REVIEW
URRENT
C
OPINION
Can anaesthetic technique effect
postoperative outcome?
Trevor Kavanagh a and Donal J. Buggy a,b
Purpose of review
Conventional wisdom maintains that multiple aspects of surgical technique and management may
affect postoperative outcome, while anaesthetic technique has little long-term effect on patient
outcomes. There is accumulating evidence that, on the contrary, anaesthetic management may in fact exert
a number of longer-term effects in postoperative outcome. Here, we review the most topical aspects of
anaesthetic management which may potentially influence later postoperative outcomes.
Recent findings
There is strong evidence that administration of supplemental oxygen and the avoidance of
perioperative hypothermia, allogeneic blood transfusion, hyperglycaemia or large swings in blood
glucose levels reduces postoperative infection rates. There is also some evidence that the use of regional
anaesthesia techniques reduces chronic postsurgical pain and that avoidance of nitrous oxide reduces
the long-term risk of myocardial infarction. Current evidence is equivocal regarding the effects of
anaesthesia techniques and cancer recurrence. The instigation of perioperative beta-blockade in
noncardiac surgery may not reduce perioperative adverse events or improve postoperative
cardiovascular risk.
Summary
Further prospective, large-scale human trials with long-term follow-up are required to clarify the association
between anaesthesia and cancer recurrence, neurotoxicity and the developing brain and long-term
postoperative cognitive dysfunction in the elderly.
Keywords
anaesthesia, cancer, long-term outcomes
INTRODUCTION
Conventional wisdom maintains that anaesthetic
technique has little influence on long-term patient
outcomes, other than securing their safety, analgesia and comfort perioperatively.
This conviction is being challenged by gradually
accumulating evidence that, on the contrary,
anaesthetic management may indeed exert some
hitherto unrecognized longer-term influences.
The list below summarizes the postoperative
outcomes evaluated in this study:
(1)
(2)
(3)
(4)
(5)
surgical site infections (SSIs);
cancer recurrence and metastases;
chronic postsurgical pain;
blood transfusion requirements;
postoperative myocardial infarction (MI) and
stroke;
(6) neurocognitive effects on the immature brain;
and
(7) cognitive dysfunction in the elderly.
WOUND HEALING AND SURGICAL SITE
INFECTION
SSI is the infection in surgical wound which occurs
postoperatively. It is a significant cause of major
morbidity and increased economic cost. All surgical
wounds become contaminated; whether it develops
into a clinical infection depends on the balance
between intrinsic patient, surgical and anaesthetic
risk factors [1]. A major requirement for resisting SSI
and successful wound healing is adequate delivery
of oxygen to the tissues. Oxygen is required not
only for tissue basal metabolism, but also for the
a
Department of Anaesthesia, Mater Misericordiae University Hospital,
Dublin, Ireland and bOutcomes Research Consortium, Cleveland, Ohio,
USA
Correspondence to Donal J. Buggy, Department of Anaesthesia, Mater
Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland. Tel:
+353 1 8301122/2281; e-mail: [email protected]; [email protected]
Curr Opin Anesthesiol 2012, 25:185–198
DOI:10.1097/ACO.0b013e32834f6c4c
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KEY POINTS
There is strong evidence that administration of
supplemental oxygen and the avoidance of
perioperative hypothermia, allogeneic blood
transfusion, hyperglycaemia or large swings in blood
glucose levels reduces postoperative infection rates.
There is some evidence that the use of regional
anaesthesia techniques reduces chronic postsurgical
pain and that avoidance of nitrous oxide reduces the
long-term risk of myocardial infarction.
Current evidence is equivocal regarding the effects of
anaesthesia techniques and cancer recurrence.
The instigation of perioperative beta-blockade in
noncardiac surgery may not reduce perioperative
adverse events or improve postoperative
cardiovascular risk.
Further prospective, large-scale human trials with longterm follow-up are required to clarify the association
between anaesthesia and cancer recurrence,
neurotoxicity and postoperative cognitive dysfunction.
formation of collagen (via proline hydroxlyase,
an oxygen-dependent enzyme) [2]. Thus, a low
tissue oxygen partial pressure can interfere with
wound healing and result in poor collagen deposition leading to scar tissue of lower tensile strength
and hence more prone to breakdown. Furthermore,
oxygen is also a vital substrate for neutrophils
and other phagocytic cells of the immune system,
where it is metabolized by the enzyme neutrophil
hydroxylase to superoxide and hydrogen peroxide
free radicals, which kill bacteria [3].
Many of the factors controlling tissue perfusion
and hence oxygenation are influenced by anaesthetic management and are encapsulated by the
Hagen–Poiseuille Law (Table 1) [1].
In addition, suppression of thermoregulatory
defence mechanisms during general anaesthesia
is dose dependent and results in perioperative
hypothermia [4]. Untreated inadvertent hypothermia causes autonomically mediated thermoregulatory vasoconstriction (increasing tissue vascular
resistance) and reduces tissue oxygen partial
pressure, thereby increasing the risk of SSI during
the critical few hours following surgery when infection is initiated [5].
The effect of active warming with a forced convective air warmer was evaluated in a prospective
study which randomized 200 patients undergoing
colorectal surgery to either routine intraoperative
thermal care (core temperature allowed to decrease
to approximately 34.58C) or active warming
(core temperature maintained at 36.58C) [6].
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Table 1. Hagen-Pouseille Law for factors affecting
flow (Q) along a tube (artery)
4
pR
Q ¼ dP8Lm
Where, DP ¼ pressure drop
m ¼ viscosity
L ¼ length of tube
r ¼ radius of circular tube
Q ¼ flow rate
Therefore flow (Q) is proportional to the
pressure gradient (i.e. perfusion pressure
of the organ), and the fourth power of the
radius of the artery. Accordingly, halving
of the effective radius of the artery
(e.g. due to atherosclerotic disease)
reduces the flow x16
SSIs were found in 19% of patients assigned to
hypothermia but in only 6% of patients assigned
to normothermia (P ¼ 0.009). Time to discharge
from hospital was prolonged in the hypothermia
group 14.7 6.5 vs. 12.1 4.4 days in the normothermia (P ¼ 0.001). Therefore, maintaining normothermia intraoperatively reduces the incidence of
SSI in patients undergoing colorectal resection and
shortens their hospitalization.
