8Indian J. Anaesth.

2002; 46 (1) : 8-20

8
INDIAN JOURNAL OF ANAESTHESIA, FEB. 2002

REVIEW ARTICLE

ANAESTHESIA IMMUNE SYSTEM INTERACTIONS:

IMPLICATIONS FOR ANAESTHESIOLOGISTS AND
CURRENT PERSPECTIVES
Dr. Ashok Kumar 1 Dr. S. Sadhasivam 2 Dr. A. K. Sethi3
SUMMARY
A good knowledge about immunological effects of anaesthesia, effects of anaesthetic agents and related perioperative interventions
(e.g., blood transfusion) on immunologically normal patients (e.g., anaphylactic / anaphylactoid reaction), immuno compromised
(e.g., malignancy) and immuno suppressed patients (transplant patients, AIDS patients), and their practical application in the day
to day anaesthetic management of our patients would serve our professions obligation to ensure patient safety and perioperative
outcome.

Keywords : Anaesthesia : Drugs : Immune system

Introduction
Immune response is a protective phenomenon against
any foreign antigen. Hypersensitivity is an exaggerated
immune response detrimental to the body. Hence immune
response is a double edged sword; at one hand it protects
the body, on the other hand it harms the body depending
upon the nature of the antigen, antibody produced, and
susceptibility of the person. Hypersensitivity can be induced
by environmental antigens in factitious agents, chemicals
and drugs.
Stevenson et al observed that anaesthesia and surgery
depress both T cell and B-cell responsiveness as well as
nonspecific host resistance mechanisms, including
phagocytosis1.
Hypersensitivity can be classified depending upon
the onset and nature of the mediator in to.
1 Immediate hypersensitivity - Antibody mediated.
2 Delayed hypersensitivity Cell mediated;
According to Coombs and Gell, hypersensitivity
can be typed as
1. MD, DA, MAMS - Prof.
2. MD - Senior Resident
3. MD, DA -Professor And Head
Dept. Of Anaesthesiology And Critical Care,
University College Of Medical Sciences And,
Guru Teg Bahadur Hospital, Shahdara, Delhi-110095
Correspond to :
Dr. A. Kumar
Flat # 5, Parivar Apartments, Plot 30, P.extention,
Patparganj, Delhi-110092
Fax:011-2290495, E-mail : Dbmi@Ucms.ernet.in

Type I Anaphylactic type IgE mediated, includes

Anaphylaxis, Atopy urticaria Angioedema, Asthma and
Rhinitis.
Type II - Cytotoxic type IgG or IgM and
complement mediated includes ABO incompatibility, drug
induced autoimmune hemolytic anaemia and
thrombcytopenia.
Type III Immune complex IgG, IgM and
complement mediated include Serum sickness followed by
immunotherapy.
Type IV Cell mediated Delayed Hypersensitivity
reactions.
Type V Stimulatory type, eg. Graves disease
Anaphylactic type of hypersensitivity (Type-I)
is the most frequently encountered type in the anaesthetic
practice. Physiologically active mediators (eg histamine )
are released from the mast cells and basophils, following
antigen binding to preformed IgE antibodies, on the
membranes of these cells. When life threatening allergic
reactions mediated by antibodies (IgE) occur, they are
defined as anaphylactic. When antibodies are not
responsible for the reaction, the Anaphylaxis and
Anaphylactoid reactions can not be clinically distinguished
from one another.
The past 25 years have witnessed the emergence in
the field of anesthesia, immune system interactions,
immunomodulation and psychoneuroimmunology. In this
review, we have discussed the immune responses during
anaesthesia and the immunomodulatory effects of drugs
and various techniques used in anaesthesia, intensive care
and pain clinics.

KUMAR, SADHASIVAM, SETHI : ANAESTHESIA IMMUNE SYSTEM

Intraoperative Allergic Immune Reactions

Allergic drug reactions account for 6-10% of all
adverse reactions 4. De Swarte suggests that the risk of
an allergic drug reaction occurring is approximately 1-3%
for most drugs 5. Intraoperative allergic reactions occur
once in every 5000-25,000 anaesthetics with 3.4%
mortality6,7. More than 90 % of allergic reactions evoked
by intravenous drugs occur within 3 minutes of
administration. In the anesthetized patient, the most
common lkife-threatening manifestation of an allergic
reaction is circulatory collapse, reflecting vasodilatation
with resulting decresed venous return. Although the
immune system functions to provide host defence, it can
respond inappropriately to produce various hypersensitivity
reactions. A spectrum of life-threatening allergic reactions
to any drug can occur in the perioperative period. The
enigma of these reactions lies in their unpredictable nature.
However, a high index of suspicion and vigilance, prompt
recognition, and appropriate and aggressive therapy can
help to avoid a disastrous outcome.
Recognition of Anaphylaxis
The onset and severity of the reaction relate to the
mediators specific end-organ effects. Antigenic challenge
in a sensitized individual usually produces immediate
clinical manifestations, allowing only a short period before
appropriate therapy. Individuals may vary greatly in their
manifestation and course of anaphylaxis, ranging from
minor clinical features to the full-blown syndrome leading
to death. The enigma of anaphylaxis lies in the
unpredictability of its occurrence, the severity of attack,
and lack of a prior allergic history6.

Management of Anaphylaxis
A plan for the treatment of anaphylactic and
anaphylactoid reactions must be established before the
event. Airway maintenance, 100% oxygen administration,
intravascular volume expansion, and adrenaline are
essential to manage the hypotension and hypoxia that
result from vasodilatation, increased capillary permeability,
bronchospasm and profound ventilation- perfusion
abnormality8,9. The treatment plan is the same for life
threatening anaphylactic or anaphylactoid reactions.
Reactions may be protracted, with persistent hypotension,
pulmonary hypertention, lower respiratory obstruction,
or laryngeal obstruction that may persist for 5-32 hours
despite vigorous therapy10 and may require aggressive
therapy. All patients who had an anaphylactic reaction
should be admitted to an intensive care unit (ICU) for 24
hours monitoring, as manifestations may recur following
successful treatment11-13.
Management of Anaphylaxis during General
Anaesthesia
Initial Therapy
1. Stop administration of antigens
2.

Maintain airway and administer 100% oxygen.

3.

Discontinue all anaesthetic agents.

4.

Start intravascular volume expansion [2-4 litres of

crystalloid ( lactated Ringers solution)/ colloid with
hypotension]. Hypotension rapidly ensues during
anaphylactic shock. Fisher has reported upto 40%
loss of intravascular fluid into the interstitial space
during anaphylactic reaction14.

5.

Administer adrenaline: (5-10 g.kg 1 iv bolus with

hypotension, titrate as needed; 0.1-1 mg iv with
cardiovascular collapse). Adrenaline is the drug of
choice when resuscitating patients during anaphylactic
shock. 1- agonistic effects vasoconstrict to reverse
hypotension, b2 receptor stimulation bronchodilates
and inhibits mediator release by increasing cyclic
adenosine monophosphate (c AMP) in mast cells
and basophils5. With cardiovascular collapse,
full iv cardiopulmonary resuscitative doses of
adrenaline (0.1-1 mg), should be administered and
repeated until haemodynamic stability resumes.
Patients with laryngeal oedema without hypotension
should receive subcutaneous adrenaline. Adrenaline
should not be administered to patients with normal
blood pressure16.

