Anaesth Intensive Care 2018 | 46:5 Nutritional prehabilitation

Review
Nutritional prehabilitation: physiological basis and clinical
evidence
N. L. Pillinger*, J. L. Robson†, P. C. A. Kam‡

Summary
In this narrative review, we describe the physiological basis for nutritional prehabilitation and evaluate the clinical evidence
for its current roles in the perioperative period. Surgical stress and fasting induce insulin resistance as a result of altered
mitochondrial function. Insulin resistance in the perioperative period leads to increased morbidity in a dose-dependent
fashion, while preoperative carbohydrate loading attenuates insulin resistance, minimises protein loss and improves
postoperative muscle function. Carbohydrate loading is an established practice in many countries and a key component of
enhanced recovery after surgery (ERAS) programs, yet its independent effects on clinical outcomes remain unclear. Amino
acid supplements may confer additional positive effects on a number of markers of clinical outcomes in the perioperative
period, but their current role is also poorly defined. Clinical studies evaluating nutritional interventions have been marred
by conflicting data, which may be due to small sample sizes, as well as heterogeneity of patients and surgical procedures.
At present, it is known that carbohydrate loading is safe and improves patients’ wellbeing, but does not appear to influence
length of hospital stay or rate of postoperative complications. This should be appreciated before its routine inclusion in ERAS
programs.

Key Words: Carbohydrate, fasting, insulin resistance, perioperative

It has been proposed that preoperative carbohydrate
loading, a practice embedded in multimodal enhanced
recovery after surgery (ERAS), has a significant independent
effect on surgical outcomes1. The clinical effects of
carbohydrate loading in the perioperative period have been
extensively studied and a number of meta-analyses and
clinical practice guidelines have been published2-4. Despite
consensus guidelines recommending the routine use of
preoperative carbohydrate drinks in a number of elective
surgical procedures5-7, doubt has now been cast over their
clinical benefit and ongoing role in perioperative care8.
Perhaps less well known are the pathophysiological effects
of fasting and surgical trauma and the physiological basis
for carbohydrate loading and nutritional interventions, a
practice collectively coined ‘nutritional prehabilitation’. A
sound understanding of these principles may help to identify
metabolically vulnerable patients, in whom nutritional
interventions may confer greater clinical benefit.
The aim of this narrative review, therefore, is to describe
* MBBCh FANZCA, Department of Anaesthetics, Royal Prince Alfred Hospital; Clinical
Lecturer, University of Sydney; Sydney, New South Wales
† MBBS MMed FANZCA, Department of Anaesthetics, Royal Prince Alfred Hospital,
Sydney, New South Wales
‡ MBBS MD FANZCA FRCA FFARCSI FHKCA (Hon), Nuffield Professor of Anaesthetics,
University of Sydney; Department of Anaesthetics, Royal Prince Alfred Hospital;
Sydney, New South Wales
Address for correspondence: Neil Pillinger. Email: neil.pillinger@sydney.edu.au
Accepted for publication on June 1, 2018
the physiological effects of perioperative fasting, specifically
‘routine’ fasting and prolonged fasting, as well as the
pathophysiology of insulin resistance and context for
carbohydrate supplementation. Furthermore, we evaluate
the clinical evidence for nutritional prehabilitation and aim to
clarify its role in clinical practice.
Methods
A literature search was performed using PubMed, EMBASE,
CINAHL and Google Scholar for relevant articles published
between 1970 and 2017. The following key words were
used: ‘ERAS’, ‘fasting’, ‘surgical stress’, ‘insulin resistance’,
‘immunonutrition’ and ‘carbohydrate loading’. The search
was limited to English language but not restricted to study
type. We excluded articles published only in abstract form,
and case reports.
Perioperative fasting
Preoperative fasting is an established practice to mitigate
the risk of pulmonary aspiration and ensuing pulmonary
injury, known as aspiration pneumonitis or Mendelson’s
syndrome9. ‘Nil by mouth from midnight’ of the day
preceding elective surgery was the traditional method used
to assure a fasted state and for many years this practice was
empirically enforced. However, over the past two decades
the scientific basis for this practice has been challenged

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and attitudes towards preoperative fasting concurrently
changed10. ‘Modern’ fasting guidelines support a more liberal
approach and patients are now encouraged to consume clear
fluids (water, carbonated drinks, clear tea, black coffee, pulp-
free juices) up to two hours before elective surgery11,12.
