Best Practice & Research Clinical Anaesthesiology

Vol. 20, No. 3, pp. 429e438, 2006

doi:10.1016/j.bpa.2006.02.004
available online at http://www.sciencedirect.com

5
The metabolic effects of fasting and surgery
Jonas Nygren*

MD, PhD

Associate Professor, Senior Consultant Surgeon

Centre of Gastrointestinal Disease, Ersta Hospital and Karolinska Institutet, P.O. Box 4622,
116 91 Stockholm, Sweden

This review discusses the metabolic changes that occur during fasting, especially in relation to
surgical stress. Currently available evidence on the relevance of different aspects of perioperative nutritional support are presented. Attenuation of surgical stress and insulin treatment in
insulin-resistant patients after surgery and trauma have been shown to markedly affect stress
metabolism as well as patient morbidity and mortality. Avoiding preoperative fasting has been
shown to be related to a substantial reduction in postoperative stress and insulin resistance. Implementation of a standardized programme with a multimodal approach using evidence-based
perioperative routines has been shown to further reduce surgical stress and to markedly enhance functional recovery also after major surgical procedures.
Key words: fasting; insulin resistance; surgery; stress metabolism.

Patients undergoing surgery are often met with various restrictions regarding nutritional intake. Many patients planned for gastrointestinal surgery present with abdominal pain, tumours or inflammation, increasing energy demands, or stricturing
processes limiting nutritional intake before surgery. Recent surveys from five northern
European countries show that a majority of surgical institutions still use bowel preparation before colorectal surgery1, despite recent evidence2, resulting in dehydration
and further aggravating preoperative fasting.3 In addition, many centres still advocate
overnight fasting before surgery.4 Postoperatively, also despite evidence5, large groups
of patients have to face restrictions in intake of food and fluids, and, when allowed to
eat, an often prolonged period of deficient energy intake due to lack of appetite, nausea or abdominal discomfort. As has been pointed out recently in editorial comments4, perioperative management still relies on tradition or personal experience,
despite the increasing availability of evidence-based data. This review focuses on the

* Tel.: 46 8 714 65 42; Fax: 46 8 714 66 80.

E-mail address: jonas.nygren@erstadiakoni.se.
1521-6896/$ - see front matter 2006 Elsevier Ltd. All rights reserved.