Recognition of Anaphylaxis during Regional and General

Anaesthesia
Systems
Respiratory

Symptoms

Signs

Dyspnoea
Chest discomfort

Coughing
Wheezing
Sneezing
Laryngeal oedema
Pulmonary complian

Cardiovascular

Dizziness
Malaise
Retrosternal
oppression

Cutaneous

Itching
Burning
Tingling

ce Pulmonary oedema
Acute respiratory failure
Disorientation
Diaphoresis
Loss of consciousness
Hypotension
Tachycardia
Arrhythmias
Systemic vascular
resistance.
Urticaria
Flushing
periorbital oedema
Perioral oedema

10

INDIAN JOURNAL OF ANAESTHESIA, FEB. 2002

Secondary Treatment
1. Antihistamines (0.5-1 mg. kg 1 of diphenhydramine)

Drug additives ( preservatives)

2.

Insulin

Catecholamine infusions-starting doses

Adrenaline: 4 - 8 mg. min 1
Noradrenaline: 4 8 mg. min 1
Isoproterenol: 0.5-1 mg. min 1; titrate to desired
effect.

3.

Aminophylline ( 5-6 mg. kg 1 over 20 minutes with

persistent bronchospasm).

4.

Corticosteroids ( 0.2 - lg hydrocortisone; alternatively,

1-2 g methylprednisolone especially if the reaction is
suspected to be mediated by complement cascade)

5.

Sodium bicarbonate ( 0.5 1 mEq. kg

persistent hypotension or acidosis)

6.

Airway evaluation ( prior to extubation).

with

Rapid and timely intervention is important when

treating anaphylaxis. Patients under general anaesthesia
may have altered sympathetic responses to acute
anaphylactic shock, whereas the patient under spinal /
epidural anaesthetic may be partially sympathectomised
and may need even larger doses of catecholamines17.
Agents Frequently Implicated in Allergic Immune
Reactions During Anaesthesia
Anaesthetic Agents.
Induction agents
: cremophor solubilized drugs,
barbiturates, etomidate, Propofol
Local anaesthetucs :

para-aminobenzoic ester agents

Muscle relaxants

suxamethonium, gallamine,
pancuronium, d-tubocurarine,
metocurine, atracurium
vecuronium, mivacurium,
doxacurium.

Opioids

pethidine, morphine, fentany1

Non-anaesthetic Agents
Antibiotics (penicillin, cephalosporins, sulfonamides,
vancomycin )
Aprotinin
Blood products ( whole blood, packed cells, fresh
frozen plasma, platelets, cryoprecipitate, Fibrin glue,
gamma globulin)
Bone cement (methyl methacrylate)
Corticosteroids
Cyclosporin A

Frusemide
Mannitol
NSAIDs
Protamine
Radiocontrast dye
Latex (natural rubber)
Streptokinase
Vascular graft material
Vitamin-K
Colliod volume expanders (dextrans, protein
fractions, albumin, hydroxyethyl starch, gelatin).
Diagnostic Tests
Tests performed during the reaction
Plasma Histamine Levels
Plasma histamine levels when elevated, particularly
to levels greater than 20 nmol-1, confirms its involvement
in the immune reaction is anaphylactic18,19. The converse
that no elevation in plasma histamine levels means a lack
of its involvement is not true. Plasma histamine levels
only rise transiently and sampling must occur within 10
minutes20.
Urinary or Plasma Methylhistamine
Even though measurement of urinary or plasma
methylhistamine has the advantages over plasma histamine
as it has a more prolonged rise and provides a simple
assay, it is less sensitive.
Immunoglobulin E Levels
Drugs specific IgE can be detected in blood taken
during an immune reaction or before a reaction and
postmortem, and usually reflects the results of delayed
sampling at the time of skin-testing20.
Complement Levels
As a diagnostic tool in clinical anaphylaxis,
complement level measurement has a limited value.
Changes in serum complement levels and activation of the
classical and alternate pathways have been demonstrated
after clinical anaphylaxis particularly due to althesin,
protamine and contrast media21,23. Activation should be
measured rather than levels of complement fraction, as
there are major dilutional effects during anaphylaxis24.

KUMAR, SADHASIVAM, SETHI : ANAESTHESIA IMMUNE SYSTEM

Mast cell Tryptase

It is an important advance in the diagnosis of
anaphylactoid reactions during anaesthesia. In anaphylactic
reactions the levels are elevated for 1-5 hours after the
beginning of the reaction, enabling the delay of sampling
until resuscitation is over25, and can be obtained in samples
taken postmortem26. Elevated mast cell tryptase levels
are highly specific and sensitive of an immune reaction,
with the exception of reactions to gelatin and contrast
media18-20. An elevated level of mast cell tryptase indicated
that testing to determine drug responsible is both mandatory
and likely to be successful. All patients with elevated
mast cell tryptase levels should be considered to have a
severe immune reaction and investigated further.
Tests after the Reaction
Skin-Testing
Skin testing is performed 4-6 weeks after the
reaction27. Skin tests have the advantages over other tests
because of the high yield of positive results (reflecting
the high incidence of IgE involvement in severe reactions)
and easiness in performing the tests27-29. Two forms of
skin testing are used- intradermal tests and prick tests.
Prick testing is less traumatic to the skin, easily done and
is safe. Their disadvantage is that, they tend to produce
more false-negatives, whereas intradermal tests tend to
produce false-positives. The consequences of a falsenegatives test for subsequent anaesthesia are obviously
greater than a false positive. Skin tests are of little value
in reactions to colloids, contrast media and blood products.
With local anaesthetics, genuine anaphylactic reactions
are rare, and the goal is to exclude allergy. Skin testing
on its own is inadequate. If there was not a clear-cut
history suggestive of anaphylaxis and a clear-cut positive
wheal and flare reaction at 1:100 dilution of 0.5% local
anaesthetic, the dosage should be increased to 2 ml of
undiluted lacal anaesthetic solution. Deaths have occurred
due to skin testing. Resuscitation facilities should be
available.
Radioimmunoassay Tests
Recently, radioimmunoassay ( RIA) tests have been
used to detect IgE-drug specific antibodies. RIA tests
have sensitivity similar to skin tests. However, RIAs are
only available for Propofol, thiopentone, suxamethonium,
vecuronium, pancuronium, gallamine, d-tubocurarine and
alcuronium. Combination of RIA and skin tests detects a
drug responsible for reaction better than either test alone.
Cross-sensitivities are better determined by RIAs than
cutaneous tests. There is significant in vitro cross-sensitivity
between thiopentone and NDMR, which is not reflected
clinically. However, in patients who are allergic to both,

11

skin tests and RIA inhibition are necessary to distinguish28.

