Acta Anaesthesiologica Taiwanica 53 (2015) 99e104

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Acta Anaesthesiologica Taiwanica

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Review Article

Anesthesia, surgical stress, and “long-term” outcomes

Masae Iwasaki 1, 2 y, Matthew Edmondson 1 y, Atsuhiro Sakamoto 2, Daqing Ma 1 *
1
Anesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and
Westminster Hospital, London, UK
2
Department of Anaesthesiology, Nippon Medical School, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: An increasing body of evidence shows that the choice of anesthetic can strongly influence more than
Received 7 May 2015 simply the quality of anesthesia. Regional and general anesthesia have often been compared to ascertain
Received in revised form whether one provides benefits through dampening the stress response or harms by accelerating cancer
29 June 2015
progression. Regional anesthesia offers considerable advantages, by suppressing cortisol and catechol-
Accepted 3 July 2015
amine levels and reducing muscle breakdown postoperatively. It also has less immunosuppressive effect
and potentially reduces the proinflammatory cytokine response. As such, vital organ functions (e.g., brain
Key words:
and kidney) may be better preserved with regional anesthetics, however, further study is needed. Vol-
anesthetic/technique;
cancer recurrence;
atile general anesthetics appear to promote cancer malignancy in comparison to regional and intrave-
organ failure; nous general anesthetics, and reduce the body's ability to act against cancer cells by suppression of
outcome; natural killer cell activity. There is not sufficient evidence to support an alteration of current clinical
postoperative cognitive dysfunction; practice, however, further research into this area is warranted due to the potential implications elicited
stress by current studies.
Copyright © 2015, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights
reserved.

1. Introduction 2. Surgical stress response

An increasing body of evidence shows that the choice of anes-
thetic can strongly influence more than just the quality of anes-
thesia. The body's stress response to surgery first became a subject
of interest in the 1920s, when David Cuthbertson1 observed that
surgical patients had a large increase in urinary muscle breakdown
metabolites postoperatively. Since then, studies have looked into
detailing the stress response and whether it can be altered to the
patient's advantage. Anesthetic choices can also have much wider
implications, affecting cancer cell biology and its progression to-
ward metastasis and invasion. This review will be looking specif-
ically at the effects of regional anesthesia (RA) compared to general
anesthesia (GA) with intravenous and volatile reagents, and the
impacts of both of them on altering the surgical stress response,
postoperative organ function and cancer progression.
Conflicts of interest: None.
* Corresponding author. Anesthetics, Pain Medicine and Intensive Care, Depart-
ment of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea
and Westminster Hospital, 369 Fulham Rd, London SW10 9NH, UK.
y
E-mail address: d.ma@imperial.ac.uk (D. Ma).
Both authors contributed equally to this work.
Surgical stress is a spectrum of changes occurring throughout
different systems in the body (Figure 1). Raised adrenocorticotropic
hormone (ACTH) induces excess cortisol release and leads to insulin
resistance, raising blood glucose levels. This can have negative
consequences, as hyperglycemia has been shown to increase
wound infection postoperatively.2 Immunological changes also
occur during surgical stress and there is an increase in leukocyte
infiltration to the area of damage,3 as well as raised levels of den-
dritic cells within the circulation.4 Surgical stress has also been
shown to have an immunosuppressive effect, reducing natural
killer (NK) cell toxicity and T-cell responses.5
The endocrine response has a large role to play within surgical
stress. Epidural anesthesia in addition to GA has been shown to
reduce the increase in cortisol and urinary epinephrine intra-
operatively, when compared to GA alone.6 When comparing intra-
venous with volatile GA, it has been reported that propofol combined
with remifentanil inhibits the ACTHecortisol axis and catechol-
amine and growth hormone increase compared to volatile GA.7
Metabolic changes secondary to surgical stress include an in-
crease in proteolysis after surgery, leading to muscle breakdown
and loss.8 The use of a combined spinal and epidural blockade

