Download anaesthesia related effects on immune function

18 January 2013
No.2
Postoperative Immune Dysfunction
B Kusel
Commentator: G Govender
Department of Anaesthetics
Moderator: S Dhooma
CONTENTS
INTRODUCTION ................................................................................................... 3
BASIC IMMUNOLOGY ......................................................................................... 3
SURGICAL EFFECTS ON IMMUNE FUNCTION ................................................. 5
ANAESTHESIA RELATED EFFECTS ON IMMUNE FUNCTION ......................... 8
OTHER PERI-OPERATIVE IMMUNE MODULATORS ....................................... 10
Pain.................................................................................................................. 11
Blood transfusion ........................................................................................... 11
Hyperglycaemia .............................................................................................. 12
Hypothermia ................................................................................................... 12
CLINICAL IMPLICATIONS: ................................................................................ 13
Anaesthetic agents and cancer surgery ....................................................... 13
Cognitive dysfunction .................................................................................... 16
HIV ................................................................................................................... 16
Infection and Sepsis....................................................................................... 17
THERAPEUTIC OPTIONS .................................................................................. 19
SUMMARY ......................................................................................................... 19
REFERENCES.................................................................................................... 20
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POSTOPERATIVE IMMUNE DYSFUNCTION
INTRODUCTION
The immune system is responsible for the identification and removal of pathogens
and foreign substances from the human body. Dysfunctions of the immune system
include an increased immune response (hyper-inflammation) and immune
suppression. 1 Both hyper-inflammation and immune suppression are undesirable
in the perioperative period. This talk will outline aspects influencing perioperative
immunity and focus on the clinical importance of these immune changes
postoperatively.
BASIC IMMUNOLOGY
The immune system consists of many components, its primary function being the
protection of the human body against factors which may damage its tissues. It
consists of physical, chemical, humoral and cellular components. The human
immune system is divided into non-specific or innate immunity and adaptive or
acquired immunity.2
Innate immunity
This is the body’s first line of defence and it is present at birth. It is non-specific
and fast, and needs no previous exposure to the antigen, as it has no ‘memory’.
The innate immune system includes physical barriers like skin and mucous
membranes; chemical barriers like gastric acid; and humoral and cellular
components.
Humoral components include:
Complement, acute phase proteins like CRP and cytokines. Complement is
important in the control of inflammation. Complement activation occurs
sequentially, amplifying the immune response. Activation leads to opsonisation,
chemotaxis, neutrophil activation and bacterial lysis. Acute phase proteins are
produced during an acute infection. They include C-reactive protein, alpha 1 antitrypsin, alpha 2 macroglobulin and fibrinectin. They are involved in the regulation
of mediators during the acute phase of the inflammatory response.
Cytokines are produced by a variety of cells. They have systemic and local
effects, modulating immune responses to surgery and infections. Under normal
conditions there is a balance between pro and anti-inflammatory cytokines.
If this balance is disturbed in favour of pro-inflammatory cytokines, it may lead to
systemic inflammatory response syndrome (SIRS) and multi-organ failure. If antiinflammatory cytokines predominate however, this leads to depressed immunity
and susceptibility to nosocomial infections.
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Cellular
Components of the innate immune system include phagocytic cells
(macrophages, monocytes and neutrophils), natural killer cells, mast cells and
antigen presenting cells.
Leukocytes are produced in response to inflammation and are transported to the
area of tissue injury. They provide a rapid response. Neutrophils kill and remove
bacteria, whilst eosinophils control parasitic infections. Mast cells are present in
connective tissue and NK cells are involved in the immunity against viral infections
and tumour cells. 2
Acquired immunity
This is the ‘memory’ arm of the immune system; it provides a specific immune
response against previously encountered antigens. This response is ‘adaptive’
and increases with repeat antigen exposure. Lymphocytes are its main
component; they produce antibodies which can control elements of the innate
immune system. 2
Lymphocytes can be divided into T lymphocytes and B lymphocytes. T
lymphocytes are predominately responsible for cellular immunity and B
lymphocytes for humoral immunity by producing antibodies.2
T lymphocytes can be divided into the following subgroups:
 Helper T lymphocytes (Th cells) or CD4 lymphocytes: these release
cytokines to activate or regulate other immune cells. These can be further
divided into Th 1 cells (which support cell mediated immunity) and Th 2 cells
(which support humoral immunity.