Surgical patients often experience restricted enteral
nutrition, such that the total duration of perioperative
fasting should be considered, that is the time until normal
calorific intake is resumed. Perioperative fasting generates an
unfavourable metabolic state, which is additive to that caused
by surgical stress, and culminates in insulin resistance13.
Insulin resistance is a key process in perioperative
inflammation and correlates with clinical recovery following
surgery14. Carbohydrate supplementation is intended to offset
unwanted metabolic consequences of fasting and surgical
trauma and therefore improve clinical outcomes.
Metabolic effects of fasting*
Metabolic effects of fasting are comprehensively reviewed
in Comprehensive Human Physiology: From Cellular
Mechanisms to Integration and readers should consult
Volume 2, Chapter 71 by Jungermann and Barth for an
in-depth explanation of energy metabolism and nutrition15.
* All values in this section are approximate and apply to
normal adults.
(a) Short-term fasting <12 hours
During short-term fasting, the liver is the primary source of
glucose via glycogenolysis, which provides 4.5 g of glucose
per hour. Fasting reduces insulin-mediated glucose uptake
into skeletal muscle, slows metabolism and reduces total
energy expenditure by 5%–10%. After an overnight fast, most
of the body’s energy is derived from free fatty acids, but
the body continues to consume glucose at a rate of 8–10 g/
hour. In the last few hours of the post-absorptive phase at
night, energy expenditure is equal to 75 kcal/hour. During
this time, hepatic glycogen is consumed at a linear rate,
with most glucose utilised by the brain and other obligate
glucose tissues (renal medulla, bone marrow, red blood cells,
peripheral nerves)16. Glucose utilisation of the brain and red
blood cells is 4.5 g/hour and 1.5 g/hour, respectively. Hepatic
energy requirements, as well as those of the heart and renal
cortex are met by lipolysis of adipose tissue, which provides
5 g of fatty acids per hour. Amino acids are the preferred
energy substrate in the intestine15.
As the body transitions to a fed (post-absorptive) state,
there is peripheral glucose uptake and glycogen stores are
replenished: equating to 50–120 g in the normal adult liver,
or up to 10% of liver mass. Importantly, hepatic glycogen
is the exclusive endogenous source of glucose; 400 g of
glycogen exists in skeletal muscle but is processed for
muscle energy alone. At the same time, there is cessation of
catabolic processes, including gluconeogenesis, proteolysis
and lipolysis. After feeding, a predominantly anabolic state
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Figure 1: Sequential phases of prolonged fasting.
persists for about four hours. The fed state is metabolically
superior in the face of stress, including surgery and its
attendant catabolic processes. It follows that six hours of
preoperative fasting induces peripheral insulin resistance,
while clear fluids alone fail to reverse this state of insulin
insensitivity. In other words, routine preoperative fasting
almost universally generates an unfavourable metabolic
condition17.
(b) Prolonged fasting—beyond 12 hours
It is nearly 20 years since the American Society of
Anesthesiologists (ASA) first published landmark guidelines
that abandoned the dogma of ‘nil by mouth from midnight’18
and despite widespread adoption of these guidelines,
prolonged fasting before surgery is still commonplace and
commonly exceeds 12 hours, especially in emergency
surgery19.
Prolonged fasting leads to a proportional increase
in peripheral insulin resistance and hepatic glycogen
consumption. The rate of glycogenolysis eventually decreases
and becomes non-linear, but hepatic (functional) glycogen
stores are virtually depleted after only 18–24 hours, which
means there is no readily available energy substrate for
critical tissues, notably the nervous system16. There is
increased reliance on gluconeogenesis and skeletal muscle is
sacrificed to generate a pool of amino acids, which is additive
to protein loss due to surgical stress. Protein loss occurs in
response to increased secretion of glucagon, catecholamines,
and cortisol, and the presence of interleukin-1. Increased
breakdown of the lean body mass supplies the liver
with amino acids to increase glucose production via the
alanine–glucose cycle: a pathway of gluconeogenesis.
The most common intracellular amino acid is glutamine,
which constitutes 50%–60% of the available amino acids
Anaesth Intensive Care 2018 | 46:5
within muscle. Glutamine is also a major substrate for renal
gluconeogenesis. It is known that glutamine levels in both
muscle and plasma acutely decline in critical illness and
following major surgery20.