http://dx.doi.org/10.1016/j.aat.2015.07.002
1875-4597/Copyright © 2015, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
100
Figure 1. Demonstration of the relationship between surgical trauma and the multi-
system effects of the surgical stress response. These are dampened to a greater extent
(indicated by a greater number of minus markers in the figure) by regional anesthesia
in comparison to general anesthesia. NK ¼ natural killer.
during hip surgery has been shown to attenuate the increase in
amino acid oxidation 24 hours after surgery, in comparison to GA.9
Among GA reagents, the use of propofol has been found to cause a
reduction in the proteolytic response to surgery, by potentially
allowing the body to make use of triglycerides contained within the
propofol emulsion as a substitute.10 The increase in glucose pro-
duction during surgery can also be prevented by epidural analgesia,
yet inhaled anesthetics appear to have no effect.11
The effects of volatile and intravenous general anesthetics on
the immune system have also been shown to differ. Ketamine,
thiopental and halothane have all been reported to suppress the
activity of NK cells; however, propofol has been reported to in-
crease interferon gamma release from NK cells.12,13 It has also been
shown that volatile and intravenous GA have a variety of effects on
cytokines depending on the anesthetic agent used.14,15 Lastly, vol-
atile GA impairs platelet aggregation and clot stability in compar-
ison to propofol.16
2.1. Surgical stress and the brain
The brain leads the surgical stress response by initiating changes
in the neuroendocrine balance; however, it can also be negatively
impacted by this alteration in homeostasis. A major consequence of
this is postoperative cognitive dysfunction (POCD). This is a
“deterioration in cognition temporally associated with surgery”17
and is associated with higher mortality three months post-
operatively.18 It has been found that alterations in the endocrine
response to surgery can influence the risk of developing POCD.
Higher cortisol levels postoperatively have been shown to be
associated with a higher chance of developing POCD,19 along with
suppression of the growth hormone axis.20 Increased presence of
M. Iwasaki et al.
proinflammatory cytokines associated with the surgical stress-
induced immune response, such as interleukin (IL)-6, IL-1b,21 and
tumor necrosis factor-alpha,22 has been shown within the hippo-
campus postoperatively and is associated with the development of
POCD in murine models.
Studies looking at the effect of RA, compared to that of GA, on
the rates of POCD present a mixed picture. Rasmussen et al23
demonstrated no significant difference between RA and GA in
rates of POCD; however, another study showed significantly poorer
cognitive function in those patients undergoing GA than RA.24 Each
study included patients undergoing noncardiac surgery, but both
had biases such as large dropout rates and failure to account for
social factors. As previously discussed, RA leads to a reduced stress
response in comparison to GA. This suggests that although levels of
surgical stress can be associated with POCD, its role as a causative
factor is still uncertain. Promising results for the therapeutic
treatment of POCD have been shown by Vizcaychipi et al,25 who
pretreated mice using atorvastatin. Atorvastatin has previously
been shown to protect against neuroinflammation, and demon-
strated a significant reduction in cognitive decline postoperatively
within their study.
Other negative sequelae of undergoing surgery, specifically
under GA, have been demonstrated, although much of the work is
still preclinical. For example, it has been shown that an elderly
person undergoing GA is at a higher risk of developing demen-
tia.26 This may be related to the fact that higher rates of brain
atrophy have been detected within elderly patients who had un-
dergone surgery, compared to those who had not.27 Tang et al28
showed that surgery, independent of anesthesia, has the ability
to propagate some of the pathological mechanisms behind Alz-
heimer's disease. Using a murine model, they demonstrated an
increase in amyloid-b plaque density, t phosphorylation, and
microglial activity. The inflammatory nature of the surgical stress
response may be a contributing factor for this. Guo et al29 showed
that deposition of amyloid plaque is dependent on systemic
inflammation in a murine model and also associated with
increased levels of inflammatory cytokines in brain tissue. One of
the initial regions to be affected by Alzheimer's disease is the
hippocampus,30 and the increase in IL-1b and IL-6 within the
hippocampus after surgery31 could be a potential driving factor for
its development. Because the systemic inflammatory response is
intertwined with surgical stress,32 it is possible that down-
regulation of the surgical stress response may show benefits in
reducing the progression and rate of Alzheimer's disease in elderly
patients undergoing surgery. Current research (Table 1) is limited
to murine models, and this is an area where future studies in
humans may prove beneficial.33
2.2. Surgical stress and other organs
A reduction in renal function secondary to surgical interference
is a well-known effect.34 As previously mentioned, the use of
opioids such as fentanyl leads to obtundation of the surgical stress
response; Kono et al35 compared the effects of halothane and
fentanyl anesthesia on renal function during coronary artery sur-
gery. They found that the use of fentanyl reduced the hormonal
response, including a reduction in cortisol, vasopressin, and
aldosterone. This led to improved creatinine clearance compared
to halothane. They concluded that the reduction in hormonal
response was likely responsible for the improved creatinine
clearance, however, it is important to still take into consideration
other factors. For example, halothane has also been shown to
decrease endothelial-mediated vasorelaxation,36 and therefore, a
comparative reduction in renal blood flow may also have
contributed to a poorer creatinine clearance. An overview of the
Anesthesia, surgical stress, and outcomes 101

Table 1
Surgery/anesthesia versus brain function.