Another prospective randomized trial of 421
patients investigating the effects of preoperative
active warming prior to surgery found reduced
infection rates 2–6 weeks after surgery, from 14%
in the nonwarmed group to 5% in the actively
warmed group [7], with an absolute risk reduction
of 7.9% [95% confidence interval (CI) 1.0–14.8]
with systemic warming and 10.1% (3.6–16.6) with
local warming.
Other perioperative factors which alter tissue
oxygen partial pressure and hence impact on SSI
are neuroendocrine stress response and acute postoperative pain. Both result in sympathetically
mediated vasoconstriction, thus potentially reducing tissue oxygen partial pressure levels sufficiently
to increase the risk of surgical wound infection [8].
Furthermore, the use of regional anaesthesia and
analgesia may be superior to opioid-based analgesic
regimens in increasing tissue oxygen tension
through vasodilatation via sympathetic blockade
[9,10].
As the final common pathway influencing
SSI risk is tissue oxygen tension, administering
supplemental perioperative oxygen reduces surgical
site infections. Patients were randomly assigned to
either 30 or 80% fraction of inspired oxygen (FiO2)
intraoperatively and for 6 h after surgery. Surgical
site infection rates were reduced from 24% in
patients administered FiO2 ¼ 0.3 compared with
15% administered FiO2 ¼ 0.8, P ¼ 0.04 [11]. The risk
of SSI was 39% lower in the FiO2 ¼ 0.8 group [relative
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Anaesthetic technique and cancer outcome Kavanagh and Buggy
risk (RR) 0.61; 95% CI 0.38–0.98] vs. the FiO2 ¼ 0.3
group.
These data are consistent with the results of
a similar previous study of 500 colorectal patients
randomized to FiO2 ¼ 0.3 or FiO2 ¼ 0.8% [12]. They
found a reduction in postoperative infection
rates from 11% (95% CI 7.3–15.1%) to 5% (95%
CI 2.4–8.0%; P ¼ 0.01). However, this benefit was
not replicated in obese patients [13,14].
Increasing the tissue oxygen tension above
a certain threshold may not reduce the risk of
infection any further. A double-blind prospective
trial of 143 women undergoing caesarean delivery
under regional anaesthesia was randomly assigned
to receive low-concentration or high-concentration
inspired oxygen via nonrebreathing mask during
the operation and for 2 h after the operation [15].
The study was halted after interim analysis of the
first 25% of the planned sample size showed no
benefit. Infection occurred in 25% (95% CI 15–
35%) of 69 women assigned to high-concentration
oxygen compared with 14% (95% CI 6–22%) of
74 women assigned to low-concentration inspired
oxygen (RR 1.8, 95% CI 0.9–3.7; P ¼ 0.13).
Taken together, it seems that an anaesthetic
management regimen that preserves physiological
perfusion pressure, maintains adequate tissue oxygenation, avoids inadvertent perioperative hypothermia and maximizes analgesia, preferably with
a regional technique, significantly reduces the risk
of SSI.
CANCER RECURRENCE
Surgery is the primary and most effective treatment
of many forms of cancer, but residual disease in
the form of scattered micrometastases and tumour
cells is inevitable. Whether minimal residual disease
results in clinical metastases depends on the balance
between host immune defence and tumour survival
and growth. At least four perioperative factors shift
the balance towards the progression of minimal
residual disease:
(1) Surgery per se depresses cell-mediated immunity, increases concentrations of proangiogenic
factors such as vascular endothelial growth
factor (VEGF) and releases growth factors that
promote growth of malignant tissue [16].
(2) Anaesthesia per se impairs numerous immune
functions, including those of neutrophils,
macrophages and natural killer cells [17].
(3) Postoperative pain, an inevitable consequence
of cancer surgery, has itself been shown to
facilitate metastatic spread of cancer in a live
animal model [18].
(4) Opioid analgesia, the mainstay of treatment
of postoperative pain and cancer pain, inhibits
cellular immune function in humans, increases
angiogenesis and promotes breast tumour
growth in rodents [19].
However, regional anaesthesia and analgesia
attenuates or prevents each of these adverse effects
by largely preventing the neuroendocrine surgical
stress response, eliminating or reducing the need for
general anaesthesia and minimizing opioid requirement [20]. Animal studies indicate that regional
anaesthesia and optimum postoperative analgesia
reduces the metastatic burden in animals inoculated
with breast adenocarcinoma cells following surgery
[21]. There appears to be an inverse relationship
between host natural killer cell activity and cancer
recurrence, and host natural killer cell activity has
been shown to be modulated by both perioperative
stress and numerous anaesthetic and analgesic drugs
[18,22,23 ].
Nitrous oxide, by inhibiting methionine synthetase, reduces DNA and purine synthesis and
suppresses neutrophil chemotaxis, potentially
facilitating cancer spread. However, a FARCT
(follow-up analysis of a previous randomized
controlled trial) of 204 patients undergoing colon
resection for bowel cancer, in which patients were
randomly assigned to nitrous oxide or air (FiO2 35%
standardized between groups) with isoflurane and
remifentanil based anaesthesia, found no statistically significant difference in cancer recurrence rates
with a hazard ratio estimate of 1.10 (95% CI 0.66–
1.83; P ¼ 0.72) [24].
Although many opiates including morphine
cause suppression of both cell-mediated and
humoral immunity [19], tramodol appears to have
the opposite effect in humans and has been shown
to enhance natural killer cell activity and reduce
surgery-induced immune suppression and the associated higher metastatic burden in animal models
and humans [25,26].