430 J. Nygren

metabolic effects of perioperative fasting, and the evidence available for clinical and
metabolic effects of avoiding perioperative fasting or semi-starvation.
METABOLIC EFFECTS OF FASTING
The human organism requires fuel to survive. Similar to the motor vehicle, energy intake is usually not supplied continuously, but on repeated occasions or meals over the
day. Thus, during the night (when sleeping) we are naturally fasted while we spend
most of the day in the postprandial state. If energy requirements are higher than energy intake over a prolonged period of time, we have a situation of fasting or starvation (see Frayn6 for an excellent review). The fuel stored as carbohydrates (0.4 kg)
lasts less than a day during starvation, while the supplies of protein (10e12 kg, where
only about 20e30% is available as fuel) and fat (10e15 kg) last much longer (21 and 55
days respectively).6 About 10e15% of the body weight may be lost without severe
functional derangement, while a weight loss of 35e40% is life-threatening.
Absolute starvation leads ultimately to death. Metabolic adaptation to starvation is
the organisms way of postponing this final endpoint as long as possible. The postabsorptive state is a situation in which the last meal has recently been absorbed,
typically after an overnight fast just before breakfast. During these conditions, glucose
enters the circulation from the liver, being derived from glycogen breakdown and gluconeogenesis. The stimulus for glucose production is a lack of substrates, resulting in
a reduction in glucose concentrations and a decreased insulin/glucagon ratio. Substrates used for gluconeogenesis are lactate, alanine (muscle) and glycerol (fat tissue).
Since liver glycogen is depleted within 24 hr, gluconeogenesis, at the expense of
muscle protein, is the sole provider of glucose for tissues which depend on glucose
for survival (i.e. the brain, renal medulla and erythrocytes). To avoid rapid depletion
of the protein stores, metabolic adaptation occurs over the first 2e3 weeks of starvation. This metabolic adaptation is characterized by a reduction in T3 levels, which
reduces the metabolic rate and muscle proteolysis.6 Activation of the adrenergic system along with reduced insulin levels result in an increased lipolysis and increased concentrations of free fatty acids (FFAs) which can be used as fuel in muscle. Increased
oxidation of FFAs also leads to increased production of ketone bodies which can be
used as fuel in many tissues, including the brain. Effective recycling of lactate (from glycolysis in glucose-dependent tissues) by liver gluconeogenesis, driven by energy from
FFA oxidation, minimizes protein oxidation.
Important mechanisms for protein-sparing when FFAs and ketone bodies are available as fuel are inhibition of key enzymes for glycolysis (pyruvate dehydrogenase) and
oxidation of BCAA (BC 2-oxo-acid dehydrogenase) by a high acetyl-CoA/CoASH
ratio.6 In starvation, the kidney excretes excess hydrogen ions as ammonia from
glutamine and glutamate, a process also leading to glucose production, and the kidney
becomes a gluconeogenetic tissue. Thus, metabolic adaptation to starvation allows us
to survive up to 2 months without food.
Even brief fasting or hypocaloric nutrition for 1e3 days, a regimen often used after
abdominal surgery, results in a marked reduction in insulin sensitivity as measured by
hyperinsulinaemic/normoglycaemic clamps in healthy subjects.7e9 The reduction in
insulin levels and the low insulin/glucagon ratio is followed by reduced insulin-like
growth factor-1 (IGF-I) activity by an increase in IGF binding protein-1 (IGFBP-1).
IGF-I is an anabolic hormone with effects on glucose and protein metabolism similar
to those of insulin.10

Metabolic effects of fasting and surgery 431

However, when a meal is absorbed, insulin levels and the insulin/glucagon ratio
increase rapidly, resulting in a switch from glycogen breakdown to glycogen synthesis,
while peripheral glucose uptake increases (mainly in muscle). Gluconeogenesis is
maintained by delivery of lactate from anaerobic glucose metabolism, although
glucose-6-phosphate during these conditions is directed into liver glycogen (the indirect pathway).6 Thus, liver glucose release is almost completely inhibited, and there
is a rapid switch from net catabolism to net anabolism. In addition, levels of IGFBP-1
decrease, and IGF-I activity increases.10
METABOLIC EFFECTS FROM SURGERY
Similarly to the situation in the fasting state, insulin resistance develops after surgery.
This occur within hours after the initiation of surgery, and a pronounced insulin resistance has been demonstrated immediately after completion of surgery.11,12 However, in
contrast to the reduction in metabolic rates seen after fasting, the metabolic response
to surgery and other trauma involves an increased metabolic rate and a state of hypermetabolism.8 Thus, substrate oxidation is markedly increased, resulting in an accelerated catabolic situation characterized by a net breakdown of glycogen, fat and protein.
Although insulin levels often are increased, blood glucose levels also increase due to the
developed insulin resistance, and the insulin/glucagon ratio is reduced, resulting in an
increased gluconeogenesis.8 Increased release of stress hormones such as catecholamines, cortisol and glucagon, as well as release of cytokines from injured tissues,
are probably of importance. In addition, increased levels of antidiuretic hormone and
aldosterone results in retention of fluid and sodium and a reduced urinary output.6
In contrast to the situation during fasting, metabolic adaptation to minimize loss of
body mass does not occur. Furthermore, injured tissues and tissues where synthesis
of acute-phase proteins occurs still rely on glucose as a substrate.6 In addition, increasing
metabolic rates result in a more severe net loss of fat and protein stores, and these responses are not to any great extent influenced by the availability of exogenous substrates.
The stress response and the degree of insulin resistance following surgery has been
shown to be related to the magnitude of the surgery performed13, and the normalization of insulin sensitivity takes 2e4 weeks after uncomplicated moderate abdominal
surgery, which is similar to the time required for recovery of the patient.14 Furthermore, the insulin resistance developed after surgery is related to the length of stay
in hospital, supporting the view that postoperative insulin resistance is a key feature
in the surgical stress response.15
Although insulin resistance may be necessary for survival in a situation where medical care in unavailable, it is still a major problem in the medical treatment of surgical
patients. In a large randomized study in patients in intensive care, normalization of
stress-induced hyperglycaemia by insulin infusion (<6.1 mM) resulted in substantially
lower mortality and complication rates as compared to patients where glucose concentrations were allowed to rise up to 12 mM before insulin was given.16 Even moderately increased glucose concentrations (6e8 mM) were associated with increased
morbidity.17 Normalizing glucose concentrations by intensive insulin treatment in critically ill patients was associated with a normalization of glucose production, while
peripheral glucose uptake and oxidation were unresponsive.18
Postoperative insulin resistance has been shown to be related to changes in the IGF-I
system, since levels of circulating IGF-I are reduced and IGFBP-1 levels increase, which
reduces IGF-I activity.10 However, proteolytic activity to the main carrier protein of