In practice, when the results of tests disagree, the patient
should be warned off all positive drugs.
An often- overlooked factor in the investigation of
patients with anaesthetic allergy is the need for accurate
documentation and communication. The patients should
be encouraged to wear a warning device stating the drugs,
which are safe. They should be further be given, what
happened, which tests were performed, the results of
those tests and the conclusion. Anaesthetic allergy has
been shown to persist up to 27 years, and few patients
lose their sensitivity29,30.
Preoperative Testing
Recently it has been argued that patients presenting
for anaesthesia should be preoperatively screened by RIA/
skin tests to reduce the risk of anaphylaxis. The case for
this testing is poor31. The selection of at-risk group, such
as women of child-bearing age with or without a history
of allergy, with improve the cost-efectiveness of testing
and testing and lead to a major reduction in reactors
detected. If screening was to be performed, prick testing
would be the only feasible and sufficiently reliable test.
The most important variable in the case of screening is
the prevalence of anaesthetic allergy, which is different
from and unlikely to be greater than the incidence of
reactions, as a number of allergic patients will fortuitously
undergo anaesthesia without exposure to a drug to which
they may be allergic. In spite of the limitations of
diagnostic tests, when patients are investigated using skin
testing and RIA where available, subsequent anaesthesia
is usually safe, irrespective of whether the reaction was
diagnosed as anaphylactic or not or whether the drug
responsible was detected.
Immuno Competence
The intact immune system involves a highly
integrated system of adaptive and nonadaptive responses
to foreign antigens. The adaptive response is 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. In contrast, the nonadaptive or natural or
innate response is rapid, non-specific for the antigen and
does not improve upon repeated exposures. This system
must be able to recognize and differentiate antigens that
it perceives as self and non-self. Deficiencies in immune
function present a broad spectrum of responses with
potentially fatal outcomes. The main cause of morbidity
and mortality in these patients is infection. For example,
pneumonia accounts for up to 40% of mortality in patients
with cancer, and 35% in renal transplant recipients32,33.

12

Patients with the rarer, primary immune deficiencies

are more prone to infections due to specific organisms
because of the absence or decreased activity of specific
immune factors. It is imperative that early diagnosis be
made in these patients to avoid the overwhelming, lifethreatening infections. Over the years, the numbers of
patients with secondary immuno deficiencies (cancer, AIDS,
autoimmune disease, patients on glucocorticoids,
immunosuppressive, myelosuppressive drugs and radiation
therapy) who present for surgery have increased. They
are more prone for serious bacterial, viral and fungal
infections. Of particular interest today is the cellular
suppression in patients with AIDS. This syndrome,
characterized by a decrease in the number and effectiveness
of the T helper lymphocytes, predisposes the patient to
opportunistic infections, including Pneumocystis
pneumonia, herpes, cytomegalo virus and Epstein-Barr
virus infections, oral candidiasis, and a virulent form of
Kaposis sarcoma. Moreover, additional infections can
occur those include hepatitis B virus, syphilis, gonorrhoea,
and multiple- drug resistant strains of tuberculosis.
These immunocompromised patients may also be at
increased risk of cancer and or host-versus-graft disease.
In addition to the immunosuppressive effects of an
underlying diseases, patients may have increased
susceptibility to infection as a result of theraopeutic agents
or procedures (e.g. patients with indwelling catheters/
prosthesis may be at greater risk of infection). The most
common drugs causing immune suppression are the antiinflammatory agents. These include the steroids prednisone,
prednisolone and methylprednisolone, and salicylates34. In
addition, antibiotics such as streptomycin, tetracycline,
kanamycin and chloramphenicol may be immunosuppressive
by altering neutrophil chemotaxis35. X-rays and alkylating
anticancer drugs such as cyclophosphomide, chlorambucil
and actinomycin-D are directly cytotoxic. Methotrexate
and melphalan may also be immunosuppressive. Of
particular importance is the use of cyclosporin A as an
immumosuppressant. Besides causing immunosuppression,
it may also interact with barbiturates, narcotics and muscle
relaxants to enhance their therapeutic effect.
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. Moreover, the
overall impact on immune activity is difficult to determine.
For example, the anaesthetic state decreases the effect of
surgery on the immune response by obtunding the reflexes
associated with pain, by maintaining cardiovascular
homeostasis, and by decreasing the release of stress

INDIAN JOURNAL OF ANAESTHESIA, FEB. 2002

hormones and acute phase reactants associated with surgical

trauma. Anaesthetic agents may produce direct and indirect
effects on the functional and regulatory components of the
immune response. 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. Alteration in
immune function as a result of perioperative interventions
needs to be considered in the anaesthetic plan in an
important subset of patients.
While operative stress is generally considered to
play a greater role in the overall inhibition of the immune
response, the contribution of anaesthetics to specific
immune changes is significant, and may be more important
than surgical stress in procedures that have less tissue
injury. Anaesthesia has adverse effects on non-specific
defences, and adaptive and non-adaptive immune responses.
For example, anaesthetic-induced impairment of respiratory
ciliary activity and tracheal mucociliary flow by
endotracheal tube placement can decrease antigen clearance
and facilitate the dissemination of the microbial spread
into the lower respiratory tract36,37.
Anaesthetic agents also affect leukocyte function
(leucopenia, bone marrow suppression and inhibition of
phagocytosis, neutrophil chemotaxis and leukocyte
motility)38,39 Halothane, enflurane, nitrous oxide and high
concentrations of isoflurane all inhibit superoxide generation
by neutrophils, while lower concertrations of isoflurane
increase the formation of superoxide40. Paradoxically,
although anaesthesia inhibits the generation of superoxide
by neutrophils, the sensitivity of the endothelial cell targets
to oxidants is increased during anaesthetic exposure. As a
result, the endothelial cell cytotoxicity of activated
neutrophils is increased with halothane or isoflurane
anaesthesia41. It has been demonstrated that halothane,
isoflurane anaesthesia inhibit interferon stimulated natural
killer cell (NK cell) cytotoxicity for 14 days42. Intravenous
agents have also been implicated in the inhibition of NK
cell cytotoxicity. For example, high doses of morphine
(30 mg. kg-1), fentany1 ( 0.3 mg.kg-1) or sufentanil ( 0.06
mg.kg-1) decrease NK cell activity for up to 12 hours43.
This effect is blocked by the opiate antagonist, naltrexone.
Chronic morphine treatment is a mechanism used in
laboratory experiments to render mice immunocompromised44.
It has been observed that morphine significantly decreases
in a dose-dependent manner the proliferation of IFNa and
IFNb, an effect reversed by naloxone45. Hence there is
substantial body of evidence, which demonstrates that
opioids and endogenous opioids peptides modulate
immune function46.

KUMAR, SADHASIVAM, SETHI : ANAESTHESIA IMMUNE SYSTEM

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. This is possible because leukocytes
express opioids, adrenergic and cholinergic receptors. This
reflects that the immune system and other systems are
mutually dependent on each other. Cytokines can be of
two types i.e. pro-inflammatory and anti-inflammatory.
The pro-inflammatory cytokines include tumour necrosis
factor alpha (TNFa), interleukin 1 beta (IL-1b),
interleukin 6 (IL-6) and interleukin 8 (IL-8). The antiinflammatory cytokines include interleukin 10 (IL-10),
IL-1 receptor antagonist (IL-1 RA), 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 TNF-SR 2).
The anti-inflammatory cytokines are found in plasma in
appreciabe quantities. In health the pro-inflammatory
cytokines are present in plasma in very low concentrations
or not at all.
Effect of Surgery on Cytokines
During lung surgery, a small but not statistically
significant increase has been observed in plasma
concentrations of IL-6, TNFa, and IL-147. A transient
increase in pro-inflammatory cytokines has also been
reported during cholecystectomy48. Various authors have
observed a more dramatic and statistically significant
increase in these cytokines during cardiac surgery48-52.
Obviously this rise in pro-inflammatory cytokines has
been referred to be due to the stress response of surgery,
but Lahat et al noted a significant rise in TNFa immediately
following induction of anaesthesia with high-dose fentany1
even before surgery commenced48. Mc Bride et al observed
a significant increase in TNF a and IL-8 at 10 minutes
following induction of anaesthesia with high-dose Fentanyl
even before intubatione and the start of surgery49.