NSAIDS work by inhibiting the enzyme cyclooxygenase which is required for prostaglandin
synthesis by tumour cells. In a live animal
model, a single perioperative dose of indomethacin,
etodolac or celecoxib blunted the surgical stressresponse induced suppression of natural killer cell
cytotoxicity and reduced lung metastatic tumour
retention (with additional benefit when used with
a single dose of propranolol) [27,28]. In a retrospective single-centre study of 327 consecutive women
undergoing breast cancer surgery, the perioperative
administration of ketorolac (but not diclofenac,
due perhaps to a drug-specific, cyclo-oxygenase
independent effect of ketorolac) was associated with
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Table 2. Retrospective analyses of anaesthesia/analgesia techniques and cancer recurrence rates
Type cancer
Authors
Journal, year
Anaesthesia/analgesia
technique
Colorectal
Gupta et al. [19]
BJA, 2011
Epidural
Reduced cancer
recurrence
Rectal CA – Yes
Colon CA – No
a
Breast
Forget et al. [29]
Anesth Analg, 2010
Intraoperative ketorolac
Yes
Breast
Exadaktylos et al. [31]
Anesthesiology, 2006
Paravertebral analgesia
Yes
Prostate
Biki et al. [32]
Anesthesiology, 2008
Epidural
Yes
Colorectal
Gottschalk et al. [33]
Anesthesiology, 2010
Epidural
No
Prostate
Tsui et al. [34]
Can J Anesth, 2010
Epidural
No
Mixed intra-abdominal
cancers
Myles et al. [35 ]
Epidural
No
&
a
BMJ, 2011
Follow-up analysis of previous randomized controlled (MASTER) trial.
a lower cancer recurrence rate (6 vs. 17%, hazard
ratio 0.41, 95% CI 0–0.19; P ¼ 0.019) [29]. Local
anaesthetic agents in animal and in-vitro models
may also have tumour-suppressive effects. In-vitro
lidocaine inhibits tumour cell proliferation and
invasiveness [30].
Given the potential immune-suppressive effects
of the surgical stress response, general anaesthetics
and opiates and the potential cancer-resistance
effects of some NSAIDs and local anaesthetics,
there appears to be a plausible rationale that an
anaesthetic technique consisting of regional anaesthesia with propofol only general anaesthesia
and nonopioid supplementary analgesia for cancer
surgery might potentially reduce recurrence or
metastasis. All human trials looking directly at
cancer recurrence rates have been retrospective
analyses. A retrospective study of 129 consecutive
patients undergoing mastectomy and axillary clearance for breast cancer found that sevoflurane anaesthesia with paravertebral analgesia was associated
with lower cancer recurrence rates (P ¼ 0.012)
compared to opioid-based analgesia [31]. A review
of 225 patients who underwent open radical
prostatectomy for invasive prostate carcinoma found
that those who received general anaesthesia plus
epidural analgesia had an estimated 57% (95% CI
17–78%) lower risk of recurrence compared with
general anaesthesia plus opioid analgesia (95% CI
0.22–0.83; P ¼ 0.012) [32].
Other retrospective reviews however, have not
found any such association [33,34] (Table 2).
A recently published long-term follow-up of the
prospectively randomized controlled MASTER trial
(n ¼ 446) in which patients were randomly assigned
to receive general anaesthesia with or without
epidural block failed to show an improved cancerfree survival in the epidural group [35 ]. The median
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time to recurrence of cancer or death was 2.8
(95% CI 0.7–8.7) years in the control group and
2.6 (0.7–8.7) years in the epidural group (P ¼ 0.61).
Recurrence-free survival was similar in both epidural
and control groups (hazard ratio 0.95, 95% CI 0.76–
1.17; P ¼ 0.61) prompting the authors to support
expedition of the established randomized trials as
soon as possible.
A prospective, international trial is ongoing,
randomizing patients with primary breast cancer
to an ‘anticancer’ anaesthetic technique (consisting
of paravertebral regional anaesthesia and analgesia
and propofol only general anaesthesia) vs. standard
balanced general anaesthesia (based on volatile
agent maintenance and opioid analgesia). Over
400 patients are enrolled already (NCT00418457).
In a smaller study (n ¼ 22), postoperative
serum from women enrolled in this trial undergoing
breast cancer surgery randomized to propofol/paravertebral anaesthesia–analgesia exhibited greater
in-vitro inhibition of the proliferation of breast
cancer cells vs. those randomized to sevoflurane
general anaesthesia with opioid analgesia (P ¼ 0.01)
[36]. This suggests that regional anaesthetic techniques, with superior analgesia, can alter the serum
molecular milieu in ways less conducive to breast
cancer cell function. In similar studies (n ¼ 40),
the propofol-paravertebral anaesthetic technique
was associated with much lower postoperative
proangiogenic levels of VEGF-C (P ¼ 0.001) and
higher levels of antiangiogenic transforming growth
factor beta (P ¼ 0.005) [37], and with increased
expression of metastasis-promoting matrix metalloproteinases [38].
Recently, the direct effect of morphine on
breast cancer cell function was evaluated in vitro
and found that it facilitates migration and
proliferation in breast cancer cells, and that this
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Anaesthetic technique and cancer outcome Kavanagh and Buggy
may be mediated by the cancer-associated NET1
gene [39].
The outcome of the ongoing clinical trial must
be awaited for definitive answers to the influence of
anaesthetic techniques on recurrence or metastases.
PERIOPERATIVE GLYCAEMIC CONTROL
AND LONG-TERM OUTCOMES
It is well established that long-term glycaemic control in diabetic patients results in lower morbidity
and mortality rates. The question here is whether
short-term tight perioperative glycaemic control
can influence longer-term outcomes.
The concept of tight glycaemic control was
developed in 2001 with a prospective trial of 1548
intensive care patients randomized to either blood
glucose maintained between 4.4 and 6.1 mmol/l
or allowed to reach 11.9 mmol/l respectively [40].
Results showed a reduction in ICU mortality from
8 to 4.6% in the tight glycaemic control group
(P ¼ 0.04). Unfortunately, these results from a single
centre have not been replicated by later, multicentre
studies. Furthermore, concern over more frequent
occurrences of hypoglycaemia [6.8 vs. 0.5%, odds
ratio (OR) 14.7; 95% CI 9.0–25.9; P < 0.001] and
increased mortality (27.5 vs. 24.9%, OR for death
with intensive control 1.14, 95% CI 1.02–1.28;
P ¼ 0.02) in those patients treated with intensive
insulin therapy have overshadowed this regimen
[41].
But what of perioperative glucose control?
In a prospective trial, 400 patients undergoing
coronary artery bypass grafting (CABG) under
cardiopulmonary bypass (CPB) were analysed comparing intraoperative tight glycaemic control
(target blood glucose 4.4–5.6 mmol/l) with conventional treatment (no insulin unless blood glucose
>11.1 mmol/l) [42]. This study included both diabetic and nondiabetic patients, as there is mounting
evidence that stress-induced hyperglycaemia is also
deleterious [43 ]. Their results showed a statistically
significant increase in the incidence of stroke in
the tight glycaemic control group from 0.0049 to
0.04% (RR 8; P ¼ 0.02) and a trend towards increased
mortality (P ¼ 0.061).