The balance between Th1 and Th 2 cells is important in immune regulation.
 Cytotoxic T lymphocytes or CD 8 lymphocytes: these cells are important in
direct apoptosis of viral infected cells and tumour cells. They may play a role
in transplant rejection
 Memory T lymphocytes: these can reproduce into effective T lymphocyte
subtypes with repeated antigen exposure to elicit a faster and stronger
immune response.
 Suppressor T lymphocytes: these cells regulate the immune response to
prevent excessive activation. They may play a role in auto immune
diseases.2
B lymphocytes
B lymphocytes supply the humoral element to the adaptive immune system.
Cytokines produced by CD4 lymphocytes lead to maturation of B lymphocytes into
plasma cells which produce antibodies directed against the specific antigen.
These antibodies bind to the antigen forming a complex. This complex is then
removed by phagocytic cells.1, 2
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SURGICAL EFFECTS ON IMMUNE FUNCTION
Surgery and major trauma lead to a ‘surgical stress response’ with endocrine,
immunologic and haematologic effects. Factors affecting the magnitude of this
response include perioperative factors and the degree of tissue injury.
 Endocrine effects:
Endocrine responses to surgery include an increased secretion of pituitary
hormones and activation of the sympathetic nervous system. Tissue injury
activates afferent nerves at the site of injury, the impulse gets transferred to
the hypothalamus via the sensory nerve roots, and activates the
hypothalamic pituitary adrenal axis. Activation of the HPA axis leads to an
increased secretion of ACTH, cortisol, aldosterone, glucagon and AVP. 3
Cortisol levels increase rapidly following tissue injury, reaching a maximum
level at around 6 hours after onset of surgery. The level depends on
severity of tissue damage. Surgical stress also impairs the negative
feedback to control ACTH levels, as both cortisol and ACTH levels remain
high postoperatively.3
Increased cortisol levels lead to hyperglycaemia, lipolysis and decrease in
inflammation by decreasing accumulation of macrophages and neutrophils.
It also leads to a decrease in prostaglandin production3 and an increased
expression of anti-inflammatory gene products.4
Activation of the sympathetic nervous system results from tissue damage.
The increase in catecholamine release results in haemodynamic changes,
including hypertension and tachycardia. Apart from the haemodynamic
effects, ß2 stimulation also leads to a decrease in T lymphocyte proliferation
and NK cell activity. 4
Surgery and trauma are non-pathogenic activators of the immune system,
with resultant changes in cellular and humoral immunity, of both the innate
and acquired immune system. 4 The initial response is pro-inflammatory and
usually short-lived, which is often followed by an anti-inflammatory
response.
The extent of surgery or injury is directly correlated to the magnitude of
immune changes; laparoscopic surgery patients had lower levels of IL6 and
CRP postoperatively3, 5. Changes in immune function are already seen on
the first day post-surgery, and will return to normal after a few days4.
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 Humoral changes:
Major tissue damage leads to the release of pro-inflammatory cytokines as
part of the acute phase response. IL-1 and TNFα are released by
monocytes and macrophages. These cytokines up regulate cell adhesion
molecules, initiate neutrophil migration, increase vascular permeability,
activate the HPA axis and initiate the coagulation cascade. 5
IL-1 and TNFα also trigger IL-6 release, which is proportional to the extent of
tissue injury and the duration of surgery. 5 IL-6 has pro and antiinflammatory effects. Pro-inflammatory effects include an acute phase
response, increasing CRP release and increased neutrophil proliferation.