Effect of Anaesthetic Agents on Cytokines

It has been observed that propofol-alfentanil
anesthesia delays the onset and reduces the magnitude of
IL-6 response during major abdominal surgery as compared
with isoflurane anaesthesia53. Probably this effect is
mediated by alfentanil acting on opioid receptors leading
to a reduction in intracellular cyclic AMP (cAMP) 54 . an
important secondary messenger in triggering the release
of IL-6 55. Ultimately a reduction in cAMP is associated
with inhibition of IL-6 synthesis.

13

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 TNFa56.
Rossano et al observed that IL-1a production was induced
mainly by propofol, and IL-6 production was induced by
ketamine56. Also Cavaillon el al noted in lymphocyte
culture as rise in interferon-gamma (IFNa) production
following propofol administration57. It has also been
reported that the anti-inflammatory cytokine intreleukin4 (IL-4) was elevated following thiopentone and Ketamine
administration, and to a lesser extent following propofol.
Anaesthetic Agents and Neutrophil Polarization
ODonnell et al observed upto 50% reduction in
neutrophil polarization by clinical concentration of propofol
and thiopentone58. In contrast, midazolam and intralipid
have no effect on neutrophil polarization58.
Anaesthetic Agents and Chemotactic Locomotion of
Neutrophils
Jensen et al observed that propofol and intralipid
reduce neutrophil chemotaxis59. It is believed that the
mechanism of action is dependent on propofols lipid
solubility, as lipid solubility in volatile anaesthetic agents
is correlated with a reduction in granulocyte migration.
Neutrophils also show a naloxone sensitive chemotactic
response to endogenous opioids in a human in vitro study
and a rat in vivo study60,61.
Anaesthetic Agents and Neutrophil Respiratory Burst
It is well established that soon after phagocytosis
there is increased oxygen consumption, which is associated
with increased activity of Hexose Mone Phosphate (HMP)
shunt and production of hydrogen peroxide and oxygen.
Kellerman et al observed that Propofol inhibits neutrophil
respiratory burst as measured by chemilunimescence in
clinical concentrations62. Barbiturates cause inhibition of
neutrophil chemiluminescence and migration in vitro. This
particular effect is 10-100 times greater for thiobarbiturates
such as thiopentone than for oxybarbiturates such as
methohexitone. Kress et al suggest that this difference in
activity depends on the presence of sulphur atom63.
Davidson et al reported a reduction in neutrophil
respiratory burst by thiopentone and ketamine, only at
concentrations greater than that used in normal clinical
practice64. It is true that neutrophils have opioid
receptors65, and hence exposure to opioid peptides rapidly
induces naloxone-reversible superoxide production in vitro
at physiological concentrations.

14

Anaesthetic Techniques and Broncho Alveolar Lavage

(BAL) Neutrophil Count
It is suggested that intermittent positive pressure
ventilation (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-hour66. This type of
reaction is independent of whether anaesthesia is inhalational
or intravenous, and is particularly prominent in smokers66.
Anaesthetic Agents and Granulocyte adhesion
Boogaerts et al reported that pentoxifylline inhibits
the expression of the granulocyte adhesion molecules i.e.
CD 11a, CD 11b, CD11c and CD 1867. It has also been
reported that adrenaline in vitro inhibits human monocyte
spreading and adherence, an effect which can be blocked
by propranolol and which is thought to be cAMPdependent, since cAMP analogues minic the effect. Bazzoni
et al noted that heparin, when added to in vitro systems,
reduces adhesion of activated neutrophils68. This was more
prominent in TNFa dependent adhesion. Skinner et al
also observed that heparin inhibits neutrophil carbohydrate
ligands binding to P-selectin (an adhesion molecule
expressed on platelets and endothetial cells)69.
Anaesthetic Agents and Changes in Immunoglobulin
Levels
Suttmann et al observed a decrease in intra and
postoperative levels of IgM, IgG and IgA antigodies70.
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. This may also
explain the reduction in complement levels observed
perioperatively.
Salo in an in vitro experiment noted that prolonged
exposure to toxic concentrations of thiopentone results in
suppressed antibody production71. Braun et al have also
observed that prolonged use of high-dose thiopentone
infusions in the management of head injury and status
epilepticus may be associated with susceptibility to bacterial
pneumonia72.
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. It would
not happen in vivo as concentrations rapidly decrease.

INDIAN JOURNAL OF ANAESTHESIA, FEB. 2002

Salo observed that local anaesthetics do have microbicidal

effects at these high concentrations in vitro experiment73.
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 immunosuppression74. This is so because betaendorphin is a potent inhibitor of PHA (phytohaemagglutinin)induced human T-cell proliferation, an effect not blocked
by naloxone.
Beta-endorphin, [Met]-enkephalin and [Leu]
enkephalins have been shown to inhibit the secretion of
the pro-inflammatory cytokine IL-6 from mouse spleen75.
Also, IL-6 production from activated peripheral blood
mononuclear cells is decreased by opioid peptides76.
Anaesthetic Drugs and Lymphocyte Subpopulation
in Vivo
Pirttikangas et al observed that following Propofol
and thiopentone anaesthesia with low-dose Fentanyl at
induction, there is an increase in the numbers of total and
memory T lymphocytes and B-lymphocytes for both the
drugs77,78. However, Propofol anaesthesia decreases helper
T cells whereas thiopentone has no effect. On the other
hand, NK-cells decrease with both drugs.
Psychoneuroimmunology of Stress and its Immune
Consequences.
Psychoneuroimmunology is a relatively new
discipline, which deals with CNS-immune system
interactions, the influence of central nervous system on
the immune system, or more specifically, whether and
how thoughts and emotions affect immune function. Recent
evidence indicates that the behavioural, nervous system
and neuroendocrine responses to stress are mediated by
hypothalamic CRF, which acts on both the sympathetic
nervous system and the HPA axis, resulting in increased
levels of corticosteroids, catecholamines, and certain opiate
substances, which are generally immunosuppressive79.
Concentrations of growth hormone and prolactin, which
are immunoenhancing, are elevated early during the
response to stress 80-83, but are later suppressed and thus
this would contribute further to the immunosuppression
seen with stress 84,85 . Although several other
neurotransmitters may also be released with stress, the net
effect of a variety of acute stressors is down regulation of
the immune functions.
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

KUMAR, SADHASIVAM, SETHI : ANAESTHESIA IMMUNE SYSTEM

chemotaxis into the site of infection86. These changes

may also adversely affect the prognosis and recurrence of
malignancies in patients with cancer. In a study, the
1-year survival for women following surgery for breast
cancer was 77% in those who received blood transfusions,
and 95% in those who did not receive87. Transfused blood
has a direct effect on antigen recognition and enhances
transplant acceptance, particularly with kidneys86.
Transfusion-induced immune-suppression has also been
implicated as a cause of increased metastases86. Antigen
recognition is inhibited following transfusion of whole
blood and certain blood products. In several retrospective
studies, tumour recurrence was associated with the number
of units transfused during colon resection86.
Effects of Stellate Ganglion Block on Free Radicals
and T-cell Activation
Kumar et al observed a significant reduction in
the levels of superoxide and hydrogen peroxide in resting
as well as PHA stimulated neutrophils, 30 minutes
following the stellate ganglion block in patients with
chronic shoulder-hand pain [88]. These levels subsequently
increased at 75 minutes. The results of this study suggested
that stellate ganglion block has an immunomodulatory
effect and possibly an anti-inflammatory effect, since
sympathetic post-ganglionic nerve terminal provides a
contribution to inflammatory response89.
Recently, in an interesting study, Sugimoto et al
reported that following stellate ganglion block, the helper
T-cell activation was significantly reduced, and the
cytotoxic T cell activation also tended to decrease89.
Cytokines and Prediction of Development of ARDS in
Intensive Care Unit (ICU)
It has been observed that raised bronchoalveolar
lavage levels of IL-8, TNFa and IL-1b predict the
development of ARDS in intensive care patients90,91.
Donnelly et al also reported that a reduction in the soluble
form of the adhesion molecule L-selectin in plasma is
predictive of ARDS in ICU patients92.
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.
Computers and Immunological Consequences
It has been observed that computers tend to set off
many different health problems that include backache,
depression, short-term memory loss, fatigue, itchy eyes,