There is net destruction of muscle as nitrogen is lost
from amino acids during each turn of the alanine–glucose
cycle, with ammonia converted to urea. In normal adults,
the loss of protein may be as much as 300 g of protein per
day during starvation. However, the body rapidly adapts to
prolonged fasting and proteolysis is reduced. In fact, after
four days there is minimal protein breakdown. Importantly, if
sepsis coexists, this adaptive mechanism does not occur and
proteolysis inexorably continues. Figure 1 summarises the
metabolic effects of continued fasting.
As starvation progresses beyond the first week, the
normal post-absorptive basal metabolic rate is reduced
from 75 kcal/hour to about 65 kcal/hour in an effort to
preserve glucose. By this time, glycogen is long exhausted
and protein is significantly depleted. Carbohydrates are no
longer the primary energy source; only triglyceride stores
are large enough to sustain long-term fasting. Lipolysis of
adipose tissue provides 6.6 g of fatty acids per hour and
muscle proteolysis provides 1.2 g of amino acids per hour15.
Starvation contributes to insulin resistance by enhancing
lipolysis, which increases fatty acid delivery to muscle tissues.
Intramyocellular accumulation of lipid metabolites impairs
glucose transporter type 4 (GLUT4) translocation due to
defects in insulin signalling caused by phosphorylation of
serine residues in Insulin Receptor Substrate-121.
In many surgical procedures and postoperative states,
enteral intake is not re-established in the immediate
postoperative period, and fasting (or a state of low calorific
intake) continues for many hours, or even days. Nygren et
al emulated a common perioperative scenario by imposing
24 hours of restricted calorific intake (50 g of glucose via
intravenous infusion) and demonstrated peripheral insulin
resistance in all subjects22. Therefore, the total duration of
fasting should be taken into account because metabolic
derangement is progressive and deleterious effects are added
to postoperative catabolism, especially in major surgery.
Importantly, fasting causes dose-dependent peripheral
insulin resistance, which is the proposed key event in
postoperative inflammation and subsequent clinical
recovery. The magnitude of insulin resistance at the time
of surgery independently predicts outcome after major
surgery23, such that the duration of preoperative fasting
becomes critically important. From a practical standpoint, it
is possible to attenuate perioperative insulin resistance by
shortening the duration of fasting, rather than attempting
to mitigate surgical stress. This is also the physiological basis
of carbohydrate loading: an attainable means of reducing
perioperative insulin resistance.
Nutritional prehabilitation
Perioperative insulin resistance
Perioperative fasting and surgical trauma both contribute
to perioperative insulin resistance. It has been demonstrated
that insulin resistance correlates positively with surgical
invasiveness24,25 and occurs following even minor surgery,
such as laparoscopic cholecystectomy26 and open inguinal
hernia repair24. Insulin sensitivity can fall dramatically in
the perioperative period and only gradually returns to
baseline; Thorell et al showed a 54% decline in mean insulin
sensitivity on the first postoperative day following elective
upper abdominal surgery using the hyperinsulinaemic-
normoglycaemic clamp technique (gold-standard measure)27.
The authors also demonstrated that insulin resistance
persisted for at least five days after the operation and
could even take up to three weeks to return to baseline,
despite an uncomplicated operative course. Besides surgical
magnitude, pain and bed rest independently contribute
to perioperative insulin insensitivity13. Additional patient
characteristics influence the development and magnitude
of insulin resistance, including diabetes mellitus, obesity,
metabolic syndrome, pregnancy, and starvation28. There is
also significant inter-individual variation in its natural history,
which implies a genetic role in the clinical phenotype.
Crucial from a clinical standpoint, postoperative insulin
resistance is implicitly linked to the duration of hospital
stay, and its return to baseline coincides with recovery from
surgery14. Moreover, insulin resistance independently predicts
major postoperative morbidity in a dose-dependent fashion23.
It is likely, therefore, that perioperative insulin resistance is
a key process in the pathophysiology of surgical stress, its
magnitude and subsequent recovery.
Pathogenesis of insulin resistance in the perioperative
period
Insulin resistance can be classified into two subtypes:
central and peripheral. Central insulin resistance is
characterised by increased hepatic glucose production in
the presence of physiological insulin concentrations, while
peripheral insulin resistance is characterised by defective
skeletal muscle glycogen synthesis, that is, non-oxidative
glucose consumption.