Anti-inflammatory effects of IL-6 include an increased release of
glucocorticoids, down regulation of IL-1 and TNFα, and stimulating
macrophages to release prostaglandin E2 which is a potent immune
suppressor.1
 Cellular changes:
Tissue trauma leads to a marked suppression of cell mediated immunity
which may predispose patients to sepsis. These changes include a
decrease in monocyte function, lasting for 3 to 5 days. The depression of
monocyte function presents as a lack of TNFα production5 and a decrease
in antigen presenting function, which is associated with poorer outcome.
HLA-DR levels on monocytes are also lower postoperatively, which is
directly correlated to the length and extent of surgery. This is also related to
the decreased monocyte function. 4 Macrophage function is also impaired
after surgery. 6
T lymphocytes show a decrease in mitogenic response after surgery, which
is correlated with the complexity of surgery. The initial response to surgery is
pro-inflammatory, with Th 1 predominating. This shifts to a predominance of
Th 2 and a depressed cellular immunity1. Animal models exposed to surgical
stress had lower levels of lymphocytes than controls, which is due to a
decrease in T cell proliferation4.
B lymphocyte function is also impaired following surgery, with a decrease in
antibody production post-operatively. This presents as an overall decrease
in immunoglobulin level. This is probably caused by a decrease in IL 2
production6.
Interaction between the immune and neuroendocrine system seem to occur,
increasing or decreasing the effect of the other. IL 1 and 6 increase ACTH
secretion, and cortisol decreases cytokine levels3. Disintegration of
regulatory systems lead to a Th1/Th2 imbalance, abnormal macrophage-T
cell interaction and an abnormal cytokine balance5.
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Figure 1 Illustrating the cytokine and corticosterone levels post trauma6
Hours Post Haemorrhage
 Cardiopulmonary bypass
Cardiopulmonary bypass (CPB) and cardiac surgery have an effect on
immune function that is over and above the effect of surgical stress on the
immune system.
Direct contact of blood with a foreign surface and ischaemia-reperfusion
injury to organs leads to further activation of the immune system, and can
result in SIRS and organ dysfunction36.
These effects are compounded by hypothermia and blood transfusion during
cardiac surgery. Off-pump cardiac surgery and minimal access surgery
seem to have fewer effects on the immune system36.
CPB affects all the parameters of the immune system, including cellular and
the humoral components of the innate and adaptive immune system. Initial
activation of the pro-inflammatory response results in SIRS and may result
in organ dysfunction.
This is followed by an anti-inflammatory response with a shift in T
lymphocyte response to Th2 cells. The clinical effect of this compensatory
anti-inflammatory response is not known37.
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ANAESTHESIA RELATED EFFECTS ON IMMUNE FUNCTION
‘It has often been thought that what we do as anaesthesia care providers, barring
any complications in the perioperative period, has little or no impact on long-term
outcome of the patients we interact with.’7 However, anaesthesia causes
reversible, transient changes in immune function, which have little effect on
outcome for most patients, but may be harmful in patients where any
postoperative immune suppression is undesirable.
Anaesthetic agents affect the immune system by direct and indirect ways.
 Direct effects:
All anaesthetic agents seem to have direct suppressive effects on cellular
and humoral aspects of the immune system8; with its main effects being on
inhibition of cell mediated immunity. Changes are time and dose
dependant1. These direct effects of anaesthetic agents include a depression
of the function of immune competent cells and a change in inflammatory
mediator gene expression and secretion9.

Indirect effects:
Indirect effects on the immune system occur by activation of the neurohumoral stress response, which increases with increased duration of use9.
Other effects include disruption of physical and chemical barriers.2
 Effect of different anaesthetic agents on immune function
Different anaesthetic agents have different effects on the immune system,
although most of the agents are immune suppressive in varying degrees.
Most studies done on the effect of anaesthetic agents have been in vitro
studies; in vivo studies are complicated by multiple different variables
affecting immunity in the perioperative period, which makes it difficult to see
the sole effect of the anaesthetic agent on the immune function.