15

running noses and sneezing and coughing among frequent

users. The computer radiation can travel 20 feet and pass
through 8 feet concrete to affect people in another room
or another floor. It has been suggested the magnetic fields
set off by radiation from the computers interfere strongly
with the small magnetic field within the body that help
maintain the immune system. The low frequency magnetic
fields account for over a third of so called sick building
syndrome. It has been also noted that crystal pieces packed
into aluminium tubes kept on the monitor, help in cutting
down aches in back and neck among the users.
Transplantation Immunology
The important factors determining the success of
transplantation involve classic ABO compatibility and the
absence of preformed antibodies in the recipient, directed
against donors one of the 51 class-I or class-II antigens
associated with the major histocompatibility or human
leukocyte an tigen (HLA) system. Perfect matching of the
HLA system is not an absolute requirement to
transplantation, although an effort to be made to obtain
the closest HLA match possible, especially in more
common renal transplantations93.
Macrophages process foreign antigens, which
sensitize both B- and T- lymphocytes, facilitated by several
interleukins. Sensitized T-lymphocytes initiate immune
injury by secreting lymphokines and lymphotoxins,
which produce direct toxicity. B lymphocytes release
antibodies directed against the transplanted tissue, which
activate complement and induce the cascade of type-II
immune hypersensitivity effects. Antibody-dependent, cellmediated cytotoxicity (ADCC) also occurs. In a hyperacute
rejection reaction, the patient is already sensitized to one
or more of the HLA antigens by prior exposure to foreign
antigens (blood transfusion, pregnancy or previous
transplantation). Deposition of preformed antibody on the
vascular epithelium of the transplanted tissue results in a
type-II hypersensitivity reaction with intravascular
coagulation leading to tissue necrosis. A chronic form
of transplant rejection reaction, characterized by
a mononuclear cell (Predominantly T cells) infiltrate,
results in the gradual loss of the transplanted tissues and
which is generally unresponsive to immune suppressive
therapy.
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 (e.g. prednisone), the antimetabolites (azathioprine,
mercaptoprine, cyclophosphomide, chlorambucil), and the
cytotoxic agents (e.g., X-rays, antilymphocyte serum,
actinomycin-D, monoclonal antibody against T-lymphocyte

16

surface antigens)94,95. Cyclosporin is the mainstay of

transplantation immune therapy. This most powerful single
immune suppressive agent prevents T cell activation and
T-helper cell function and inhibits the production of
IL-296.
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, in more severe cases, a failure to
thrive or even mortality.
Tumour Immunology
The 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 corollary
to this hypothesis is that tumours occur secondary to a
breakdown in immune surveillance. This hypothesis has
been questioned by evidence against immune surveillance
theory97.
T-lymphocyte activity is important in the protection
of the organism against viral oncogenesis; however this
probably reflects normal protective T cell function against
virus infection and not immune surveillance per se.
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.
Non-specific immune mechanisms, involving the
monocytes and NK-cells, are probably more important in
the defence against cancer than specific immune
mechanisms98. 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
exposure42. This has been directly correlated to an increase
in experimental tumour metastasis99.
Regardless of immune mechanisms involved in
carcinogenesis, tumour cells probably undergo an immune
attack similar to that which is seen during transplant
rejection, and are, therefore, impaired by agents that
suppress transplant rejection.
AIDS and Anaesthesia related immune suppression
Morphine has been shown to reactivate or stimulate
HIV reproduction in in vitro cultures of human Kupffer
cells or peripheral blood monocytes100. Morphine may
also activate HIV-I transinfection into cultured human

INDIAN JOURNAL OF ANAESTHESIA, FEB. 2002

neurobalstoma cells101. Opiates may activate latent CNS

HIV infection101. However, the in vitro effects of morphine
were not reversible with naltrexone.
In vivo animal models have also shown that opiate
agonist will suppress humoral and cell-mediated immune
responses102-4.
Clinical data demonstrating an adverse immunologic
effect of either opiate treatment or anaesthesia in general
is indirect or absent105. The increased susceptibility to
infection in opiate addicts has been documented to be
caused by immunologic dysfunction106. Inclusion of an
opiate in an epidural anaesthetic technique in obstetric
patients has been associated with a reaction of herpes
simplex labialis107. 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
anaesthesia108.
Most studies demonstrating the opiates
immunosuppressive and viral reactivations have required
long-term use of high dose of opioids. The clinical data
do not appear to be sufficient to justify the avoidance of
opiate agonists, because of immunosuppressive side effects,
as part of anaesthetic management of HIV-infected
patients105.
Conclusion
It is well established now that the preoperative
immune response can not be solely attributed to surgical
trauma alone. Many anaesthetic drugs and regional
anaesthetic techniques such as stellate ganglion block have
been shown to have immunomodulatory properties. The
recent explosive increase in the knowledge of cytokines
have clearly proved the roles of pro-inflammatory cytokines
and that the increase in concentration of circulating IL-6
is approximately proportional to the severity of the surgery.
There is also enough evidence now to prove that
opioids use in both the surgical and critically ill patients
would have a profound immunomodulatory effects and as
anaesthesiologists we should be cognizant of the this effect
when we chose own anaesthetic, analgesic or sedative
technique. The unraveling of the role of cytokines, and
immunological sequelae left by anaesthetic drugs and
techniques offer an exciting immunologic challenge to the
anaesthesiologists to marry the findings of basic science of
the present millennium. We are optimistic of the conception
and delivery of answers to the important epidemiological
and clinical anaesthesia issues on our immunological
journey to the next millennium.

KUMAR, SADHASIVAM, SETHI : ANAESTHESIA IMMUNE SYSTEM

References
1. Stevenson GW, Hall SC, Rudnik S, et al.The effects of
anaesthetic agents on the human immune response.
Anesthesiology 1990;72:144.
2. Gell PGH, Coombs RRA, Lachmann, eds: Clinical aspects of
Immunology, 3rd ed. Oxford, Blackwell Scientific Publications,
1975.
3. Watkins J. Anaphylactoid reactions to I.V. substances. British
Journal of Anaesthesia 1979;51:51.
4. Borda IT, Slone D, Jick H. Assessment of adverse reactions
within drug surveillance program. JAMA 1968;205:645.
5. De Swarte RD, Drug Allergy: Problems and strategies. J
Allergy Clin Immunol 1984;74:209.
6. Fisher MM, More DG. The epidemiology and clinical features
of anaphylactic reactions in anaesthesia. Anaesthesia and
Intensive Care 1981;9:226.
7. Weiss ME, Adkinson NF, Hirshman CA. Evaluation of allergic
reactions in the perioperative period. Anaesthesiology
1989;71:438.
8. Levy JH. The allergic Response. In: Clinical Anaesthesia,
Barash PG, Cullen EF, Stoelting RK, eds, 3 rd edition,
Lippincott-Raven Publishers, Philadelphia 1996; 1205-17.
9. Levy JH. Anaphylactic reactions in anaesthesia and intensive
care, 2nd ed. Boston, Butterworth-Heinemann, 1992.
10. Stark BJ, Sullivan TJ. Biphasic and protracted anaophylaxis.
H Allergy Clin Immunol 1986;78:76.