Perioperative insulin resistance is associated with
diminished circulating insulin-like growth factor–1
(IGF-1) levels and an increase in IGF-binding protein–1
concentrations17. IGF-1 is an anabolic hormone with insulin-
like effects on glucose and protein metabolism. It is produced
primarily in the liver and stimulated by growth hormone. IGF-
binding protein–1 inhibits IGF-1 activity. In skeletal muscle
cells, there is reduced glycogen synthase activity, which
limits glycogenesis. In addition, circulating catecholamines
inhibit the binding of insulin to its receptor and sequentially
prevents GLUT4 translocation from intracellular vesicles to
the muscle membrane29. GLUT4 translocation and glucose
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Figure 2. Effects of surgery and fasting on glycaemic control. IL-6, interleukin-6;
TNF, tumour necrosis factor; Glut 4, glucose transporter type 4.
transport are interrupted, such that skeletal muscle is
rendered refractory to the physiological actions of insulin.
The net result is peripheral insulin resistance. In this setting,
glucose uptake into cells that are normally insensitive
to insulin (nerve, renal and blood cells) is permitted and
governed by the glucose concentration gradient in plasma
and the extracellular space30.
The development of insulin resistance is also associated
with mitochondrial defects. Increased glucose uptake results
in excess glycolysis, generating oxygen free radicals in the
mitochondria. These oxygen free radicals cause changes
in metabolism and gene expression, at the same time
promoting cytokine production. Boirie et al found that
mitochondrial protein synthesis, mitochondrial enzyme
activity and oxidative phosphorylation were all stimulated
by insulin31. It was suggested that a decrease in insulin
concentration during fasting impaired mitochondrial function
and oxidative capacity, resulting in an accumulation of
intramyocellular lipid which is inversely correlated with
muscle insulin sensitivity32. Accumulation of these lipid
metabolites causes defects in insulin signalling, failure of
GLUT4 translocation, and reduced insulin-stimulated glucose
uptake21.
Relevance of the surgical stress response
Surgery activates a cascade of immune, metabolic,
endocrine and autonomic changes, often referred to
collectively as the ‘stress response’33. Postoperative
metabolism favours a catabolic state characterised by
peripheral insulin resistance, glycogenolysis, enhanced
gluconeogenesis, proteolysis, and lipolysis. Counter-
regulatory hormones (catecholamines, cortisol, growth
hormone, glucagon) and pro-inflammatory cytokines
are released as part of this process; the end result is
hyperglycaemia and loss of nitrogen34.
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The stress response is initiated by pro-inflammatory
cytokines, such as interleukin-1 (IL-1) and tumour necrosis
factor (TNF), which are released at the site of surgical trauma
by leukocytes and endothelial cells33. Interleukin-6 (IL-6)
appears to be the main acute phase protein in this process
and plasma concentrations have been shown to correlate
positively with both magnitude and duration of surgery35.
Pro-inflammatory cytokines lead to the development of
insulin resistance and a compensatory increase in insulin
release. Despite this, blood glucose levels increase because
of an overriding state of insulin resistance14 (Figure 2). The
magnitude of the stress response also exhibits large inter-
individual variability, suggesting a genetic component in its
pathogenesis13.
Pro-inflammatory cytokines released during the stress
response play an important role in the pathogenesis of
perioperative insulin resistance. In the endothelium TNF-α
reduces tyrosine phosphorylation and expression of the
insulin receptor36, while in liver, muscle, and fat cells, it blunts
phosphoinositide 3–kinase (PI3K) activation37. IL-1 and IL-6
both inhibit insulin-mediated glycogen synthesis38.
The stress response also leads to abnormal protein
metabolism, which can manifest as clinically significant
muscle loss. It has been shown that patients undergoing
elective open abdominal surgery cumulatively lose 40 to
80 g of nitrogen39, while losses from sepsis and burns can
be several times higher. Peripheral insulin resistance is a key
process in the pathogenesis of proteolysis, resulting primarily
from amino acid mobilisation to fuel gluconeogenesis. Amino
acids are also mobilised to synthesise acute phase proteins,
which are important molecules in postoperative stress.
Adverse clinical outcomes include muscle weakness, impaired
immune function and delayed wound healing. In fact, loss
of lean body mass is directly proportional to the time taken
to return to normal physiological function following hospital
discharge34.