In a prospective study of 2467 diabetic patients
undergoing open heart surgery, perioperative tight
glycaemic control via a continuous insulin infusion
vs. intermittent insulin injections with more lax
blood glucose targets was associated with a 66%
decrease in deep sternal wound infections (0.8 vs.
2%, P ¼ 0.01) [44]. But, it has been suggested that
this benefit may be attributable to reduced variability in patient blood glucose levels rather than
lower blood glucose levels per se.
&
Another prospective, single-centre trial looking
at the rates of perioperative hypoglycaemic episodes
randomized 483 normal patients undergoing
elective or emergent intracranial procedures to
intensive or conventional glycaemic management
[45]. A greater fraction of patients in the intensive
glucose treatment group had hypoglycaemic
episodes (94 vs. 63% for conventional treatment;
P ¼ 0.0001), but they also had a lower incidence of
infections (26 vs. 39% for conventional therapy;
P ¼ 0.002).
In a single-centre, prospective, observational
study looking at tight perioperative glycaemic
control in vascular surgery, 236 normal nondiabetic
patients were randomly assigned to continuous
insulin infusion (target glucose 5.6–8.3 mmol/l,
aimed at reducing hypoglycaemic events during
the study period) or to a standard intermittent
insulin bolus (treat glucose >8.3 mmol/l) [46].
Treatments continued for 48 h with patients being
followed until hospital discharge. Results showed
a significant reduction in composite primary endpoints (all-cause death, MI and acute congestive
heart failure) to 3.5% compared with 12.3% in
the control group (RR 0.29; 95% CI 0.10–0.83;
P ¼ 0.013). Multivariate analysis demonstrated that
continuous insulin infusion was a negative independent predictor (OR 0.28; 95% CI 0.09–0.87;
P ¼ 0.027) of adverse events.
A retrospective analysis of 4302 patients was
conducted to compare the influence of intraoperative vs. postoperative glucose concentrations
on risk of postoperative adverse outcomes after
cardiac surgery [47 ]. Patients (with and without
diabetes) who had intraoperative hyperglycaemia
of more than 11.1 mmol/l had a 90% increase in
OR for mortality and approximately 50% increase in
OR for overall morbidity. Patients with diabetes,
despite being at increased risk for adverse outcome
because of having diabetes, were at similar risk as
patients without diabetes related to the degree of
hyperglycaemia. Increased postoperative glycaemic
variability was also associated with increased risk for
adverse outcomes. Those patients who showed mild
intraoperative hyperglycaemia (7.8–9.4 mmol/l)
showed the lowest risk of mortality and overall
morbidity. Postoperative hyperglycaemia is also
an independent risk factor for surgical site infections
[44,48].
A review in 2009 concluded that ‘Although
it is clear that hyperglycaemia is harmful, there is
currently insufficient evidence to support the
routine use of tight glycaemic control (target blood
glucose 4.4–6.1 mmol/l) in the operating room
or the ICU’ [49]. The role of perioperative tight
glycaemic control and its effects in modulating
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the long-term neurological outcome in patients
who have experienced or are at risk for ischaemic
brain injury remains to be elucidated. However,
there emerging evidence that long-term infection
risk and cardiovascular morbidity/mortality, may be
optimized by:
(1) avoiding perioperative hyperglycaemia (while
accepting higher blood glucose values than
originally described by van den Berghe) in both
diabetic and nondiabetic patients; and
(2) administering insulin via a continuous intravenous infusion thereby avoiding large swings
in blood glucose values.
BLOOD TRANSFUSION
Complications from blood transfusions are well
documented [50]. Although many of these occur
immediately or early in the perioperative period,
others occur much later. The immunomodulatory
effects of transfused allogeneic blood products have
the potential to increase the risk of postoperative
infections and cancer recurrence. A meta-analysis of
prospective, randomized controlled trials totalling
13 152 patients comparing those who did and did
not receive allogeneic blood (without distinguishing
quantity) showed an OR in those transfused of 3.45
(range 1.43–15.15) for increased risk of all types of
postoperative bacterial infection [51]. The effects of
transfusion-related immunomodulation on cancer
recurrence rates remains controversial [52], but there
is growing evidence that transfusion of allogeneic
red cells, especially those stored for more than 9 days,
promotes tumour growth [53]. A retrospective
analysis of 6002 patients who received blood during
CABG or heart valve surgery found that those
who received blood stored for more than 14 days
(n ¼ 2872, median 20 days) had higher rates of
in-hospital mortality (2.8 vs. 1.7%, P ¼ 0.004), renal
failure (2.7 vs. 1.6%, P ¼ 0.003), and sepsis (4.0 vs.
2.8%, P ¼ 0.01) compared to those who received
blood which had been stored for less than 14 days
(n ¼ 3130, median 11 days) [54]. At 1 year, mortality
was significantly less in patients given blood less
than 14 days old (7.4 vs. 11.0%, P < 0.001).
A long-term follow-up study (mean survival
49 months) of 67 patients who underwent pancreatoduodenectomy for carcinoma found that
transfusion of 3 or more units of allogeneic red cells
was associated with significantly poorer median
(25 months) and cumulative 3-year and 5-year
survivals (36.7 and 30.2%) than those of patients
transfused with 2 units and/or nontransfused
patients and was an independent poor prognostic
factor (RR 2.082, 95% CI 1.48–4.315; P ¼ 0.036) [55].
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So how can anaesthetic and perioperative management reduce blood transfusion requirements?
One of the most significant predictors of
requirement for allogeneic transfusion is a low preoperative haemoglobin level. Anaesthetists aware of
preoperative anaemia may address this by preoperative treatment with (intravenous) iron and
erythropoietin [56]. Mild inadvertent hypothermia
(core body temperature <36.48C), with its deleterious effects on coagulation, significantly increases
perioperative blood loss and increases allogeneic
transfusion requirements [57]. Therefore, maintaining intraoperative normothermia using active
warming methods not only reduces postoperative
infection rates and reduces hospital length of stay,
vide supra, but also reduces perioperative surgical
bleeding and blood transfusion requirements and its
associated longer-term complications.