Authors Journal Species/model Anesthetics/pharmacological Protocol Major findings

agents

Steinmetz et al18 Anesthesiology Human Not mentioned Neuropsychological test before, POCD was associated with increased
2-centre study at 1 wk after, at 3 mo after mortality (hazard ratio 1.63), risk of
noncardiac surgery leaving the labor market prematurely
(hazard ratio 2.26), and dependency on
social transfer payments (prevalence
ratio 1.45)
Fidalgo et al21 Neurosci Lett Mice LPS 50 mg/kg or 100 mg/kg i.p. After fear conditioned, add LPS Subclinical inflammation by LPS (50 ng/
LPS inflammation Surgery group ISO (2.1%), injections/surgery/ kg) failed to significantly affect freezing
buprenorphine (0.1 mg/kg i.p.) surgery þ LPS time (p > 0.05). IL-1b in plasma and
hippocampus by ELISA increased at 6 h
after LPS injection/surgery
Terrando et al22 PNAS Mice ISO (2.1%), buprenorphine Osteotomy performed Plasma TNFa, HMGB-1, IL-1b, and IL-6
Sepsis model (Buprenex, 0.1 mg/kg s.c.) Add NS/TNF-neutralizing increased after surgery. Inflammation
antibody (100 mg) caused hippocampal-dependent
Freezing behavior recorded memory impairment (p < 0.05) on Day
3. Pretreatment with anti-TNF
significantly ameliorated this cognitive
dysfunction (p < 0.05)
Rasmussen et al23 AAS Human GA (agents not mentioned) Cognitive function was assessed POCD after 1 wk was greater after GA
Multicenter RA (epidural/spinal), propofol before, at 1 wk after, at 3 mo than after RA (19.7% vs. 18.3%). No
prospective study after noncardiac surgery significant difference was found in the
Patients >60 y incidence of cognitive dysfunction 3 mo
after GA/RA
Mandal et al24 JETS Human GA Cognitive function was assessed MMSE scores decreased after GA in
Prospective, Induction: fentanyl (2 mg/kg), before, at 1 wk after hip and comparison to RA (p ¼ 0.0051). No
randomized, parallel- Thio (4e6 mg/kg), Vb (100 mg/ knee surgery statistical differences in other
group study kg) neuropsychological tests
Maintenance: NO (66%), O2,
Halo (0.5 MAC)
RA
Lumbar epidural 0.5% Bupi (16
e18 mL)
Kline et al27 Anesthesiology Human None Structural MRI following 3 y Lateral ventricular volume decreased
Prospective study after surgery/nonsurgery faster in surgery group (1.39 ± 0.43%)
Age 55e90 y than in nonsurgery group (0.25 ± 0.25%)
within 5 mo and 9 mo
Tang et al28 Ann Surg Mice DES: DES (1.5 MAC for Morris water maze at 2 wk and An increase in amyloid-b plaque
3  TgAD and WT mice induction, 9% at maintenance) 13 wk postoperatively density, t phosphorylation, and
for 30 min Amyloid and tau pathology for microglial activity in gray matter and
DES þ surgery: same DES brain tissue hippocampus of 3  TgAD mice, after
protocol, laparoscopic DES þ surgery
appendectomy, 0.25% Bupi
(10 mg/kg) s.c.
Control: O2 (30%), N2
Clarke et al33 JBC Rat Atorvastatin (5 mg/kg/d for IL-1b, IFNg, and IL-4 in Atorvastatin abrogates the LPS-induced
C57BL/6, IL-4e/emice mice, 10 mg/kg/d for rat) p.o. hippocampus activation of p38 and NFkB for 3 wk
LPS, LTP Saline/LPS (100 mg/kg) i.p. (p < 0.01), and reverses the LPS-induced
Urethan (1.2e1.5 g/kg) i.p. up to impairment in LTP (p < 0.01)
2 g/kg

AAS ¼ Acta Anaesthesiologica Scandinavica; Ann Surg ¼ Annals of Surgery; Bupi ¼ bupivacaine; DES ¼ desflurane; ELISA ¼ enzyme-linked immunosorbent assay;
GA ¼ general anesthesia; Halo ¼ halothane; IFNg ¼ interferon gamma; IL ¼ interleukin; ISO ¼ isoflurane; JBC ¼ The Journal of Biological Chemistry; JETS ¼ Journal of
Emergencies, Trauma and Shock; LPS ¼ lipopolysaccharide; LTP ¼ long-term potentiation; MMSE ¼ mini-mental state examination; MRI ¼ magnetic resonance imaging;
Neurosci Lett ¼ Neuroscience Letters; NFkB ¼ nuclear factor kappa beta; NS ¼ normal saline; PNAS ¼ Proceedings of the National Academy of Sciences of the United States of
America; POCD ¼ postoperative cognitive dysfunction; RA ¼ regional anesthesia; Thio ¼ thiopental; TNF ¼ tumor necrosis factor; Vb ¼ vecuronium.