Immune response and clinical implications
The fasted state combined with surgical stress suppresses
the immune system. This occurs primarily through atrophy
of lymph nodes, a decline in IgA production and inhibition
of cellular immunity. T-lymphocytes and natural killer cells
are adversely affected by the advent of surgery, ultimately
leading to an increased risk of infection for surgical patients40.
Glutamine, arginine, nucleotides and omega-3 fatty acids
are ‘immunonutrients’ which can positively modulate
perioperative immune responses41. Glutamine is the most
abundant free amino acid in the body and is important
for rapidly proliferating cells, including those of the
gastrointestinal, central nervous, and immune systems.
Glutamine is essential in the body’s defence against stress
and injury, with roles in immune cell function, glycaemic
control, nitrogen balance, gastrointestinal function and
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Table 1 to identify malnutrition and sarcopenia. Moving forward,

Summary of randomised controlled trials investigating preoperative there is still a need for high-quality randomised trials to
carbohydrate loading and its effects on perioperative insulin resistance better define the composition and timing of perioperative
immunonutrients, and interrogate methods to enhance risk
Effect on
Author Surgery type N Intervention insulin
stratification and patient selection.
resistance
Fujikuni et al48 Gastrectomy 80 Oral CHO Reduced Carbohydrate loading
2016 ERAS vs P <0.014
standard care Perioperative carbohydrate loading is now an established
strategy to reduce the impact of surgical stress and modulate
Okabayashi Liver resection 26 Oral CHO + Reduced
et al49 2010 amino acids P <0.039 insulin sensitivity both intraoperatively and postoperatively46.
Faria et al26 Laparoscopic 21 Oral CHO Reduced
Ljungqvist et al postulated that insulin sensitivity can
2009 cholecystectomy vs fasting P <0.03 be improved by the ingestion of carbohydrate-rich drinks,
overnight although the precise mechanism of action was unclear47.
Svanfeldt et al50 Colorectal 12 Oral high No significant More recently, several studies have confirmed that
2007 CHO difference preoperative carbohydrate loading reduces insulin resistance,
vs oral low
CHO summarised in Table 1.
Nygren et al51 Colorectal 14 Oral CHO Reduced 24% Physiological basis
1999 Total hip 16 vs placebo Reduced 37%
replacement Carbohydrate loading is provided in the form of
Ljungqvist Open 12 IV glucose Reduced
carbohydrate-rich drinks consumed in the preoperative
et al52 1994 cholecystectomy vs fasting P <0.01 period. Studies utilising intravenous glucose infusions
CHO, carbohydrate loading; ERAS, enhanced recovery after surgery; N,
at a rate of 5 mg/kg/minute showed a 50% reduction in
number of subjects. the development of postoperative insulin resistance in
those receiving supplemental carbohydrates53. Clinically
this equates to a rapid infusion of 20% dextrose solution:
attenuation of pro-inflammatory cytokines20. Parenteral sufficient to induce an insulin response, but also causes
glutamine supplementation has been shown to reduce thrombophlebitis54. Commonly used low-concentration
insulin resistance42, while enteral consumption is safe and glucose solutions, for example 5% dextrose, fail to stimulate
does not prolong gastric emptying43. Arginine also has insulin release sufficiently to induce a metabolic effect55.
important immune effects, enhancing T-cell maturation and Sport drinks, typically containing 6%–7% carbohydrates,
activation, while omega-3 fatty acids modify the production also fail to stimulate insulin production sufficiently to
of inflammatory mediators including interleukins, cytokines, promote protein-sparing effects43. To avoid thrombophlebitis,
and eicosanoids41. enteral carbohydrate-rich solutions containing complex
Immunonutrient supplements, including combinations of carbohydrates were developed.
arginine, glutamine, nucleotides, and omega-3 fatty acids, Oral carbohydrate solutions are iso-osmolar and promote
have all been studied in the perioperative period and, despite gastric emptying54; 12.5% enteral carbohydrates (50 g in 400
a number of published meta-analyses, their clinical role is ml) stimulate an insulin response similar to that observed
yet to be defined. A 2017 meta-analysis of more than 7,000 after a meal17. The key ingredient is maltodextrin, which
patients undergoing major abdominal surgery concluded that is manufactured into a 12.5% high-energy drink, with an
immunonutrition reduces infectious and overall complications osmolality of 135 mOsm/kg. Importantly, it is formulated
and shortens hospital stay by almost two days44. However, so that it reliably empties from the stomach after one
treatment effects were confounded by low to moderate hour (physiologically behaving as a clear fluid). In a typical
quality of evidence and a high risk of bias amongst included ERAS protocol, 800 ml is consumed on the evening before
trials. In fact, in a subgroup analysis, all treatment effects surgery and 400 ml two hours before surgery. The evening
became non-significant when the risk of bias was corrected. dose enhances hepatic glycogen storage but does not
A recent review by Gupta and Senagore summarised the preserve perioperative insulin sensitivity. The subsequent
difficulties in placing immunonutrients into perioperative morning dose effectively changes the patient from a fasted
care, including a predominance of low-quality evidence, to fed state, which minimises insulin resistance56 (Figure 3).