Cell salvage is safe and effective at reducing
allogeneic blood transfusion requirements and
should be considered in all cases where significant
blood loss is expected [58]. Not only does cell salvage
reduce allogeneic transfusion requirements, it may
also increase survival after oesophagectomy when
compared with allogeneic blood transfusion [59].
The use of antifibrinolytic agents has been shown
to reduce blood loss during cardiac, urologic and
orthopaedic procedures [60].
The effects of perioperative haemodilution
in reducing transfusion requirements is less clear,
as the dilutional effect occurs not only on red cells
but also on coagulation factors and hence may be
counterproductive, leading to reduced haemostasis.
A recent prospective randomized study of 192
patients undergoing cardiac surgery under CPB
found that restrictive intraoperative fluid administration [intravenous fluids preoperatively limited to
500 ml hydroxyethylstarch 6% (Voluven) accounted
for 95% of fluid administered; 328 157 ml] led to
reduced red cell transfusion requirements compared
with liberal fluid administration (at anaesthetists
discretion: HES 6% accounted for 50% with the
rest being crystalloid; 642 222 ml). Those who
were transfused required fewer red cell units intraoperatively: 31 units in 19 patients vs. 111 units in
62 patients; P < 0.001 [61 ].
Propofol was associated with greater peripheral
blood flow compared with sevoflurane as assessed by
laser Doppler flowmeter during the prehypotensive
intraoperative period and also the hypotensive
intraoperative period in 28 patients undergoing
spine surgery [62]. Despite this, blood loss and intraoperative bleeding were significantly reduced in the
propofol group (106 59 vs. 315 99 ml; P ¼ 0.004).
The authors suggest a selective vasodilatory effect
of propofol (postcapillary, venous vasodilation),
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Anaesthetic technique and cancer outcome Kavanagh and Buggy
different from that of sevoflurane (precapillary,
arteriolar vasodilation).
A well performed, prospective, randomized
controlled trial looking at induced intraoperative
hypotension (hypotension achieved by increasing
the inspired isoflurane concentration) during
orthognathic surgery found that MAP of 55–
65 mmHg was associated with significantly less total
blood loss (454 211 ml) compared to MAP 75–
85 mmHg (755 334 ml; P < 0.001) [63]. There is
little evidence that any one method of controlled
intraoperative hypotension is superior in reducing
intraoperative blood loss.
Strategies to minimize perioperative allogeneic
blood transfusion are summarized in Table 3.
PERIOPERATIVE b-BLOCKADE
Perioperative b-blockade, by attenuating the perioperative stress response, has been hypothesized
to reduce the risk of cardiovascular events following
noncardiac surgery. A recent meta-analysis of 33
trials including 12 306 patients looking at the use
of b-blockers in noncardiac surgery extracted data
for 30-day all-cause mortality, cardiovascular
mortality, nonfatal MI, nonfatal stroke, heart
failure and myocardial ischaemia [64]. The authors
concluded that ‘evidence does not support the use
of b-blocker therapy for the prevention of perioperative clinical outcomes in patients having
noncardiac surgery’. But, does the temporary perioperative instigation of b-blocker therapy in
patients not already on a b-blocker alter the longerterm postoperative cardiovascular risk?
The largest, randomized, placebo-controlled,
blinded, multicentre trial published to date looking
at this question investigated 921 diabetic patients
undergoing major noncardiac surgery [65]. Patients
were randomized to 100 mg metoprolol extended
release (n ¼ 462) or placebo (n ¼ 459) administered
from the day before surgery to a maximum of eight
perioperative days. The composite primary outcome
measure was time to all-cause mortality, acute MI,
unstable angina or congestive heart failure. The
primary outcome occurred in 21% of patients
in the metoprolol group and 20% of patients in
the placebo group (hazard ratio 1.06, 0.80–1.41)
during a median follow-up of 18 months. All-cause
mortality was 16% (74/462) in the metoprolol
group and 15.7% (72/459) in the placebo group
(1.03, 0.74–1.42).
The POISE trial [PeriOperative Ischaemic
Evaluation trial: perioperative extended-release
metoprolol succinate (n ¼ 4174) started 2–4 h before
surgery and continued for 30 days vs. placebo
(n ¼ 4177)] included a total of 8351 patients with,
or at risk of, atherosclerotic disease who were
undergoing noncardiac surgery [66]. The primary
endpoint was a composite of cardiovascular death,
nonfatal MI and nonfatal cardiac arrest within
30 days. Although fewer patients in the metoprolol
group than in the placebo group had an MI (4.2 vs.
5.7%, P ¼ 0.0017), there were more deaths in the
metoprolol group than in the placebo group (3.1 vs.
2.3%, P ¼ 0.0317). More patients in the metoprolol
group than in the placebo group had a stroke (1.0 vs.
0.5%, P ¼ 0.0053). The report on the 1-year followup data from this study, which will represent by far
the largest such long-term follow-up of the effects
of perioperative b-blockade, is still awaited. If these
data demonstrate a benefit at 1 year, clinicians
and patients will have to balance this benefit
against the 30 day excess of death and stroke with
a b-blocker, as demonstrated in the original POISE
study and subsequent meta-analysis.
THE USE OF NITROUS OXIDE
The continued use of nitrous oxide in modern
anaesthetic practice, despite its long history, has
been repeatedly called into question. There are
plausible reasons to suspect increased long-term
cardiovascular risk in patients receiving significant
exposure to nitrous oxide. Nitrous oxide oxidizes
the cobalt atom on vitamin B12, inactivating
methionine synthase and causes a dose-dependent
Table 3. Strategies to minimize perioperative allogeneic blood transfusion
Strategy for reducing perioperative blood loss and transfusion
Putative mechanism
Preoperative treatment with iron and erythropoietin [56]
Increases preoperative haemoglobin level
Maintenance of intraoperative normothermia [57]
Avoids deleterious effects of hypothermia on coagulation function
Cell salvage [58]
Reduces exposure to allogeneic blood
Antifibrinolytic agents [60]
Reduces blood loss
Intraoperative fluid restriction precardiopulmonary bypass [61 ]
Reduces haemodilution
Propofol anaesthesia [62]
Less arteriolar vasodilatation and blood loss
Hypotensive anaesthesia [63]
Lowers mean arterial pressure
&
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Ethics, economics and outcome
increase in plasma homocysteine concentrations
for days after surgery [67]. Acutely increased plasma
homocysteine concentrations impair endothelial
function, enhance platelet aggregation, induce
oxidative stress and potentially destabilize coronary
artery plaques [68]. Nitrous oxide -based anaesthesia
has been reported to increase the incidence of myocardial ischaemia within 48 h and cardiovascular
events within 30 h postoperatively [69].
