appear that anaesthesia and surgery may enhance tumour spread by suppressing the immune responses. CONCLUSION The available evidence supports the concept that anaesthetic agents influence a wide variety of specific and non-specific host defences. However, the precise role of anaesthesia alone in the pathogenesis of perioperative infection remains to be defined with clarity. Although large amounts of data have

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demonstrated postoperative impairment of the immune response, further s t u d i e s a r e n e c e s s a r y to c o r r e l a t e in v i v o a n d in v i t r o s t u d i e s o f i m m u n o competence and the occurrence of postoperative infections. Anaesthetici n d u c e d d e p r e s s i o n o f t h e i m m u n e s y s t e m is s h o r t - l i v e d a n d r e v e r s i b l e ; h o w e v e r , this d e p r e s s i o n c a n i n f l u e n c e p e r i o p e r a t i v e m o r b i d i t y a n d m o r t a l i t y in s u s c e p t i b l e p a t i e n t s . B y u n d e r s t a n d i n g t h e n a t u r e o f t h e s e d e f e c t s , a n d b y m e t i c u l o u s p r e o p e r a t i v e a n d i n t r a o p e r a t i v e m a n a g e m e n t , w e m a y b e a b l e to prevent perioperative morbidity and mortality.

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