Volatile anaesthetic agents:
 Cellular and humoral immune suppressive effect
 effect is dose and time dependant7, 8.
 decreased neutrophil and macrophage phagocytosis
 decreased reactive oxygen species
 decreased antibody production
 increased lymphocyte apoptosis
 decreased NK cytotoxic activity1, 7.
Propofol:
 immune suppressive effect on the innate immune system similar to
that of volatile agents
 no effect on lymphocyte function
 less perioperative suppression of Th1 cells or NK activity
 overall less immune suppressive than volatile agents. 1
Page 8 of 22
Schneemilch et al compared changes in immune cells postoperatively
between TIVA and volatile anaesthesia groups. Patients who underwent a
balanced anaesthesia with volatile had a greater change in levels of
monocytes postoperatively.
They also had a greater suppression in CD3, CD4 and CD8 cells and a
higher value of IL 6 post-operatively as compared to the propofol group.
Changes in T-lymphocyte distribution where related to post-operative pain.
Thus, propofol seems to have a lesser effect on immune dysfunction than
volatile anaesthesia11.
i.
Midazolam:
 as an infusion in ICU has greater immune suppressive properties than
propofol9.
ii.
Morphine:
 suppression in cellular and humoral elements of the immune system
 likely due to the binding of morphine to μ3-receptors on immune
competent cells, impairing their function1, 7.
 Indirect effects via modulation of the sympathetic nervous system
response and HPA axis activation.
iii.
Synthetic opioids:
 do not intensify postoperative immune suppression
 do not bind to mu receptors
 less immunosuppressive than morphine1.
iv.
Ketamine:
 lower levels of pro-inflammatory cytokines
 depressed neutrophil function
 decreased oxygen free radical production
 decreased adhesion molecule expression9.
Effect of Regional Anaesthesia on immune function
Regional anaesthesia has beneficial effects on the immune function. If used intraoperatively, it decreases the hormonal and metabolic stress response by inhibition
of the activation of the neuro-endocrine system. This is evidenced by lower
levels of cortisol postoperatively, better preserved lymphocyte function, a
maintained Th1: Th2 balance and better NK function1.
Ahlers et al compared the effect of intra-operative use of thoracic epidural
analgesia (TEA) and opioid use on post-operative immune function. TEA
decreased the intra-operative stress response, which was evidenced by lower
intra-operative levels of noradrenaline and cortisol10.
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TEA patients also had higher levels of lymphocytes, T helper cells and IL 10 levels
postoperatively. The clinical outcome between patients was similar. TEA use intraoperatively was found to be useful in decreasing the intra-operative stress
response and its associated impairment in lymphocyte function10.
Other drugs
Other drugs used peri-operatively to decrease the surgical stress response, like
clonidine and ß-blockers, also seem to have favourable effects on the immune
system. ß-blockers supress noradrenaline levels during surgery, leading to a
decrease in monocyte activation. Its indirect anti-inflammatory effects may also be
beneficial for atherosclerosis7.
Clonidine used intra-operatively, showed lower levels of catecholamines and
lower levels of anti-inflammatory immune changes1.
The ideal anaesthesia for patients where any postoperative immune dysfunction is
undesirable could thus include a propofol TCI combined with regional
anaesthesia.
OTHER PERI-OPERATIVE IMMUNE MODULATORS
Perioperative immune modulators include surgical stress, anaesthesia, blood
transfusion, pain and hyperglycaemia1.
Figure 2 – Perioperative immune modulators8
Page 10 of 22
Pain
Pain leads to neuroendocrine activation and adequate postoperative analgesia
can decrease surgical induced immune suppression1, 8.
Surgical tissue trauma stimulates A-delta and C fibres and stimulates release of
cytokines, histamine and prostaglandins.
These combine to activate the neuroendocrine system, leading to release of
glucocorticoids and catecholamines. This leads to an imbalance between Th 1
and Th2 lymphocytes in favour of Th2, resulting in immune suppression1.