17

20. Laroche D, Lefrancois C, Gerard JL, et al. Early diagnosis

of anaphylactic reactions to neuromuscular blocking drugs.
Br J Anaesth 1992;69:611-4.
21. Watkins J, Appleyard TN, Thornton JA. Immune mediated
reactions to altheisn (alphaxalone). Br J Anaesth 1976;
48:881-6.
22. Best N, Teisner B, Grudzinskas JG, Fisher MM. Classic
pathway activation during an adverse response toprotamine
sulphate. Br J Anaesth1983;55:1149-53.
23. Cogen FC, Norman ME, Dunsky E, Hirshfield J, Zweiman B.
Histamine release and complement changes following injection
of contrast media in humans. J Allergy Clin Immunol
1979;64:299-303.
24. Fisher MM. Tiessner B, Charlesworth JC. Significance of
sequential changes in serum complement levels during
anaphylactoid reactions. Crit Care Med 1984;12:351-4.
25. Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D.
Time course of appearance and disappearance of human mast
cell tryptase in the circulation after anaphylaxis. J Clin Invest
1989;83:1551-5.
26. Yunginger JW, Nelson DR, Squilace DL, et al. Laboratory
investigations of death due toanaphylaxis. J. Forensic Sci
1991;36:857-65.
27. Fisher MM. Intradermal testing after anaphylactoid reaction
to anaesthetic drugs: practical aspects of performance and
interpretation. Anaesth Intensive Care 1984;12:115-20.

11. Levy JH, Rockoff MR. Anaphylaxis to meperidine. Anaesth

Analg 1982;62:301.

28. Sage D. Intradermal drug testing following anaphylactoid

reactions during anaesthesia. Anaesth Intensive Care
1981;9:381-6.

12. Knignt PR, Tait AR. Immunological aspect of anaesthesia. In:

International Practice of Anaesthesia, Prys-Roberts C, Brown
BR Jr, eds, first edition, Butterworth- Heinemann, Oxford
1996; volume 1(84):1-16.

29. Moscicki RA, Sockin SM, Corsello BF, Ostro MG, Bloch KJ.
Anaphylaxis during induction of general anaesthesia:
subsequent evaluation and management. J Allergy Clin
Immunol 1990;86:325-32.

13. Fisher MM. Anaphylactoid reactions during anaesthesia. In:

International Practice of Anaesthesia, Prys-Roberts C, Brown
BR Jr, eds, first edition, Butterworth-Heinemann, Oxford 1996;
volume 1 (85) : 1-13.

30. Harle DG, Baldo BA. Smal MA, Wajon P, Fisher MM.
Detection of thiopentone-reative IgE antibodies following
anaphylactoid reactions during anaesthesia. Clin Allergy
1986;16:493-8.

14. Fisher MM. Blood volume replacement in acute anaphylactic

cardiovascular collapse related to anaesthesia. Br J Anaesth
1977;49:1023.

31. Fisher MM, Baldo BA. Persistence of allergy to anaesthetic

drugs. Anaesth Intensive Care 1992;20:143-6.

15. Kelly JF, Patterson R. Anaphylaxis: course, mechanisms and

treatment. JAMA 1974;227:1431.
16. Levy JH. Anaphylactic and anaphylactoid reactions during
cardiac surgery. J Clin Anesth 1989;1:426.
17. Barnett A, Hirshman CA. Anaphylactic reaction to cephapirin
during spinal anaesthesia. Anesth Analg 1979;58:337.
18. Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard
H, Biochemical markers of anaphylactoid reactions to drugs.
Comparison of plasma histamine and tryptase. Anaesthesiology
1991; 75:945-9.
19. Laroche D, Gallet E, Bricard H. Blood histamine and early
retrospective diagnosis of anaphylactic shock (in French). Ann
Fr Anesth Reanim 1988;7:425-6.

32. Hughes WT. Fatal infections in childhood leukemia. Am J

Dis Child 1971;122:283-7.
33. Levine AS, Gran RG Jr, Young RC. Management of infections
in patients with leukemia and lymphoma: current concepts
and experimental approaches. Semin Hematol 1972;
9:141-79.
34. Crout JE, Hepburn B, Ritts RE. Suppression of lymphocyte
formation after aspirin ingestion. N Engl J Med 1975;292:221.
35. Majeski JA, Mc Clellan MA, Alexander JW. Evaluation of
leukocyte chemotactic response in the presence of antibiotics.
Surg Forum 1975;26:83.
36. Manawadu BR, Mostow SR, La Force FM. Impairment of
tracheal ring ciliary activity in vitro. Anesth Analg
1979;58:500.

18
37. Lee KS, Park SS. Effect of halothane, enflurane and nitrous
oxide on tracheal ciliary activity in vitro. Anesth Analg
979;58:500.
38. Nunn JF, Sharp JA, Kimball KL. Reversible effect of an
inhalational anaesthetic on lymphocyte motility. Nature
1970;226:85-6.
39. Stanley TH, Hill GE, Portas MR, Hogan MA, Hill HR.
Neutrophil chemotasix during and after anaesthesia and
operation. Anesth Analg 1976;55:668.
40. Nakagawara M, Takashige K, Takamatsu J, Takahashi S,
Yoshitake J, Minakami S, Inhibition of superoxide production
and Ca2+ moblilization in human neutrophils by halothane,
enflurane and isoflurane. Anesthesiology 1986; 64: 4-12.
41. Shayevitz JR, Varani J, Ward PA, Knight PR. Halothane and
isoflurane increase pulmonary artery endothelial cell sensitivity
to oxidant-mediated injury. Anesthesiology 1991; 74: 1067.
42. Markovic SN, Knight PR, Murasko DM. Inhibition of
interferon stimulation of natural killer cell activity in mice
anaesthetized with halothane or isoflurane. Anaesthesiology
1993 ; 78 : 700-6.
43. Beilin B, Martin FC, Shavit Y, Gale RP, Liebeshkind JC.
Suppression of killer cell activity by high-dose narcotic
anaesthesia in rats. Brain, Behavior and Immunol 1989; 3:
129.
44. Di Francesco P, Guziano R, Casalinuovo IA, et al. Antifungal
and immunoadjuvant properties of fluconazole in mice
immunosuppressed with morphine. Chemotherapy 1997; 43:
198-203.