432 J. Nygren

circulating IGF-I, IGFBP-3, increases, which is a counter-regulatory response associated

with increased levels of free IGF-I and increased IGF-I activity19, thus attenuating or preventing the reduction in postoperative IGF-I activity.20 Normalization of glucose levels
by insulin treatment in intensive care patients showed that persistent elevation of circulating IGFBP-1 levels were more common in patients who ultimately died.21 Studies in
patients after colorectal surgery demonstrated that hyperinsulinaemia (in the upper
physiological range) during insulin infusion further increased proteolytic activity to
IGFBP-3 and reduced IGFBP-1 levels, thereby increasing levels of free IGF-I.10
Insulin treatment in postoperative/post-traumatic patients has also been shown to normalize other metabolic processes, including fat and protein metabolism.22,23 Insulin treatment in burn patients has been shown to improve wound healing and reduce protein
catabolism.24,25 In a multivariate analysis, clinical effects from intensive insulin treatment
after surgery were related to glucose control and not to insulin levels per se17, which
may be related to toxic effects of high levels of glucose on the immune system26 and to
increased oxidative stress due to increased inflow of glucose into the cells.27e29 Thus,
improved glucose control by intensive insulin treatment in critically ill patients was
associated with an attenuation of the inflammatory response30 and normal mitochondrial
structure as opposed to the mitochondrial damage observed in hyperglycaemic patients.31
This is in agreement with previous data showing a linear correlation between postoperative reduction in insulin sensitivity and the increase in plasma IL-6 concentrations.32
METABOLIC EFFECTS RELATED TO FASTING BEFORE SURGERY
Since the introduction of general anaesthesia it has been a routine worldwide to starve
patients overnight before a surgical procedure. Only recently has it been shown that
intake of clear fluids up to 2 hr before surgery may be permitted without an increase in
gastric residual volumes or risk of aspiration of gastric contents.33 Thus, anaesthetic
societies in many countries now have guidelines allowing free intake of clear fluids before surgery.34 However, free fluids do not provide what is required to change the
fasted state. To test the hypothesis that the metabolic state at the time of surgery
may have importance for the development of postoperative stress, a series of randomized studies has been performed (Figure 1) where glucose was administered either as a
preoperative infusion or as a beverage taken 2e3 hr before surgery.35 A carbohydraterich drink (400 mL, 50 g glucose) was found to be useful for this purpose before
surgery. Scintigraphic studies showed that gastric emptying was complete within
2 hr after intake of this beverage.36 The amount of energy in this beverage was enough
to increase insulin to levels seen after a mixed meal, and insulin action enhanced by
about 50% was shown 2e3 hr after intake.37
Randomized studies involving either preoperative glucose infusion or the
carbohydrate-rich beverage all show that postoperative insulin resistance may be
reduced by about 50% when preoperative fasting is avoided.11,12,38,39 The bettermaintained insulin sensitivity after surgery has been shown to be due to less reduced
peripheral glucose uptake and oxidation in the early postoperative phase. In a study after
hip replacement surgery, where postoperative insulin sensitivity was measured on the
third postoperative day, less increased glucose production at basal and during insulin
stimulation was found in patients given the carbohydrate drink as compared to placebo.40 The increase in metabolic rates and the inhibition of insulin-stimulated nonoxidative glucose disposal seen after surgery has not been shown to be affected by
this treatment.

