EFFECTS OF ANAESTHESIA ON IMMUNE SYSTEM

Presentor : Dr.Kumar M.D

Immune response is a protective phenomenon against any foreign antigen.

Hypersensitivity is an exaggerated immune response detrimental to the body.

Immune response is a “double edged sword”

The functional importance of the immune system

Innate Immunity

AdaptiveImmunitY

Innate immunity: always present (ready to attack); many pathogenic microbes have evolved to resist innate immunityAdaptive immunity: stimulated by exposure to microbe; more potent

Innate and adaptive immunity

Active and passive immunity

Active immunity: long-lasting protection (memory), multiple effector mechanisms activated, lag time

Passive immunity: rapid protection, short duration

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011

Classes of lymphocytes

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier

Hypersensitivity can be classified depending upon the onset and nature of the mediator in to.

Immediate hypersensitivity - Antibody mediated.

Delayed hypersensitivity – Cell mediated

According to Coombs and Gell, hypersensitivity can be typed as

Type I – Anaphylactic type – IgE mediated, includesAnaphylaxis, Atopy urticaria Angioedema, Asthma andRhinitis.

Type II - Cytotoxic type – IgG or IgM andcomplement mediated includes ABO incompatibility, druginduced autoimmune hemolytic anaemia andthrombcytopenia.

Type III – Immune complex IgG, IgM andcomplement mediated include Serum sickness followed byimmunotherapy.

Type IV – Cell mediated – Delayed Hypersensitivityreactions.

Type V – Stimulatory type, eg. Graves disease

Preoperative Testingpreoperatively screened by RIA/ skin tests to

reduce the risk of anaphylaxis

Prick testing would be the only feasible and sufficiently reliable test

Radioimmunoassay ( RIA) tests have been used to detect IgE-drug specific antibodies

RIAs are only available for Propofol, thiopentone, suxamethonium, vecuronium, pancuronium, gallamine, d-tubocurarine

Combination of RIA and skin tests detects a drug responsible for reaction better than either test alone

Immuno CompetenceThe intact immune system involves a

highly integrated system of

1. adaptive responses to foreign antigens

2. nonadaptive responses to foreign antigens.

adaptive response

It is a highly specific for a particular antigen and improves upon successive exposure to that antigen,

constituting a memory mechanism, which protects against future encounters with the antigen

Nonadaptivethe nonadaptive or natural or innate response

It is rapid, non-specific for the antigen

does not improve upon repeated exposures.

This system must be able to recognize and differentiate antigens that it perceives as self and non-self

Perioperative Interventions and Immune Mechanisms

It is difficult to separate the individual effects of anaesthesia, surgery and other perioperative interventions on the immune responses of the patient.

Anaesthetic agents may produce direct and indirect effects on the functional and regulatory components of the immune response

the anaesthetic state decreases the effect of surgery on the immune response by

1. obtunding the reflexes associated with pain, 2. by maintaining cardiovascular homeostasis,

and3. by decreasing the release of stress hormones

and acute phase reactants associated with surgical trauma.

Since the immune system not only protects from invading pathogens and tumour metastases, but is also involved in the homeostatic control and regulation of many physiological systems

Anaesthesia has adverse effects on non-specific defences, and adaptive and non-adaptive immune responses.

1. anaesthetic-induced impairment of respiratory ciliary activity

2. tracheal mucociliary flow by endotracheal tube placement can decrease antigen clearance and facilitate the dissemination of the microbial spread into the lower respiratory tract.

Anaesthetic agents may produce direct and indirect effects on the functional and regulatory components of the immune response

Perioperative Immunomodulation of Cytokine Balance

Cytokines are glycosylated and non-glycosylated polypeptides that act as the soluble messengers of the immune system

They are multifunctional and appear to work alone or synergistically with other cytokines to control both immune cells and non immune cells such as endothelium.

The production of cytokines is under complex neurohumoral control.

Cytokines can be of two types i.e. pro-inflammatory and anti-inflammatory.

The pro-inflammatory cytokines include

1. tumour necrosis factor alpha (TNFa),

2. interleukin 1 – beta (IL-1b),

3. interleukin –6 (IL-6) and

4. interleukin –8 (IL-8).

The anti-inflammatory cytokines1. interleukin –10 (IL-10)2. IL-1 receptor antagonist

(IL-1 RA)3. TNF binding proteins 1

and 2 (TNF-BP1 and TNF-BP 2). These are also known as the soluble TNF receptors (TNF-SR 1 and SR 2)

Effect of Surgery on Cytokinessignificant increase has been observed in

plasma concentrations of IL-6, TNFa, and IL-1

A transient increase in pro-inflammatory cytokines has also been reported during open surgical procedures when compared to laparascopic surgeries

this rise in pro-inflammatory cytokines has been referred to be due to the stress response of surgery

Effect of Anaesthetic Agents on Cytokines

In vitro studies have indicated that intravenous induction agents induce cytokine production in monocyte culture systems.