Analgesia inhibits activation of the neuroendocrine system, decreasing the
negative effects of pain on immunity. On comparing the efficacy of different
postoperative analgesic regimens, Beilin et al found that patient controlled
epidural analgesia had the least immune modulating effects.
They compared patients receiving postoperative opioids on demand to opioids via
PCA and epidural analgesia. Patients in the epidural group had lower pain scores,
and the least suppression of lymphocyte proliferation.
The improved immune function may be due to improved analgesia or due to a
decrease in opioid usage, which has intrinsic immune suppressive properties12.
Blood transfusion
Patients receiving blood transfusions intra-operatively have higher rates of postoperative infection; this is partly due to post-transfusion immune suppression, also
known as TRIM (transfusion related immune modulation). Transfusing red blood
cells has pro-inflammatory and immunosuppressive effects.
The extent of these changes depends on an interplay of blood transfused, genetic
factors and current illness of the patient38. Blood transfusion has a negative
impact on cellular immunity via depressed lymphocyte dysfunction and a Th1 to
Th 2 imbalance8. Blood transfusions also depress NK cell function and
macrophage function13. TRIM can lead to an increased risk of bacterial infection,
an increase in cancer metastases and an increase in multiple organ failure40.
Many adverse effects of allogenic blood transfusions are related to the leukocytes
in the transfused blood. Leukodepletion can lead to an improved outcome for
some patients40. Removing white blood cells pre-storage can lead to a decrease
in WBC derived bio-active factors which may lead to a decrease in alloimmunisation. Leukodepletion can also alter the ratio of the pro-inflammatory vs.
immune depressive response38.
Benefits of using leukodepleted blood include a decrease in febrile non-haemolytic
transfusion reaction in susceptible patients, a decrease in CMV infection, a
decreased rejection of haemopoetic stem cell transplants and benefits in neonates
and infants39. The value of using leukocyte depleted blood perioperatively is not
known, but limited evidence shows some value in a select group of patients40.
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Table 1: Putative clinical benefits of leukocyte reduction, subdivided as to
whether each benefit has been proven by evidence-based guidelines to
be: Relevant clinically, likely relevant clinically, or are unproven to be
clinically relevant40
A. Proven relevant clinically:
1. Reduced frequency and severity of NHFTRs;
2. Reduced risk of CMV transmission;
3. Reduced risk of HLA-alloimmunization and platelet refractoriness.
B. Likely clinically relevant:
1. Reduced infectious risk associated with immunomodulation (TRIM);
2. Reduced organ-dysfunction and mortality;
3. Reduced direct risk of transfusion-transmission bacteria.
C. Unproven clinically:
1. Avoidance of vCJD transmission.
2. Avoidance of HTLV I/II, EBV etc.
3. Reduced risk of GVHD.
4. Reduced risk of TRALI.
Hyperglycaemia
Perioperative hyperglycaemia has
Hyperglycaemia has negative effects on
of neutrophil phagocytosis, impairment
increased release of pro-inflammatory
adhesion molecules.
pro and anti-inflammatory effects.
leukocyte function. It causes impairment
of reactive oxygen species production,
cytokines and upregulation of cellular
Hyperglycaemia also leads to the glycosylation of circulating immunoglobulins,
rendering them ineffective8. This makes the patient more susceptible to infections
in the perioperative period. Insulin in the perioperative period is beneficial in
preventing a decrease in lymphocyte count in diabetic and non-diabetic cardiac
patients14.
Hypothermia
Perioperative hypothermia can cause impaired wound healing and an increased
risk of postoperative infection. This is due to the impairment of various immune
functions by hypothermia.
Beilin et al. compared patients with mild perioperative hypothermia to patients with
normothermia. The patients that had mild hypothermia (defined as a temperature
of 35) had supressed lymphocyte function and decreased levels of certain
cytokines. This may contribute to the postoperative immune alterations15.
