Immunomodulatory effects of anaesthetic and analgesic drugs

Helen F Galley, Senior Lecturer, Academic Unit of Anaesthesia & Intensive Care, University of Aberdeen, Scotland.

The immune system has developed to protect us from invading organisms and cancer, enabling the recognition and elimination of foreign cells and molecules. A huge number of studies have shown that many of the analgesic, sedative and anaesthetic agents commonly used both during surgery and in critically ill patients on the intensive care unit modify components of the immune response in vitro. The in vivo relevance of these findings, and the possible mechanisms involved are much less clear.

There are two types of immune responses, non-specific and acquired. The first is the pre-existing resistance to disease, and requires no previous exposure to a foreign antigen and includes the inflammatory response. Ingestion of foreign material occurs by phagocytosis by polymorphonuclear neutrophils, mast cells, macrophages, endothelial cells and hepatocytes. The inflammatory response is characterised by vasodilatation, increased capillary permeability, influx of phagocytic cells under the influence of chemotactic mediators and adhesion molecules, and production of cytokines. Acquired immunity is a specific immune response occurring on secondary exposure to antigens and is further classified into humoral or cell mediated immunity. The humoral component involves the interaction of B cells with antigen and their proliferation and differentiation into antibody secreting plasma cells. T cells are responsible for cell-mediated immunity and there are two types of T cells, T helper (Th) cells and T cytotoxic (Tc) cells. Th cells secrete cytokines, each Th cell subset secretes a specific array of cytokines which further augment the differentiation into that subset. Th1 cells produce interferon g (IFNg) and favour cell mediated immune responses, and Th2 cells secrete interleukin-4 (IL-4) and favour humoral immunity, leading to fibrosis and ultimately immunosuppression.

Alterations in immune responses have been described both after surgery and in the critically ill patient on the intensive care unit (ICU). There are a number of possible contributory factors to modulation of immune responses. During surgery, in addition to the neuroendocrine stress response, haemorrhage, hypotension and blood transfusion may affect immune competence, and ischaemia/reperfusion can activate cellular immune responses. Drugs such as steroids and prostaglandins have a variety of effects, including modulation of cell adhesion, but H2 antagonists also increase Th1 responses and some antibiotics alter cytokine release. Variation in immune competence in terms of age and sex-related responses are accepted, but polymorphisms in the genes for cytokines, their antagonists and receptors can have profound effects on an individual’s response to infection or trauma. The effects of anaesthesia, sedation and analgesia are therefore diluted by these other confounding factors and this has to be considered in the interpretation of the available data. Pronounced changes in immunological responses occur during and after surgery and in the critically ill. What is not clear is the relative contribution of anaesthesia/sedation and analgesia. Nowhere is this more relevant than in the intensive care unit, where patients routinely receive continuous infusions of agents such as propofol, benzodiazepines, thiopentone, and opioids for several days. These observations have prompted investigation of the specific comparative in vitro effects of anaesthetic and analgesic agents on aspects of immune function.

There have been few studies on the effect of local anaesthetics on immune function although it is clear that the physiological consequences reach further than local anaesthesia alone. Intravenous anaesthetics have differential effects on cellular function in vitro, although there are many conflicting reports. There have been few in vivo studies comparing anaesthetic agents and fewer still where patients have been randomised to a particular anaesthetic regimen. In addition, in vivo drugs are constantly being metabolised and redistributed, unlike in vitro, where concentrations remain constant. Most studies strongly suggest that alteration in immune responses during surgery are due primarily to the magnitude of the neuroendocrine stress response. Attenuation of the stress response, resulting in smaller increases in cortisol and catecholamines and abrogated interleukin-6 (IL-6) responses have been described for spinal/epidural anaesthesia. IL-6 is important in that it stimulates ACTH and cortisol secretion, and is one of the array of cytokines produced by Th2 lymphocytes. Thus decreased IL-6 may not only reduce the stress response, but may also predispose to a predominance of Th1, rather than Th2-like immune responses.

There are several conclusions which can be drawn from the array of available confusing data. Results from in vitro studies are dependent upon the concentration of agent used, the stimulus or mitogen employed, the aspect of immunity under study and the method chosen for its measurement, and, most importantly the conditions under which experiments were performed. Given the right experimental conditions, all intravenous anaesthetic agents modify some aspect of the immune response. The relevance of such in vitro findings to physiological circumstances must be questioned. In vivo studies do not uphold, on the whole, the in vitro findings. There is little evidence to support the concept of clinically relevant immune modulation by anaesthetics during surgery. Any effects are likely to be overwhelmed by the neuroendocrine stress response. The use of epidural anesthesia results in dampening of cortisol and IL-6 responses, and an appropriate Th cell balance is likely. Further clinical studies should be directed towards the immunological and morbidity benefit of epidural versus general anaesthesia.

In intensive care patients, anaesthetic agents, such as propofol, midazolam and thiopentone, and opioids, are used for long periods. Clearly there is more scope for clinically meaningful modulation of immune responses under such conditions. It is not known what effects anaesthetic and analgesic agents have on Th1/Th2 balance in ICU patients. Further work should be directed at determining the influence of sedation regime on immunological parameters, specifically Th cell balance, through randomised controlled trials, complemented by mechanistic in vitro studies. In vitro studies have a very important role in determining the way in which drugs exert physiological effects but there is little more to be achieved by yet another report of an anaesthetic agent inhibiting in vitro neutrophil function. Clearly trials of sedation and analgesia regime on morbidity and mortality studies are logistically extremely difficult, given the lack of homogeneity in ICU patient populations, the numbers of patients required and the financial implications, but not impossible.