The largest, prospective, randomized, multicentre trial (ENIGMA trial) looking at the effects
of nitrous oxide-based anaesthesia and postoperative outcomes recruited 2050 patients having noncardiac surgery lasting more than 2 h [70]. Patients
were randomized to nitrous oxide-based (70 : 30)
or nitrous oxide-free anaesthesia (80 : 20, O2 : N2).
Within 30 days of surgery, 16 patients had died
(nine in the nitrous oxide group and three in the
nitrous oxide-free group; P ¼ 0.10). Thirteen patients
in nitrous oxide vs. seven patients in nitrous
oxide-free group had a confirmed postoperative MI
(P ¼ 0.20). There was no significant difference in the
hospital length of stay.
A subsequent long-term follow-up study of the
ENIGMA patients (median follow-up of 3.5 years)
found that the administration of nitrous oxide was
associated with an increased long-term risk of MI
(37/641, 5.8% vs. 54/649, 8.3%, adjusted OR 1.59,
95% CI 1.01–2.51; P ¼ 0.04) but not of death or
stroke in patients enrolled in the ENIGMA trial
[71 ].
A potential limitation of the ENIGMA trial was
that inspired O2 concentrations were not the same
in the two groups. Relatively, unselected patients
were recruited with low 30-day and long-term event
rates. The study therefore may have been underpowered to confidently confirm a ‘true’ increased
risk of early postoperative MI in patients receiving
nitrous oxide. Consequently, a larger multicentre
randomized blinded trial of nitrous oxide-based vs.
nitrous oxide–free anaesthesia in 7000 noncardiac
surgery patients who have or are at risk of ischaemic
heart disease has been commenced (ENIGMA-II
trial) [72]. The results of this large international trial,
due to be completed next year, will help clarify
the association between nitrous oxide-based anaesthesia and long-term cardiovascular complications.
&&
PERIOPERATIVE PAIN MANAGEMENT
AND THE DEVELOPMENT OF CHRONIC
PAIN
Chronic postsurgical pain (CPSP) is a pain syndrome
whereby postoperative pain persists for more than
2 months after surgery with other causes for pain
(e.g., pre-existing disease, recurrence of malignancy,
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chronic infection, etc.) excluded [73]. Known risk
factors include patient factors (female sex, young
age, obesity, preoperative anxiety, catastrophizing
attitude and pre-existing pain) and surgical factors
(invasive procedures: redo interventions, surgery
in a previously injured area and particular surgical
techniques) [74]. Acute postoperative pain intensity
is also a strong predictor for the development of
CPSP, though prospective studies on this point
have produced mixed results. In a double-blinded,
randomized controlled trial (n ¼ 82), maximal
movement-evoked pain intensity over the first
two postoperative days following total hip arthroplasty failed to predict the presence of CPSP
6 months later (P ¼ 0.38) [75]. Conversely, higher
postdelivery pain following casesarean section was
indeed found to be a predictor of chronic pain [76].
Some investigators believe that surgery, by cutting
nerves or initiating prolonged inflammatory
reactions, is the major determinant of CPSP [77].
Although no large prospective trial has confirmed
that any specific anaesthetic intervention reduces
the risk of CPSP, there is some evidence in smaller
trials. In a single-centre, prospective, randomized
controlled trial of 38 consecutive eligible patients
undergoing elective thoracotomy under general
anaesthesia, patients were randomized to either
high-dose remifentanil with epidural analgesia
started and at the end of surgery or low-dose remifentanil with epidural analgesia (0.5% ropivacaine)
started at the beginning of anaesthesia [78]. The
incidence of allodynia around the surgical incision
and chronic pain (at 3, 6 and 9 months) was much
higher in the group who received high-dose remifentanyl compared to those who received lowdose remifentanil with epidural analgesia during
surgery (P < 0.001, and P ¼ 0.013, 0.008 and 0.009,
respectively).
A recent, prospective, randomized controlled
trial of perioperative analgesia in patients undergoing limb amputation surgery (n ¼ 65) found
that optimized epidural analgesia or intravenous
patient-controlled analgesia (PCA), starting 48 h
preoperatively and continuing for 48 h postoperatively, decreased phantom limb pain at 6 months
[79 ]. The incidence of phantom limb pain at
6 months was one of 13 patients who had an
epidural from 48 h preoperatively to 48 h postoperatively, four of 13 patients who had a preoperative
PCA followed by epidural anaesthesia/analgesia
extending to 48 h postoperatively, three of 13
patients who had a preoperative and postoperative
PCA with a general anaesthetic vs. nine of 12 control
patients who received a general anaesthesia
with preoperative and postoperative conventional
analgesia (P ¼ 0.001, 0.027 and 0.009, respectively).
&
Volume 25 Number 2 April 2012
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Anaesthetic technique and cancer outcome Kavanagh and Buggy
A prospective, single-centre trial of patients
undergoing breast surgery with axillary clearance
randomized patients to a standard intraoperative
and postoperative analgesic regimen (morphine
sulphate, diclofenac, dextropropoxyphene hydrochloride plus acetaminophen prn, n ¼ 15) or a continuous paravertebral block for 48 h (n ¼ 14) with
acetaminophen and parecoxib [80]. Acute postoperative pain scores were less in the paravertebral
group at multiple time points extending from 30 min
to day 4 postoperatively (P ¼ 0.005). Twelve (80%, a
high incidence compared to other studies) patients
in the standard analgesic group and no patients in
the paravertebral group developed CPSP (P ¼ 0.009).
Although adequate treatment of acute postoperative pain is obligatory, there is no consistent
prospective evidence that it prevents the development of CPSP. The literature currently available
suggests that regional anaesthesia may help prevent
the development of chronic postoperative pain.
Large scale, prospective studies are required to
clarify this important potential benefit of regional
anaesthesia.