Metabolic effects of fasting and surgery 433

IV

Drink

IV+insulin

Drink

60
40

change

20
0

Control
CHO

-20
-40
-60
-80
Cholecystectomy

Colorectal

Hip arthroplasty Hip arthroplasty

Figure 1. The relative change in insulin sensitivity at postoperative measurement versus before surgery in
patients fasted overnight before surgery (Control) and patients given carbohydrates (CHO) as an intravenous infusion (IV)38, an intravenous infusion together with insulin before and during surgery (IV insulin)11,
or as a carbohydrate-rich beverage 2 hr before surgery (Drink).12,39 *P < 0.05, **P < 0.01 versus control,
#P < 0.001 versus control (when duration of surgery was taken into account in a multivariate analysis).

The effects on postoperative glucose production of avoiding preoperative fasting

indicate that there also may be effects on protein breakdown and gluconeogenesis.
In support of this, other placebo-controlled, randomized studies have shown bettermaintained lean body mass (mid-arm circumference) and less reduced muscle strength
(voluntary quadriceps strength) after gastrointestinal surgery when preoperative
fasting was avoided.41,42 In addition, patients given glucose infusion before major abdominal surgery displayed less nitrogen loss as compared to patients fasted overnight
before surgery.43 So far, the less affected postoperative insulin sensitivity by avoidance
of preoperative fasting has not been associated with differences in cytokine levels. In
addition, no strong relationship between insulin resistance after surgery and changes in
stress hormones has been found, apart from a study in hip replacement patients where
glucose as well as insulin was infused throughout surgery. In these patients, insulin sensitivity postoperatively was completely comparable to that in healthy subjects undergoing the same protocol (without anaesthesia or surgery), and this was associated with
lower FFA, cortisol, glucagon and IGFBP-1 levels compared to those in patients undergoing the same surgical procedure after an overnight fast. Furthermore, improved insulin sensitivity after major colorectal surgery in patients given a preoperative
carbohydrate drink was associated with higher levels of free IGF-I, as indicated by increased proteolysis of IGFBP-3, as compared to patients fasted overnight before surgery.19 In addition to the metabolic effects, providing fluid and energy before surgery
using a carbohydrate-rich drink versus placebo was also shown in randomized trials to
affect patient well-being (thirst, hunger, anxiety) before surgery44 and to reduce postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy.45
Indeed, there are also other important determinants of the surgical stress response.
Both minimally invasive procedures as well as epidural anaesthesia have been shown to
reduce postoperative insulin resistance.46,47 Mechanisms related to these effects may
be a reduction in cytokine responses (laparoscopic surgery)48 and lower release of
stress hormones (epidural anaesthesia).49 In a recent placebo-controlled randomized
study where patients undergoing open colorectal surgery were treated with an enhanced recovery protocol e including avoidance of preoperative fasting and epidural
anaesthesia e postoperative insulin sensitivity was surprisingly well maintained.50