literature comparing the effects of RA and GA on morbidity and
mortality showed that the use of RA reduced the rates of renal
failure.37 With regard to the gastrointestinal tract, a meta-analysis
found that epidural anesthesia reduces the incidence of paralytic
ileus after abdominal surgery.38 This may be due to the blocking
effect of RA on the adrenergic response.39 Catecholamines have
been shown to reduce gut motility, an effect that has also been
demonstrated in animal studies to be potentiated by the opioid
sufentanil.40 In cardiac surgery, thoracic epidural anesthesia, in
comparison to GA, has been shown to reduce both supraventric-
ular tachyarrhythmias and respiratory complications.41 To date, no
studies have shown that this is linked to an improvement in
mortality, once again presenting an area where longer-term
studies may show a benefit.
3. Influence of anesthetic type on cancer outcomes and
recurrence
Previous research indicates that the choice of anesthetic tech-
nique may have an effect on cancer progression by influencing cell
invasion, migration, proliferation and metastasis. Clinical studies
indicate that RA and/or intravenous GA can be preferable for cancer
patients in comparison to volatile GA, with regard to outcomes.
Breast cancer patients who underwent surgery with a para-
vertebral nerve block in combination with GA have a lower inci-
dence of cancer recurrence or metastasis than those undergoing
surgery with GA and patient-controlled morphine analgesia.42
Another study has shown that the recurrence rate of prostate
cancer after prostatectomy under GA with epidural analgesia was
102 M. Iwasaki et al.

Table 2
Anesthesia versus cancer.

Authors Journal Species/model Anesthetics/pharmacological Protocol Major findings

agents

Exadaktylos et al42 Anesthesiology Retrospective study Paravertebral anesthesia (Th2/
Single center 3, 0.25% Bupi 0.2 mL/kg)
GA [fentanyl 0.5 mg/kg, propofol
1.5e3.0 mg/kg, Sevo
(2e3%)] þ paravertebral
anesthesia (Th2/3, 0.25% Bupi
0.2 mL/kg)
GA þ postoperative morphine
(0.05 mg/kg, i.v.)
Lin et al44 BJA Retrospective study Epi: Epidural (MDZ 0.04 mg/kg,
Single center Th11/12 or L2/3, Bupi 0.125% or
Ropi 0.150%) þ analgesia
(morphine 6e8 mg)
GA: GA (MDZ 0.04 mg/kg,
fentanyl 3e4 mg/kg, propofol 1
e2 mg/kg, Vb 0.1 mg/kg, Sevo 2
e3%, or Iso 1.5e2.5%) þ
postoperative i.v. fentanyl
Schlagenhauff et al45 Melanoma Res Retrospective study Not available
Single center
Enlund et al46 Ups J Med Sci Retrospective study GA: propofol ± epidural
Single center GA: Sevo þ N2O ± epidural
Doses not mentioned
Mastectomy and axillary
clearance for breast cancer
KaplaneMeier method
Surgery for ovarian serous
adenocarcinoma
Cox proportional hazards
analysis
Surgery for primary melanoma
Cox proportional hazards
analysis
Surgery for breast, colon, or
rectal cancers
KaplaneMeier method
Cox proportional hazard
analysis
The paravertebral group had
slower time to recurrence
(p ¼ 0.013) in 1-y follow up. No
significant differences in
patients or surgical details,
tumor presentation, or
prognostic factors
Epi reduced mortality
compared to GA during the
initial years of follow up
(hazard ratio 1.214, p ¼ 0.043)
GA decreased the survival rate
compared to RA (relative risk
1.46, p < 0.0001)
Overall 1- and 5-y survival rates
of propofol are better than
sevoflurane anesthesia. No
significant differences in the 1-
y survival for patients operated
for colon cancer after
adjustment

BJA ¼ British Journal of Anaesthesia; Bupi ¼ bupivacaine; Epi ¼ epidural; GA ¼ general anesthesia; Iso ¼ isoflurane; Melanoma Res ¼ Melanoma Research; MDZ ¼ midazoram;
RA ¼ regional anesthesia; Ropi ¼ ropivacaine; Sevo ¼ sevoflurane; Th ¼ T-Helper cells; Ups J Med Sci ¼ Upsala Journal of Medical Sciences; Vb ¼ vecuromium.