Page 12 of 22
Hypothermia may also contribute to decreased wound healing by
vasoconstriction, leading to decreased oxygen delivery to the injured tissue.
Intraoperative hypothermia can thus contribute to or exacerbate the surgical
induced immune suppression.
CLINICAL IMPLICATIONS:
 Cancer
Oncology patients often present for resection of tumours. However, surgery
itself can lead to an increased risk of metastases. The reason for this is
multifactorial. It includes: shedding cells into the circulation, decreasing
antiangiogenic factors and postoperative immune suppression16. Cancer
patients already have a fragile immune system, supressed from
chemotherapy, radiotherapy and malnutrition. Their immunity can often not
cope with the added stress of surgery17.
A competent immune system is important to fight cancerous cells. CD4
(especially Th 1 cells), CD8 and NK cells are important in cancer immunity.
An increase in Th2 cells relative to Th 1 cells can lead to decreased
immunity and increase in metastases17.
Natural killer cells are important for controlling malignant cells and
preventing metastases. NK cells identify and lyse tumour infected cells.
Patients with higher levels of NK cells have better prognoses. Surgery leads
to decrease in NK level and activity, which can decrease resistance to
tumour growth and metastases18.
Other important factors in the perioperative period also play a role in
immune suppression and cancer recurrence. These include stress, pain,
anaesthetic agents, hypoxia, hypotension, hypothermia, hyperglycaemia
and blood transfusion17.
Anaesthetic agents and cancer surgery
The studies of the effect of anaesthetic agents on cancer spread stems mainly
from in vitro studies, animal studies or retrospective human studies. Data
extrapolated from these are that most anaesthetic agents contribute to
postoperative immune suppression and compromise the patients’ resistance to
metastases. This is mainly via a suppression of NK activity.
Melamed et al compared the effect of ketamine, thiopentone and propofol on NK
activity in rats. Propofol had the least suppressive effect on NK activity;
thiopentone and ketamine had higher rates of tumour retention and metastases.
Thiopentone and ketamine supressed NK activity, but ketamine more than
thiopentone16. Ketamine had the highest risk of metastases in rats. This is
probably due to its sympathetic stimulation and can be partially prevented by ßblocker pre-treatment16.
Page 13 of 22
Propofol does not supress NK activity or lymphocyte activity and had no increase
in metastases in animal studies16. In a small study by Ren et al, Propofol
promoted activation of T lymphocytes, which could assist with anti-tumour
immunity19.
Volatile agents also supress NK activity and increase risk of metastases. This
effect increases with duration of anaesthesia16 .General anaesthesia with volatile
anaesthesia showed worse outcome on survival than local anaesthesia for
melanoma excision20.
Morphine suppresses immunity via actions on μ3 receptors, decreasing NK
activity and impairing cell mediated immunity. This can lead to increase in
metastases of certain cancers. Fentanyl has a dose dependant effect on NK
activity, but remifentanil doesn’t seem to affect NK activity17. Tramadol has
beneficial effects, stimulating NK activity21.
Regional anaesthesia decreases HPA and sympathetic nervous system
activation, preventing perioperative immune suppression. Regional anaesthesia
leads to better preserved NK function and Th1 to Th2 balance.
Further beneficial effects on immunity include decrease in opioid use and
decrease in volatile use, thus negating their negative effects on immunity17 Animal
studies confirm the finding that regional anaesthesia is beneficial in cancer
surgery as compared to general anaesthesia. Spinal anaesthesia led to less
suppression of NK cells and better preservation of Th1/Th2 balance than
sevoflurane alone24.
Three retrospective studies showed an improved recurrence-free survival with
regional anaesthesia compared to general anaesthesia. Exadaktylos compared
mastectomy patients with paravertebral blocks to those without paravertebral
blocks. The patients who had a block had an increased metastatic free survival
rate22. Biki et al compared patients for radical prostatectomy who had received
epidural analgesia to those who didn’t.