Propofol, thiopentone and ketamine have been associated with increased production of TNFa

Rossano et al observed that IL-1a production was induced mainly by propofol, and IL-6 production was induced by ketamine

Cavaillon el al noted in lymphocyte culture as rise in interferon-gamma (IFNa) production following propofol administration .

It has also been reported that the anti-inflammatory cytokine intreleukin-4 (IL-4) was elevated following thiopentone and Ketamin administration, and to a lesser extent following propofol.

Anaesthetic Agents and Neutrophil Respiratory Burst

After phagocytosis there is increased oxygen consumption, which is associated with increased activity of (HMP) shunt and production of hydrogen peroxide and oxygen.

Kellerman et al observed that Propofol inhibits neutrophil respiratory burst

Davidson et al reported a reduction in neutrophil respiratory burst by thiopentone and ketamine, only at concentrations greater than that used in normal clinical practice.

This particular effect is 10-100 times greater for thiobarbiturates such as thiopentone than for oxybarbiturates such as methohexitone

Anaesthetic Techniques and Broncho Alveolar Lavage(BAL) Neutrophil Count

IPPV by virtue of increasing pulmonary vascular resistance, may cause neutrophil lung infiltration, irrespective of whether a volatile or total intravenous anaesthetic technique is used.

Elinaz et al observed a marked increase in BAL neutrophil count in adults anaesthetized and ventilated for 1-hour.

This type of reaction is independent of whether anaesthesia is inhalational or intravenous, and is particularly prominent in smokers

Anaesthetic Agents and Changes in Immunoglobulin Levels

Suttmann et al observed a decrease in intra and postoperative levels of IgM, IgG and IgA antigodies

Following general anaesthesia, slight fall in their levels has been reported during the post-induction period and this also lasts temporarily into the postoperative period.

The exact mechanism of this fall remains unexplained.

It may be partly haemodilutional and partly due to formation of immune complexes & reduction in complement levels observed perioperatively.

It has also been observed that lignocaine and bupivacaine suppress immunoglobulin production in vitro experiments.

Especially in situations where there is prolonged exposure to concentrations, which greatly exceed the plasma concentration during local infiltration.

Salo observed that local anaesthetics do have microbicidal effects at these high concentrations in vitroexperiment

Anaesthetic Drugs and Lymphocyte Proliferation in vitro

McCain et al observed that following major stress and trauma, endogenous opioids may contribute to the cell mediated immunosuppression

This is so because beta-endorphin is a potent inhibitor of PHA (phytohaemagglutinin)-induced human T-cell proliferation, an effect not blocked by naloxone.

IL-6 production from activated peripheral blood mononuclear cells is decreased by opioid peptides

Perioperative Blood Transfusion and Immune Response

Patients receiving blood transfusions may also have a decrease in T-cytotoxic lymphocyte (Tc) production, tumour necrosis factor (TNF) levels and macrophage chemotaxis into the site of infection.

These changes may also adversely affect the prognosis and recurrence of malignancies in patients with cancer.

Transfusion-induced immune-suppression has also been implicated as a cause of increased metastases

Antigen recognition is inhibited following transfusion of whole blood and certain blood products

Chronic Pain and Immunologic Changes

Active lymphocytes increase significantly in most of the chronic pain patients.

There may be some abnormal changes such as decrease in suppressor t-cells and helper T cells or an increase in inducer T-cells.

It is possible that immunological system in chronic pain patients may get affected due to chronic pain stress.

Transplantation Immunology

The suppression of the immune rejection response against the transplanted tissue is easier to achieve before the immune response occurs.

The specific drugs used to induce immune suppression include the adenocorticoid steroids , the antimetabolites and the cytotoxic agents

The main concerns in patients on immune suppressive agents are higher postoperative infection interactions with anaesthetic agents (e.g. azathioprine and NDMR), and graft-versus-host reactions, which can increase perioperative morbidity

Tumour ImmunologyThe immune surveillance hypothesis states that the vast

majority of neoplastic cells, which arise spontaneously, are detected and eliminated by immune mechanisms before they become tumours.

The relationship of the immune system and oncogenesis is complex and anaesthesia and surgical trauma alter this complex relationship.

Volatile anaesthetics and the surgical stress response alter the initiation of inflammatory response against tumour establishment and growth.

The ability of NK cells to increase cytotoxic activity in response to stimulation is depressed in the postoperative period as a direct result of anaesthetic exposure.

AIDS and Anaesthesia related immune suppression

Morphine has been shown to reactivate or stimulate HIV reproduction in in vitrocultures of human Kupffer cells or peripheral blood monocytes.

Opiates may activate latent CNS HIV infection.

One group has suggested that general anaesthesia be avoided, when a regional anaesthetic technique is possible, in AIDS patients because of apparent depression of cell-mediated immunity after general anaesthesia