significantly lower than that under GA with postoperative opioid
analgesia.43 In addition, patients with ovarian adenocarcinoma
who underwent surgery with epidural anesthesia and analgesia
had better long-term outcomes than those who were given only
GA,44 and excision of melanoma under GA has been associated with
a decreased survival rate when compared to patients who had
excision under a local anesthetic.45 Furthermore, a retrospective
study, reporting the data from 2838 patients registered for surgery
for breast, colon, or rectal cancer, showed that propofol anesthesia
might be better than sevoflurane in surgery for some cancer types
for 1-year survival, however, after adjustment for several con-
founders, the observed differences were not statistically signifi-
cant.46 These studies are summarized in Table 2.
3.1. Effect of anesthetic choice on anticancer immunity
Cell-mediated immunity with T-helper 1 (Th1) cells and NK cells
is considered an important mechanism in enabling the body to act
against cancer. It has been associated with reduced risk of cancer
recurrence after surgical resection, because NK cells are reported to
have cytolytic activity against cancer cells.47,48 Volatile GA has been
shown to suppress this anticancer immunity.14 It has also been
reported that NK cells target cancer cells and prevent metastases,49
which is supported by evidence showing a correlation between
higher recurrence rates and reduced NK cell activity.50 NK cell
cytotoxicity is decreased by all types of anesthesia, but GA in
particular appears to have a greater effect.51 Ketamine, thiopental,
and halothane reduced NK cell activity and increased tumor
retention and metastasis.13,52 Propofol has been shown to have
protective effects through a variety of mechanisms that enhance
antitumor immunity.53 A possible reason for this is that intrave-
nous GA, when compared to volatile GA has been shown to increase
IL-10, which is known to have antitumor activity and help with
healing and repair.15,54 Epidural anesthesia in combination with GA,
compared to GA alone, has been shown to increase the ratio of Th1
cells to Th2 cells in patients with hepatocellular carcinoma,
potentially promoting antitumor activity.55 The Th1⁄Th2 ratio has
also been shown to decrease after volatile GA, whereas propofol did
not induce any change.56 These findings show that volatile GA is
more likely to suppress anticancer immunity to a greater extent
than intravenous GA or RA.
3.2. Effects on “oncogenes,” matrix metalloproteinase, and hypoxia
inducible factors
Volatile GA has been shown to modulate gene expression in
breast and brain tumor cell cultures, occurring in a unique and
time-dependent manner.57 Compared with volatile GA, intravenous
GA with RA reduces postoperative IL-1b, suppresses elevation of
matrix metalloproteinase (MMP)-3 and MMP-9, and also reduces
the increase in hypoxia inducible factor (HIF)-1a and HIF-2a.15
MMPs are known to be involved in cancer cell invasion, migra-
tion, and metastasis. HIF-1a overexpression is associated with poor
survival rates and a reduced disease-free rate in colorectal cancer.58
It has also been shown to reduce response to therapy and shorten
disease-free survival in breast cancer patients.59 Volatile GA has
been shown to upregulate HIF-1a expression60 and enhance cancer
malignancy.61 Recent studies have demonstrated that isoflurane
upregulates HIF-1a in prostate cancer cells, but propofol down-
regulates these increases.62 Both HIF-1a and HIF-2a were upregu-
lated by isoflurane in renal cancer cells63 as well. Other inhalational
anesthetics also upregulate the HIF system, and the possible link to
cancer malignancy has been discussed previously.64 In addition to
this, barbiturates have been shown to inhibit HIF-1a activation,65
whereas local anesthetics used in RA reduced HIF-1a expres-
sion.66 These studies indicate that volatile GA enhances cancer in-
vasion and metastasis to a greater extent than intravenous GA or
RA. However, further research, including large clinical trials, are
Anesthesia, surgical stress, and outcomes
needed prior to concluding that specific anesthetics and techniques
influence cancer recurrence postoperatively.
4. Conclusion
It is difficult to perform a conclusive comparison between GA
and RA due to the huge variety of anesthetic techniques available,
as well as the varying anesthetic demands in surgery for a wide
range of issues, including malignancy. The current literature looks
at specific scenarios and is significantly limited by the lack of
applicability to a wider context.
There is a strong argument supporting the wider and prefer-
ential use of RA and intravenous GA compared to volatile GA in
specific circumstances where possible. These might include pa-
tients with diagnosed or potentially malignant tumors, or those
particularly vulnerable to the surgical stress response. Sufficient
evidence to support an immediate alteration of current clinical
practice is lacking; however, further research into this area is
warranted due to the potential implications elicited by the current
research.
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