ANAESTHESIA AND THE DEVELOPING
BRAIN
Several laboratory studies in neonatal animal
models have demonstrated that administration
of anaesthetic drugs is associated with an increase
in apoptotic neuronal degeneration. This phenomenon has fuelled controversy about the implications for paediatric anaesthesia.
Apoptosis, or programmed cell death, is a vital
part of neonatal central nervous system development. During normal foetal and neonatal development, neurons are produced in excess with
subsequent neuronal degeneration occurring naturally in up to 70% of neurons and progenitor cells.
However, the cellular mechanism for the activation
of the apoptotic cascade and the cellular selectivity
remains unresolved. It also remains unclear whether
anaesthetics accelerate cell death in neurons
destined to die because of natural apoptosis or if
they trigger it in healthy neurons, which would have
otherwise survived [81].
Almost all animal models looking at the
effects of anaesthetic agents on the developing
brain are based on the 7-day-old mouse and rat.
The equivalent time period in humans may be
17–20 weeks of gestation, potentially rendering
the most commonly used animal models irrelevant
for common paediatric anaesthesia practice [82].
In contrast to the neurotoxicity model, there
is some evidence that impaired neurogenesis and
not cell death, particularly in the hippocampus,
mediates anaesthesia-induced neurocognitive dysfunction [83].
Direct evidence for the neurotoxic effect
of anaesthetic agents on the developing brain
comes entirely from in-vitro and animal models
where dose-dependent neurodegeneration has
been observed following exposure to thiopental,
ketamine, propofol and isoflurane [84] but not
nitrous oxide [85].
It has long been known that surgery and anaesthesia in young children can lead to prolonged
behavioural abnormalities [86]. But to what extent
this is because of the neurotoxic effects of general
anaesthetics as opposed to the psychological impact
of the underlying illness, family reaction and
the entire hospital experience as a whole remains
uncertain.
There are reasons to suspect that anaesthetic
neurotoxicity may not be to blame for these behavioural abnormalities. For example, the addition of a
benzodiazepine before general anaesthesia has been
shown not to exacerbate postoperative behavioural
abnormalities, as expected for a cytotoxic cause,
but rather significantly reduce abnormal behavioral
symptoms [87].
A population-based, retrospective, birth cohort
study (n ¼ 5357), looking at the association between
anaesthetic exposure before the age of 4 years
and the development of language and numerical
learning disabilities, found that compared with
those not receiving anaesthesia (n ¼ 4764), a single
general anaesthesia (n ¼ 449) was not associated
with an increased risk of learning disabilities (hazard
ratio ¼ 1.0; 95% CI 0.79–1.27) [88]. However,
children receiving two anaesthetics (n ¼ 100) or
three or more anaesthetics (n ¼ 44) were at increased
risk for learning disabilities (hazard ratio ¼ 1.59;
95% CI 1.06–2.37 and hazard ratio ¼ 2.60; 95% CI
1.60–4.24, respectively). This study suggests a dose–
response relation (both in terms of number of
anaesthetics received and the length of anaesthesia)
between exposure to anaesthetic agents and
the development of learning disabilities. It is also
plausible that requiring multiple anaesthetics is a
marker, rather than a cause, for conditions that
increase the risk of learning disabilities.
A retrospective cohort study of siblings who
had surgery/anaesthesia prior to 3 years of age
(n ¼ 304) compared to an unexposed cohort
(n ¼ 10 146) found that the risk of being subsequently diagnosed with a developmental and
behavioural disorder was 60% greater than that of
a similar group of siblings who did not undergo
surgery [89]. The incidence of developmental
and behavioural disorders was 128.2 diagnoses per
1000 person-years for the exposed cohort and
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Ethics, economics and outcome
56.3 diagnoses per 1000 person-years for the
unexposed cohort, P ¼ 0.04.
In contrast, a large Danish cohort study comparing the academic performance of all children who
had undergone inguinal hernia repair in infancy
(n ¼ 2689) to a randomly selected, age-matched
5% population sample (n ¼ 14 575) found no evidence that a single, general anaesthesia exposure in
infancy reduced academic performance at age 15 or
16 after adjusting for known confounding factors
[90 ].
Given the importance of potential longer-term
neurocognitive effects of anaesthetic agents on the
developing human brain, large-scale, prospective,
randomized controlled trials with long-term followup are required. To this end, a large multisite
randomized controlled trial – Pediatric Anaesthesia & Neurodevelopment Assessment (PANDA)
project – is in progress (www.kidspandastudy.org/).
The PANDA study is a sibling matched cohort study
that will enrol a total of 1000 children or 500 sibling
pairs. The period of anaesthesia exposure will be
before 36 months of age, with exposure limited to
a single episode of general anaesthesia for inguinal
hernia repair in ASA I and ASA II patients.
&
ANAESTHESIA AND POSTOPERATIVE
COGNITIVE DYSFUNCTION
Postoperative cognitive dysfunction (POCD) is a
poorly defined condition with numerous studies
using different definitions and neuropsychological
tests to detect potentially altered short or longerterm memory, motor control or information
processing following anaesthesia. There is evidence
that altered intraoperative physiology may influence POCD and longer-term outcomes: for example,
a significant relationship between minimum intraoperative blood pressure in hypertensive patients
undergoing spinal surgery and decline in cognitive
function 1 day and 1 month after surgery has been
observed [91]. POCD has an incidence of up to
80% following CPB and has been attributed, at least
in part, to surgery-related trauma, microembolization, temperature changes and altered cerebral
oxygenation/perfusion. We are focussing here on
noncardiac surgical patients and the possible lasting
effects of anaesthetic agents on the brain.
There is in-vitro and animal model evidence
that neurotoxic effects of anaesthetics are not
confined to the developing brain. Isoflurane has
been shown to activate the membrane-bound IP3
receptor producing excessive calcium release and
triggering apoptosis in cells [92].
In-vitro experiments suggest that some anaesthetics act in the processing of amyloid b-peptide
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providing a possible link between the effects of
anaesthetics and postoperative cognitive sequelae.
Clinical concentrations of isoflurane cause altered
processing of amyloid precursor protein and
increase amyloid b-peptide production in both
human neuroglioma and mice brain cell lines
[93]. There is also enhancement of Ab oligomerization that is thought to be responsible for synaptic
dysfunction and neurodegeneration [94].