Patients with epidural analgesia also had improved recurrence free survival
rates23. De Oliveira et al showed an increase in time to recurrence of ovarian
cancer with intra-operative epidural use, this effect was not found in patients who
had only postoperative epidural use.
Other retrospective studies showed a decrease in recurrence of cancer42 but no
improved outcome43; or only a decreased recurrence in elderly patients, which
may be related to specific tumour types44. Prospective studies are needed to
validate these findings, but these studies do seem to support the theory that
intraoperative use of regional anaesthesia can improve outcome.
Page 14 of 22
Other drugs used in the perioperative period have also been shown to affect
cancer immunity. COX 2- Inhibitors can prevent or decrease morphine induced
tumour growth. It also prevents tumour angiogenesis and tumour growth in
animals21. In a retrospective study, ketorolac administered intra-operatively to
patients for breast cancer surgery decreased the risk of relapse of the breast
cancer25.
ß-blockers can decrease tumour spread by blocking the catecholamine effect.
Chronic high levels of catecholamines shift the lymphocyte balance to Th2 cells.
This leads to a depressed cell mediated immunity. Noradrenaline induces tumour
growth and metastases. In a retrospective study done by Powe et al patients on ßblocker therapy for hypertension had lower tumour recurrence rates and improved
disease free survival following breast cancer surgery26.
 Perioperative events
Hypotension, hypovolaemia and hypoxia activate the HPA and sympathetic
nervous system, which lead to immune suppression and suppressed Th1
response. Tissue hypoperfusion also leads to cellular hypoxia17.
The number of hypotensive episodes (MAP less than 80% of baseline)
during liver metastases resection was the single most important factor
determining recurrence of colorectal cancer, and hypotension should be
avoided to prevent recurrence27.
Hypothermia also supresses immunity by inhibiting NK activity, which can
increase metastatic risk17. However, in the study done by Melamed et al,
hypothermia did not have a significant effect on tumour metastases16.
Hyperglycaemia supresses immunity, but there is currently no data that it
aids tumour spread.
Blood transfusions could also increase the risk of metastases, but the
results are heterogeneous. A meta-analysis by Amato et al, showed a
moderate association between perioperative transfusion and recurrence of
colorectal cancer28.
It could reflect its related immune suppression, but could also be a marker
for a sicker patient or for more extensive surgery17. However, another metaanalysis by McAlister et al. showed no increased risk of death, cancer
recurrence or infection with perioperative blood transfusion in cancer
patients41.
Perioperative nutrition can alleviate some of the postoperative immune
suppression. Immunonutrion with argenine and omega 3 fatty acids can
improve NK function and shift the balance back to Th1 cells. This may aid in
decreasing the risk of metastases17.
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 In summary:
Anaesthetists do play a role in reducing post-operative cancer recurrence
and metastases. Even though most studies are small and retrospective, the
recommendations include the use of propofol TIVA, COX 2 inhibition, and
regional anaesthesia to decrease opioid use. Other future prospects to
improve perioperative immune function are interferon, which induces NK
activity. Results on outcomes for cancer patients are pending21.
Cognitive dysfunction
Postoperative cognitive dysfunction can be caused by direct brain insults from
hypoglycaemia, hypoxia, hypotension or electrolyte disturbances. It can also be
caused by the perioperative immune response29.
Other risk factors include advanced age, increased duration of surgery, previous
stroke, multiple surgeries and postoperative respiratory complications or
infection30. Even though most patients will not develop delirium or cognitive
dysfunction postoperatively, patients with decreased cognitive reserve cannot
compensate for the brain inflammation caused by surgery1.
The immune system and central nervous system are closely related. In the
elderly, any systemic infection can lead to behavioural and cognitive changes.
This is mediated by pro-inflammatory cytokines, which affect the vulnerable brain
of the elderly. Stress and trauma also increase the blood brain permeability to
these cytokines29.