INDIAN JOURNAL OF ANAESTHESIA, FEB. 2002

bypass: participation of interleukin 8 and 6 in reperfusion
injury. Canadian Journal of Anaesthesia 1993; 40: 1016-21.
53. Crozier TA, Muller JE, Quttkatt D, et al. Effect of anaesthesia
on the cytokine response to abdominal surgery. British Journal
of Anaesthesia 1994; 72: 280-5.
54. Kavellars A, Ballieux RE, Heijnen CJ. Differential effects of
beta-endorphine on CAMP levels in human peripheral blood
mononuclear cells. Brain, Behaviour and Immunity 1990; 4:
171-9.
55. Zhang Y, Lin JX, Vilcek J. Synthesis of interleukin-6 in human
fibroblasts is triggered by an increase of intracellular cyclic
AMP. Journal of Biological Chemistry 1988;263:6177-82.
56. Rosanno F, Tufano R, Cipollaro DLEG, et al. Anaesthetic
agents induce human nmonuclear leukocytes to release
cytokines. Immunopharmacology 1992; 14: 439-50.
57. Haefner-Cavaillon N, Roussellier N, Ponzio O, et al. Induction
of interleukin-1 production in patients undergoing
cardiopulmonary bypass. Journal of Thoracic and
Cardiovascular Surgery 1989; 98: 1100-6.
58. O Donnell NG, Mc Sharry CP, Wilkinson PC, et al.
Comparison of the inhibitory effect of Propofol, thiopentone
and midazolam on neutrophil polarization in vitro in the
presence or absence of human serum albumin. British Journal
of Anaesthesia 1992; 69: 70-4.
59. Jensen AG, Dahlgren C, Eintrel C. Propofol decreases random
and chemotactic stimulated locomotion of human neutrophils
in vitro. British Journal of Anaesthesia 1993; 70: 99-100.

45. Nair MP, Schwartz SA, Polasani R, et al. Immunopregulatory

effects of morphine on human lymphocytes. Clinical and
Diagnostic Laboratory Immunology 1997; 4: 127- 32.

60. Sharp BM, Keane WF, Suh HJ, et al. Opioid peptides
rapidly stimulate superoxide production by human
polymorphonuclear leukocytes and macrophages.
Endocrinology 1985; 117: 793-5.

46. Stefano GB, Lalzet B, Fricchione GL. Enkelytin and opioids

peptide association in invertebrates and vertebrates: immune
activation and pain. Immunology Today 1998; 19: 265-8.

61. Van Epps DE, Saland L. -endorphin and met-enkephalin

stimulate human peripheral blood mononuclear cell chemotaxis.
Journal of Immunology 1984; 132: 3046-53.

47. Tonnesen E, Wancher M, Hohndorf K, et al. Effect of

methylprednisolone on the cytokine response in patients
undergoing lung surgery. Acta Anaesthesiologica Scandinavica
1993; 37: 410-4.

62. Kellermann W, Rothe G, Briegel J, et al. Determination of

respitatory burst of polymorphonuclear neutrophils by Propofol.
Anaesthesiology 1993; 79: 430.

48. Lahat N. Zlotnick AY, Shtiller R, et al. Serum levels of

IL-1, IL-6 and TNF in patients undergoing coronary artery
bypass grafts on cholecystectomy. Clinical and Experimental
Immunology 1992; 89: 255-60.
49. McBride WT, Armstrong MA, Crockard AD, et al. Selective
reduction in leukocyte antigen expression following high dose
fentanyl administration at cardiac surgery. British Journal of
Anaesthesia 1994; 73:717-8.
50. Butter J, Chong GL, Baigrie RJ, et al. Cytokine response to
cardiopulmonary bypass with membrane and bubble
oxygenation. Annals of Thoracic Surgery 1992; 53: 833-8.
51. Jansen NJG, Van Oeveren W, Gu YJ, et al. Endotoxin release
and tumor necrosis factor formation during cardiopulmonary
bypass. Annals of Thoracic Surgery 1992; 54: 744-7.
52. Kawamura T, Wakusawa R, Okada K, et al. Elevation of
cytokines during open heart surgery with cardiopulmonary

63. Kress HG, Eberlein T, Horber B, et al. Suppression of

neutrophils migration and chemiluminescence is due to the
sulphur atom in the thiobarbiturate molecule. Acta
Anaesthesiologica Scandinavica 1989; 33: 122-8.
64. Davidson JAH, Boom SJ, Pearsall FJ, et al. Comparison of
the effects of four i.v. anaesthetic agents on polymorhonuclear
leukocyte function. British Journal of Anaesthesia 1995;
74:315-8.
65. Lopker A, Abood LG, Hoss W, et al. Stereoselective muscarinic
acetylecholine and opiate receptors in human phagocytic
leukocytes. Biochemical Pharmacology 1980; 29: 1361-5.
66. Eliraz A, Ezri T, Guttman R, et al. Inflammatory cells in
bronchial lavage fluid after general anaesthesia and artificial
respiratrion. HaRefuah (Heb) 1990; 118(3):139-41.
67. Boogaerts MA, Malbrain S, Meeus P, et al. In vitro modulation
of normal and diseased neutrophil function by pentoxifylline.
Blut 1990; 61:60-5.

KUMAR, SADHASIVAM, SETHI : ANAESTHESIA IMMUNE SYSTEM

19

68. Bazzoni G, Beltran NA, Mascellani G, et al. Effect of heparin,

dermatan sulphate, and related oligo-derivatives on human
polymorphonuclear functions. Journal of Laboratory and
Clinical Medicine 1993; 121: 268-75.

86. Waymack JP, Fernandes G, Cappelli PJ, et al. Alteration in

host defense associated with anaesthesia and blood
transfusions. II: Effect of response to endotoxin. Arch Surg
1991; 12: 59-62.

69. Skinner MP, Lucas CM, Burns GF, et al. GMP-140 binding
to neutrophils is inhibited by sulfated glycans. Journal of
Biological Chemistry 1991;266:5371-4.

87. Tarterr PI, Burrows L, Papatestas AE. Perioperative blood

transfusion has prognostic significance for breast cancer.
Surgery 1985; 97: 225.

70. Suttman H, Doenicke A, Bretz C, et al. Einfluss der Narkose

auf humorale parameter. Beitrage zur Anaesthesiologie und
Intensivmedzin 1982;1:39-65.

88. Kumar A, Tripathi SS, Tripathi AK, et al. Evaluation of

superoxide and hydrogen peroxide radicals following stellate
ganglion block in patients witgh chronic shoulder-hand pain.
Submitted for publication to Anaesthesia, 1999.