outdated study designs, and uncertain relevance in the era Randomised studies of preoperative glucose infusions and
of minimally-invasive surgery and ERAS protocols45. They also carbohydrate-rich beverages reported a 50% reduction in
identify the need for preoperative strategies to better stratify postoperative insulin resistance57,58.
risk with respect to immunonutrient supplementation,
including the use of novel imaging techniques and biomarkers

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Figure 3: Effects of preoperative carbohydrate loading on insulin resistance.
Cellular effects
Compared to placebo, carbohydrate drinks containing
glutamine and antioxidants are associated with a decreased
expression of muscle pyruvate dehydrogenase 4 (PDK4)
mRNA, PDK4 protein and metallothionein 1A59. PDK4
protein inactivates the pyruvate dehydrogenase complex
(PDC): a complex of three enzymes that regulates entry
of pyruvate (derived from carbohydrate metabolism) into
the citric acid cycle. It follows that decreased expression of
PDK4 in muscle due to carbohydrate loading sequentially
enhances PDC activity and carbohydrate oxidation; the end
result is improved insulin sensitivity60. Carbohydrate loading
also enhances tyrosine kinase and PI3K activity, as well as
expression of protein kinase B, all of which are involved in the
metabolic actions of insulin and attenuate peripheral insulin
resistance61.
Glycaemic effects
Gianotti et al (2017) demonstrated that oral preoperative
carbohydrate loading was an effective method of avoiding
perioperative hyperglycaemia in non-diabetic patients (blood
glucose >10 mmol/l), as well as reducing the need for insulin,
without increasing the incidence of postoperative infection62.
It has also been shown that glycaemic variability is reduced
with preoperative low-dose complex carbohydrate loading in
patients undergoing colorectal surgery63.
Preoperative carbohydrate loading has been shown to
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Anaesth Intensive Care 2018 | 46:5
be safe in patients with well-controlled type 2 diabetes
mellitus. Gustafsson et al (2008) examined the glycaemic
effects of a 400 ml carbohydrate-based drink administered
three hours before anaesthesia in 25 patients with type 2
diabetes (mean HbA1c 6.2%) and in ten healthy controls.
They reported that there was no significant difference in
gastric emptying between the diabetic group and control
group, and blood glucose levels returned to pre-drink levels
within three hours64. Poorly-controlled diabetic patients with
autonomic neuropathy can have delayed gastric emptying,
thus increasing the risk of aspiration65.
Perioperative safety
A major concern to anaesthetists is the ingestion of 400 ml
of a carbohydrate drink in the immediate preoperative period
and a perceived elevated risk of pulmonary aspiration. The
half-time of gastric emptying of 500 ml of isotonic saline (a
neutral and iso-osmolar inert solution) is 12 minutes; 90%
passes through the pylorus within one hour and clearance
is nearly complete within two hours. Several studies
have demonstrated safe consumption of preoperative
carbohydrate drinks, with gastric emptying complete within
90–120 minutes66,67. A scintigraphic study employing a gamma
camera showed that gastric emptying of 400 ml of a 12.5%
carbohydrate drink was achieved within 90 minutes in both
healthy volunteers and in preoperative patients. Before
induction of anaesthesia, there was no significant difference
in residual gastric volumes compared to placebo67.
Hausel et al (2001) randomised 252 patients (ASA physical
status I and II with no increased baseline risk of pulmonary
aspiration) into three groups: fasted overnight, flavoured
water (placebo) and carbohydrate loading. The placebo and
carbohydrate groups consumed 800 ml of their respective
study fluid on the evening prior to surgery and a further 400
ml at least two hours preoperatively. Gastric fluid volumes
(GFVs) and pH were measured after induction of anaesthesia
(via nasogastric tube aspiration and a single-marker dilution
technique). GFVs were small in all groups (fasted median
GFV 22 ml; placebo 20 ml; carbohydrate 20 ml). There were
no significant differences in GFV between treatment groups.