The surgical induced inflammatory response plays a role in the pathogenesis of
postoperative delirium and cognitive dysfunction. The surgical stress response
results in increased levels of IL 6, IL 8 and TNF. These affect the microglial cells,
which secrete cytokines in response. This results in a central inflammatory
response, which is important in the pathophysiology of POCD29, 30.There seems to
be a correlation between increased levels of cytokines and delirium in the
elderly29.
The effect of anaesthesia on POCD is controversial. Some authors have
suggested a protective effect of anaesthetic agents as they are anti-inflammatory,
but this needs to be balanced against their direct toxic effects30.
HIV
The number of HIV infected patients presenting for surgery is rising. This is partly
because of an increased survival of patients with HIV and also because of side
effects form antiretroviral therapy (ART). HIV infects cells of the immune system,
including CD4 cells and macrophages, leading to an impaired cell mediated
immunity.
Page 16 of 22
Surgery is also associated with impairment in cell mediated immunity, however, in
most studies done comparing pre and postoperative CD4 counts, no major
differences were found31, 32 or the decline in CD4 count could not be related to
surgery33. These studies were small and retrospective, but don’t show a decrease
in CD4 count in HIV patients related to surgery or anaesthesia.
Infection and Sepsis
Perioperative alterations in immune function range from an increase in
inflammation which can present as SIRS to a depressed immunity complicated
with wound infection and sepsis. An extensive initial inflammatory response is
often followed by a long lasting immune depression. In fact, the greater the initial
inflammatory response, the greater the subsequent anti-inflammatory counter
regulatory response seems to be34.
Figure 3: Immune changes following trauma6
The initial response to surgery or trauma is often widespread inflammation, which
is beneficial if controlled as it will contain the infection. However if widespread it
can result in SIRS and Multi organ failure. Often SIRS is later followed by CARS
(compensatory anti-inflammatory syndrome) 46. CARS serves to counter regulate
this inflammatory process.
It usually follows SIRS but they can occur concomitantly35. If the antiinflammatory response is uncontrolled it can lead to an increased risk of
infections. Both, SIRS and CARS and lead to complications and mortality5. Most
authors view CARS as compensatory, as a response to SIRS and not as an entity
occurring in isolation46.
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Figure 4: SIRS and CARS46
Postoperatively if anti-inflammatory cytokines predominate, it can predispose
patients to wound infections and sepsis.
The anti-inflammatory response, and thus the infection risk, is proportional to the
magnitude and duration of surgery and the amount of blood lost. Patient with a
decreased T-lymphocyte response are predisposed to sepsis.
A well-functioning perioperative immune system can protect the patient from
postoperative infections. Minimizing changes in immune function can assist in
decreasing infection rate.
This can be done by opting for minimally invasive surgery, perioperative enteral
nutrition, minimizing blood transfusions and avoiding drugs that supress immune
function1.
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THERAPEUTIC OPTIONS
Avoidance of the disturbance of the immune balance can avoid the negative
consequences of post-operative immune dysfunction. This is mainly achieved by
minimally invasive surgery, including laparoscopic surgery, endovascular surgery
and off-pump cardiac surgery.
Other novel therapeutic options include:
 IFN ƴ – can restore monocyte function, it is currently studied in septic
patients
 Indomethacin by blocking the effects of PGE2
 Recombinant G-CSF
 Dietary supplements: glutamine, arginine and omega 3
 Ranitidine
 Pentoxyfilline
 Hydroxyethyl starch
All of the above aim to restore the immune balance, but need further investigation
before routine use in clinical practise6.
SUMMARY
We as anaesthetists often think that our role in the treatment of patients ends
once the patient has been discharged from the recovery unit, or at the very latest,
once the patient has been discharged from hospital. This talk was aimed to
introduce the idea that what we do peri-operatively can have long-lasting
implications for the patient. Inflammation plays a vital role in many diseases and
its implications peri-operatively are widespread, including cancer spread, cognition
and infection. Managing the inflammatory response appropriately in the
perioperative period can lead to improved outcomes for certain groups of patients.
Page 19 of 22
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