Volatile anaesthetics, ketamine and barbiturates
are potent inhibitors of acetylcholine receptors –
the very receptors that anticholinesterase drugs,
used for the treatment of dementia, seek to enhance.
A meta-analysis of 21 studies on POCD and
postoperative delirium (POD) found no effect of
anaesthesia type on the OR of developing POD
(0.88, 95% CI 0.51–1.51) [95]. In a small subgroup
analysis of a prospective, randomized controlled
trial [General Anaesthesia vs. Local Anaesthesia
(GALA) study], 40 patients undergoing carotid
endarterectomy (CEA) were randomized to receive
either local anaesthesia (n ¼ 17) or general anaesthesia (n ¼ 23) [96]. Despite carotid clamping times
being longer in the local anaesthesia group [mean
24 min (SD 10) vs. 15 min (SD 8), P ¼ 0.003] and less
patients in the local anaesthesia group receiving a
shunt [5 (9%) vs. 9 (39%), P ¼ 0.001], information
processing, during psychometric testing, was found
to be significantly slowed in the general anaesthesia
group at 5 and 29 h but not at 77 h postoperatively,
as compared to their preoperative baseline tests.
There was no significant difference between the
preoperative and postoperative results in the local
anaesthesia group at any of the time points. This is
the first prospective, randomized, albeit small,
clinical study to show a beneficial effect of local
anaesthesia on early postoperative cognitive function in CEA patients.
An observational study of 701 patients enrolled
in two multicentre studies of POCD found that
POCD at 3 months, but not at 1 week, was associated
with increased mortality [hazard ratio, 1.63 (95% CI,
1.11–2.38); P ¼ 0.01, adjusted for sex, age and
cancer] [97]. POCD is associated with poorer outcomes in terms of earlier retirement, increased
dependency on social support and 70% 5-year
mortality rate compared to 35% in those without
POCD.
In an effort to discover a dose–response relationship between anaesthesia and POCD, a prospective
observational study of 70 patients over 60 years
of age undergoing elective noncardiac surgery
measured depth of anaesthesia using a cerebral state
monitor and compared the measured cerebral state
index (CSI) to the performance of the patients on
neuropsychological testing 1 week after surgery [98].
Volume 25 Number 2 April 2012
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Anaesthetic technique and cancer outcome Kavanagh and Buggy
Table 4. Summary of evidence base for specific perioperative interventions in postoperative outcomes
Anaesthetic technique /intervention
Postoperative outcome advantage
Level of evidencea
Proposed
recommendation from
currently available data
Maintenance of intraoperative normothermia
Reduced postoperative surgical
site infection rates
Level A [6,7]
Class I
Regional anaesthesia
Level B [9,10]
Class IIb
Supplemental perioperative oxygen
(FiO2 80%)
Level B [11,12]
Class I
Avoiding perioperative hyperglycaemia
in both diabetic and nondiabetic patients
Level B [42,43 ,47 ,49]
Class IIa
Administering insulin via a continuous
intravenous infusion thereby avoiding
large swings in blood glucose values
Level A [44,46]
Class IIa
&
&
Level C [21,30–34,35 ]
Class IIb
Avoidance of nitrous oxide
Level C [24]
Class IIb
Use of perioperative NSAIDs
Level C [27–29]
Class IIb
Propofol anaesthesia
Level C [36–38]
Class IIb
Avoidance of allogeneic blood transfusion
Level C [54,55]
Class IIb
Regional anaesthesia
Reduced cancer recurrence rates
&
Avoidance of allogeneic blood transfusion
Reduced postoperative infections
Level A [51,54]
Class IIa
Preoperative treatment with iron and
erythropoietin
Reduced blood transfusion
requirements
Level B [56]
Class IIa
Level B [57]
Class IIb
Level C [61 ]
Class IIb
Maintenance of intraoperative
normothermia
Intraoperative fluid restriction
precardiopulmonary bypass
&
Antifibrinolytic agents
Level A [60]
Class IIa
Cell salvage
Level A [58]
Class I
Hypotensive anaesthesia
Level B [63]
Class IIb
Propofol anaesthesia
Level C [62]
Class IIb
Level C [78–80]
Class IIa
Level B [64–66]
Class III
Epidural anaesthesia commenced
preincision
Perioperative b-blockade in
noncardiac surgery
Reduced occurrence of chronic
surgical pain
Reduced postoperative cardiovascular
risk
Use of nitrous oxide free anaesthesia
Reduced long-term risk of MI
(but not death or stroke)
Level B [68–70,71 ]
Class IIb
Avoidance of general anaesthesia in
young children
Reduced long-term neurocognitive
side-effects of general anaesthetics
on the immature brain
Level C [83,84,86,
&
88,89,90 ]
Class III
Avoidance of general anaesthesia in
the elderly
Reduced postoperative long-term
cognitive dysfunction
Level C [93–98]
Class III
&&
a
From the AHA/ACC Manual for Guideline Writing Committees at http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/documents/
downloadable/ucm_319826.pdf. MI, myocardial infarction.
The mean CSI was 40 and 43 in patients with (n ¼ 9)
and without (n ¼ 56) POCD, P ¼ 0.41. The cumulated time of both deep anaesthesia (CSI <40) and
light anaesthesia (CSI >60) did not differ significantly, and no significant correlation was found
between the mean CSI and risk of POCD.
Persistent cognitive decline may be attributable
to underlying undiagnosed neurological disease
or other comorbidities rather than to surgery or to
anaesthesia per se. There are other perioperative
influences to which elderly people are more
susceptible such as altered environment and sleep
disturbance. Further large-scale prospective studies
are required to investigate the possible prolonged
effects of even short-acting anaesthetics on the
elderly brain.
CONCLUSION
There is accumulating evidence that anaesthetic
management may indeed exert a number of
influences on longer-term postoperative outcomes.
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195
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Ethics, economics and outcome
Table 4 outlines the level of evidence currently
available. Further prospective, randomized, largescale, human trials with long-term follow-up
are required to clarify the association between
anaesthesia and cancer recurrence, neurotoxicity
and the developing brain and long-term POCD in
the elderly.
Acknowledgements
Donal J. Buggy is supported by a research grant from the
Sisk Healthcare Foundation.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 264).
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&
Perioperative epidural analgesia for major abdominal surgery for cancer and
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