Maximum volumes aspirated were 287 ml in the placebo
group, 245 ml in the carbohydrate group and 103 ml in the
fasted group. Median gastric pH was 1.9–2.1, with non-
significant differences between the groups. The authors
concluded that administration of a carbohydrate drink two
hours before surgery did not increase either GFV or gastric
acidity68.
Studies have also compared preoperative consumption
of carbohydrate-based drinks with other types of drinks. A
double-blind randomised crossover study in eight patients
compared two beverages: Nutricia preOp (Danone, Dublin,
Ireland) (beverage A) and a fruit-based lemonade (beverage
B) 69. Gastric emptying (measured by scintigraphy) and
hormonal responses were studied, specifically plasma levels
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Table 2
Summary of clinical outcomes of meta-analyses comparing carbohydrate loading with control

Author N Clinical effects Additional comments

Li et al4 2012 22 trials No effect on length of hospital stay or ICU stay Low to moderate quality evidence
N=1905 No effect on nausea or vomiting across all outcomes
Reduced thirst compared with fasting Different CHO regimens grouped
together
Awad et al2 21 trials N=1685 No effect on length of stay overall Low to moderate quality evidence
2013 Reduced length of stay in major open abdominal surgery 1.08 days across all outcomes
(95% CI 1.87–0.29) Controls (fasting/water/placebo)
No effect on pulmonary or surgical complications grouped into single treatment arm
Smith et al3 27 trials N=1976 Reduced length of hospital stay by 0.3 days (95% CI 0.56–0.04) Low quality evidence
2014 Shortened time to passage of flatus 0.39 days (95% CI 0.7–0.07) Inadequate blinding
No effect on postoperative complications Controls (fasting/water/placebo)
grouped into single treatment arm
Amer et al8 43 trials Small reduction in length of hospital stay compared with fasting Network meta-analysis (multiple
2017 N=3110 alone treatment comparisons)
Low dose CHO 0.4 days (95% CI 0.03–0.7) Low to moderate quality evidence
High dose CHO 0.2 days (95% CI 0.04–0.4) Moderate statistical heterogeneity
No effect on length of stay compared with water or placebo No significant differences between
No effective on postoperative complications high dose and low dose CHO
CHO, carbohydrate loading; N, number of subjects; ICU, intensive care unit; CI, confidence intervals.

of glucose, insulin, C-peptide, glucagon-like peptide (GLP-1;
delays gastric emptying and stimulates insulin secretion),
peptide YY (PYY; delays gastric emptying), total glucagon
and ghrelin (enhances gastric motility and emptying). At two
hours post-consumption, the median residual volumes were
0 ml and 48.3 ml for beverages A and B, respectively: a non-
significant difference. Beverage A emptied from the stomach
more rapidly in the first 15 minutes, which may account for
the increased plasma levels of glucose, insulin, and C-peptide
observed. It is proposed that the rapid emptying of beverage
A may be due to its hypo-osmolality; beverage A was
specially developed with a higher polysaccharide content,
which reduced its osmolality. The non-significant difference
in median residual volumes confirmed the findings of
previous studies, that is, the concentration rather than type
of carbohydrates in the beverage is the principal determinant
of gastric emptying70. This study also showed that both
beverages increased levels of glucose, insulin, C-peptide,
GLP-1, glucagon and PYY, while ghrelin levels decreased.
Gastric emptying half-time and gastric residual volumes were
not correlated with glucose, insulin, total glucagon, PYY or
ghrelin. Increased levels of glucose, insulin, and C-peptide
indicated an anabolic state arising from consumption of both
the carbohydrate-based drink and the fruit-based lemonade.
Clinical effects
Early randomised controlled trials suggested that
carbohydrate loading could have an extraordinarily large
treatment effect, leading to significant reductions in hospital
stay1. Subjects given carbohydrate drinks preoperatively
were also shown to experience a reduction in postoperative
anxiety, thirst, and hunger68. Furthermore, in a randomised
study of patients undergoing laparoscopic cholecystectomy,
the preoperative carbohydrate drink group had a significant
reduction in postoperative nausea and vomiting compared
with the fasted group71. Preoperative carbohydrate drinks
also positively modulate muscle strength and maintain
muscle mass, with potentially long-lasting effects. In patients
receiving carbohydrate loading preoperatively, higher activity
in glycogen synthase in the vastus lateralis muscle biopsies
were reported up to one month postoperatively72.