71. Salo M, Effects of thiopentone on immunoglobulin production

in vitro. British Journal of Anaesthesia 1989; 63: 716-20.
72. Braun SR, Levin AB, Clark KL. Role of corticosteroids in the
development of pneumonia in mechanically ventilated head
trauma victims. Critical Care Medicine 1986; 14: 198-201.
73. Salo M. Effects of lignocaine and bupivacaine on
immunoglobulin synthesis in vitro. European Journal of
Anaesthesiology 1990;7: 133-40.
74. McCain HW, Lamster IB, Bozzone JM, et al. Beta-endorphin
modulated human immune activity via non-opiate receptor
mechanisms. Life Sciences 1982; 31: 1619-24.
75. Straub RH, Herrmann M, Berkmiller G, et al. Neuronal
regulation of interleukin-6 secretion in murine spleen:
adrenergic and opioidergic control. Journal of Neurochemistry
1997; 68: 1633-9.
76. Morgan EL. Regulation of human B-lymphocyte activation
by opioids peptide hormones. Inhibition of IgG production
by opioids receptor class (mu, kappa, and delta) selective
agonists. Journal of Neuroimmunology 1996; 65: 21-30.
77. Pirttikangas CO, Perttila J, Salo M. Propofol emulsion
reduces proliferative responses of lymphocytes from intensive
care patients. Intensive Care Medicine 1993; 19: 299-302.
78. Pirttikangas CO, Perttila J, Salo M, et al. Propofol infusion
anaesthesia and immune response in minor surgery.
Anaesthesia 1994; 49: 13-6.
79. Black PH. Central Nervous System-Immune System
interactions: Psychoneuroendocrinology of stress and its
immune consequences. Antimicrobial agents and
Chemotherapy 1994; 38: 1-6.
80. Dantzer R, Kelley KW. Stress and Immunity: an integrated
view of relationships between the brain and the immune
system. Life Sciences 1989; 44: 1995-2008.
81. Kelley KW. Growth hormone, lymphocytes and macrophage.
Biochemical Pharmacology 1989;38: 705-13.
82. Matera L, Bellone G, Cesano A,. Prolactin and the
neuroimmune network. Adv Neuroimmunol 1991; 1: 158-72.
83. Khansari DN, Murgo AJ, Faith RE. Effects of stress on the
immune system. Immunology Today 1990; 11: 170-5.
84. Gilbert MS, Payan DG. Interactions between the nervous and
the immune systems. Frontiers Neuroendocrinol 1991; 12:
299-322.
85. Wuttke WW, Dunker E, Vaupel R. The neutoendocrinology of
stress. Frpntiers Neuroendocrinol 1987; 12: 1-22.

89. Sugimoto M, Shimaoka M, Taenaka N, et al. Lymphocyte

activation is attenuated by stellate ganglion block. Regional
Anaesthesia and Pain Medicine 1999; 24 (1): 30-5.
90. Suter PM, Suter S, Girardin E, et al. High bronchoalveolar
lavege levels of tumor necrosis factor and its inhibitors,
interleukin-1, interferon, and elastase in patients with adult
respiratory distress syndrome after trauma, shock or sepsis.
American Review of Respiratory Diseases 1992;145:101622.
91. Donnelly SC, Strieter RM, Kunkel SL, et al, Interleukin 8
and development of adult respiratory distress syndrome in atrisk groups. Lancet 1993: 341: 643-7.
92. Donnelly SC, Haslett C, Dransfield I, et al. Role of selectins
in development of adult respiratory distress syndromw. Lancet
1994; 344: 215-9.
93. Stenze KH, Whitsell JC, Cheigh JC, et al. Effects of HLA
matching and immune responsiveness of cadaver kidney graft
survival. Transplant Proc 1974; 6 :89-93.
94. Calabresi P, Parks RE Jr. Antiproliferative agents and drugs
used for immunosuppression. In: The Pharmacological Basis
of Theraopeutics, edited by Gilman AG, Goodman LS, Rall
TW, Murad F, MacMillan, New York, 1980; 1247-306.
95. McGiffin DC, Kirklin JK, Naftel DC. Acute renal failure after
heart transplantation and cyclosporin therapy. Heart Transplant
1985; 4: 396-9.
96. Lafferty KJ, Borel JF, Hodgekin P. Cyclosporin-A (Cs-A):
models for the mechanism of action. Transplant Proc 1983;15
(suppl): 2241-7.
97. Moller G, Moller G. The concept of immunological
surveillance against neoplasia. Transplantation 1976;38:3-16.
98. Herbermann RB, Ortaldo JR. Natural killer cells: their role
in defenses against disease. Science 1981; 214: 24-30.
99. Marcovic SN, Murasko DM. Inhibition of induction of natural
killer activity in mice by general anaesthesia ( Avertin): role
of interferon. Clin Immunol Immunopathol 1991; 60: 181-9.
100. Schweitzer C, Keller F, Schmitt MP, Jaeck D, Adloff M,
Schmitt C, Royer C, Kirm A, Aubertin MM. Morphine
stimulates HIV replication in primary cultures of human
Kupffer cells. Res Virol 1991; 142: 189-195.
101. Squinto SP, Mondal D, Block AL, Prakash D. Morphine
induced transactivation of HIV-1 LTR in human
neuroblastoma cells. AIDS Res Hum Retroviruses 1990; 6:
1163-8.

20

INDIAN JOURNAL OF ANAESTHESIA, FEB. 2002

102. Bryant H, Bernton E, Holaday J. Immunosuppressive effects

of chronic morphine treatment in mice. Life Sci 1992; 41:
1731-8.
103. Bayer BM, Daussin S, Hernanadez M, Irvin L. Morphine
inhibition of lymphocyte activity is mediated by an opioidsdependent mechanism. Neuropharmacology 1990;
29:369-74.

Suggested Reading :
u
Griffis CA.Human immunodeficiency virus/acquired
immune deficiency syndrome-related drug therapy:
anesthetic implications.
CRNA. 1999 Aug;10(3): 107-16. Review.
u

104. Beilin B, Martin FC, Shavit Y, Gale RP, Liebeskind JC.

Suppression of natural killer cell activity by high doses
narcotic anaesthesia. Brain, Behav Immun 1989; 3:
129-37.
105. Shapiro HM, Grant F, Weinger MB. AIDS and the Central
Nervous System. Implications for the Anaesthesiologists.
Anesthesiology 1994; 80: 187-200.
106. Brown S, Stimmel B, Taub R, Kochwa S, Rosenfield R.
Immunologic dysfunction in herion addicts. Arch Intern Med
1974; 134: 1001-6.
107. Crone LA, Storgard C, Zbitnew A, Cronk SL, Rea LM, Greer
K, Berenbaum E, Tan TK, To T. Herpes labialis in parturients
receiving epidural morophine following cesarean section.
Anaesthesiology 1990; 73: 208-13.
108. Schwartz D, Schwartz T, Cooper E. Anaesthesia and the
child with HIV infection. Can J Anaesth 1991: 38: 26-33.

Augustin M,Zschocke I, Godau N, BuskeKirschbaum A, Peschen M, Sommer B, Sattler G.

Skin surgery under local anesthesia leads to stressinduced alterations of psychological, physical, and
immune functions. Dermatol Surg. 1999
Nov;25(11):868-71.
Helmiz SAK, Al-Aetiyah RJ The immunomodulatory
effects of prolonged I/V infection of propofol versus
midraolan in critically ill surgical patients
Anaesthesia.2001;56:4-8.
Hollman MW, Gross A et al. Local Anesthetic effects
on priminig and activation of human
neutropils..Anaesthiology.2001;95:113-122
Avidan MS, Jones N, Pozniak AL.The implications
of HIV for the anaesthetist and the intensivist.
Anaesthesia. 2000 Apr;55(4):344-54. Review.

Indian Journal of Anaesthesia

-Peer Review Process.
The editorial board is happy to learn that there are members ISA of who would like to participate in The peer review
process of the journal If any of the member likes to be considered as a reviewer for our journal please complete this form
and send it to our editorial office. Thank you for your interest. Type or print your name and the best address for you to
receive the manuscripts.
Name :_____________________________________I.S/A No._________
Address: ____________________________________________________
____________________________________________________________
E-mail :

Telephone :

Indicate your area of interest in the subject in which you like to receive the manuscripts.

IMPORTANT NOTICE
The Indian Journal of Anaesthesia has implemented a change in the reference style.
We retain the Vancouver style, but the journal name is now abbreviated as for eg.
Indian J. Anaesth 2001; 45(2):44-8