434 J. Nygren

Although not recommended in well-fed patients, preoperative total parenteral nutrition for 7e10 days has been shown to reduce postoperative morbidity in patients
with malnutrition.51,52 Less is known regarding preoperative feeding using the oral
route. In patients planned for surgery and unselected for nutritional status, a recent
randomized study showed that adding nutritional supplements to a normal diet before
and/or after surgery improved energy intake, resulting in a better-maintained body
weight postoperatively and fewer infectious complications, as compared to control patients where supplements not were provided.53 Adding supplements to the diet did
not affect food intake but resulted in increased energy intake.
METABOLIC EFFECTS RELATED TO FASTING IN
THE POSTOPERATIVE PERIOD
Recently, two randomized studies in patients undergoing major colorectal surgery
were performed where thoracic epidural and a preoperative carbohydrate drink
were used for stress reduction. Postoperatively, patients were randomized to hypocaloric nutrition (both studies) versus enteral50 or parenteral54 nutrition to fully cover
energy requirements. Insulin sensitivity was measured before surgery and on the 3rd54
or 4th50 postoperative days. Surprisingly, insulin resistance postoperatively was no different whether the patients energy requirements were met or not, confirming previous experience that nutritional support in the postoperative period has only little
effect on postoperative metabolism. However, in these patients, in whom the postoperative stress response was largely prevented, nutritional support was related to
marked improvements in nitrogen balance along with only minor increments in glucose concentrations during feeding.
ENHANCED RECOVERY AFTER SURGERY PROGRAMME
There is increasing evidence that a multimodal approach to perioperative care markedly reduces surgical stress and enhances recovery also after major surgical procedures.55 Thus, functional recovery to the point that hospital resources are no
longer required was reduced to 2e3 days after elective colonic resection, regardless
of whether an open or a laparoscopic approach was used.56 Such a programme will
increase the success with single interventions such as postoperative oral feeding
due to the beneficial effects on gastrointestinal function.57 In addition, the implementation of such a programme may lead to markedly improved outcome from surgery.58
However, many single perioperative interventions that were previously evaluated in
the context of traditional care may need to be carefully repeated in the future, within
such a standardized perioperative programme, in order to be proved effective. This is
a challenge for the surgical units where this multimodal perioperative treatment has
been successfully implemented, in order to evaluate and continuously revise principles
for perioperative surgical care.
CONCLUSION
Fasting slows metabolic rates and induces insulin resistance, but feeding rapidly
changes metabolism. Avoiding fasting before surgery markedly reduces postoperative

Metabolic effects of fasting and surgery 435

insulin resistance, which has beneficial effects on postoperative glucose and protein
metabolism. This allows postoperative feeding with less risk for hyperglycaemia, and
improves maintenance of postoperative lean body mass and muscle function. In the
postoperative period energy intake is important for nitrogen balance and maintenance
of lean body mass, but has not been shown to affect the degree of postoperative insulin resistance. In patients with malnutrition, adequate energy intake before and after
surgery may be vital for survival, while this has not been shown in patients in a normal
nutritional state. Enhanced recovery programmes in abdominal surgery markedly
attenuate surgical stress and enhance functional recovery. Implementation of evidencebased perioperative routines is a challenge for the surgical community.

Practice points

fasting rapidly affects metabolism, although gradually adaptation occurs to minimize protein losses

surgery increases metabolic rate and catabolism, of which insulin resistance is
related to the magnitude of surgery

insulin treatment in insulin-resistant patients after surgery or trauma markedly
improves body metabolism and reduces morbidity and mortality

avoiding preoperative fasting reduces postoperative insulin resistance by about
50% and attenuates postoperative impairment in nitrogen losses, lean body
mass and muscle function

fasting or deficient energy intake after surgery does not affect postoperative
insulin resistance but does accelerate nitrogen losses

perioperative parenteral nutrition has been shown to reduce morbidity and
mortality in patients with malnutrition, but has no beneficial effects in well
fed patients

oral supplements perioperatively may attenuate postoperative weight loss and
reduce infectious complications

patients undergoing surgery within a multimodal programme designed to reduce stress and to improve postoperative function display only minor insulin
resistance, which allows feeding without hyperglycaemia

Research agenda

evidence for single interventions in perioperative care may need to be reevaluated within the context of an enhanced recovery programme

implementation of a standardized multimodal programme needs to be evaluated in a multicentre study in order to provide guidelines that improve the
chances for successful implementation of such a programme in general surgical
care

improved prospective audit of surgical care and compliance with evidencebased perioperative routines could form a basis for multicentre collaboration
to study the effects of single interventions in randomized trials

436 J. Nygren

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