A randomised trial conducted on cardiac surgical patients
(ASA physical status III and IV) used exogenous insulin
requirement as a marker for postoperative insulin resistance.
Whilst it was found that administration of preoperative
carbohydrate before cardiac surgery did not influence
postoperative insulin resistance, intraoperative inotropic
requirements (a tertiary outcome measure) were reduced
in the carbohydrate group compared with the placebo or
control groups, suggesting improved cardiac performance73.
Further investigation is required to elucidate whether
preoperative carbohydrate administration has clinically
significant independent effects on myocardial function.
A randomised study involving 30 patients undergoing
orthopaedic procedures investigated the effect of
preoperative carbohydrates on the immune system58.
Patients were randomised into three groups: two groups
received carbohydrate-rich drinks preoperatively (Beverage
A: Nutricia preOp and Beverage B: diluted fruit-based syrup)
while the third group fasted overnight. Human leukocyte
antigen (HLA)-DR expression on monocytes was measured
the day prior to surgery and the day after surgery. HLA-DR
is required for antigen presentation and reduced expression
of HLA-DR is linked to an increased risk of postoperative

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infection. The degree of postoperative immunosuppression
increases with the magnitude of surgery. In the fasted group,
HLA-DR expression decreased (P <0.05) whereas there
was no significant change in the two groups that received
a carbohydrate-rich beverage. There was no significant
difference between the two carbohydrate-rich groups.
This study showed that preoperative carbohydrate loading
prevented the reduction in the expression of HLA-DR on
monocytes and hence the risk of developing postoperative
infection.
Three recent meta-analyses shed light on the overall
clinical value of preoperative carbohydrate loading. Awad
et al showed a small but significant reduction in the length
of stay in abdominal surgery by 1.08 days (95% confidence
intervals, CI, 1.87 to 0.29 days) with reduced postoperative
infection rates2. A Cochrane meta-analysis by Smith et al
showed a comparatively smaller reduction in length of stay
(0.3 days; 95% CI 0.56 to 0.04) for patients undergoing
elective surgery3. However, these meta-analyses did not
account for different doses of carbohydrates administered
or different control methods used. A more recent network
(multiple treatments comparisons) meta-analysis of 43 trials
(3,110 subjects), concluded that preoperative carbohydrate
loading before elective surgery resulted in a small reduction
in length of stay compared with fasting, but not compared
with water or placebo8. There was no significant difference
in the postoperative complication rates for patients receiving
a carbohydrate load compared with patients who fasted
or those who received water or a placebo drink. There
was moderate statistical heterogeneity and inconsistencies
for some outcomes due to the differences in trial design,
outcome measures and clinical settings. Table 2 summarises
the main findings of meta-analyses comparing carbohydrate
loading with control.
A consistent theme in these meta-analyses is that the
quality of evidence is low to moderate for virtually all
outcomes. Furthermore, data on the clinical effects, such as
length of stay and rates of complications, are conflicting due
to a small number of trials and small sample sizes, as well as
heterogeneity of patients and type of surgery. Administration
of oral carbohydrate drinks two hours preoperatively is safe
and has been embedded in ERAS protocols, albeit without
strong evidence to support an independent effect on clinical
outcomes. The evidence overall indicates that carbohydrate
loading fails to influence either length of stay or complication
rates after surgery, provided that patients are permitted to
consume clear fluids in the preoperative period. This finding
reinforces the importance of adhering to modern fasting
guidelines and the move away from the practice of ‘nil by
mouth from midnight’. We also agree that the economic
implications of these drinks should be considered before
their routine administration and uncontested inclusion in
ERAS programs8.
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Anaesth Intensive Care 2018 | 46:5
Conclusion
The strength of this review is that it revisits the basic
science behind nutritional prehabilitation, which enables
the reader to anticipate the burden of perioperative insulin
resistance and, at the same time, identify patient groups
that might benefit most from nutritional supplements.
We also emphasise the value of simple interventions that
mitigate insulin resistance, including minimising the duration
of preoperative fasting, providing effective analgesia
and promoting early postoperative enteral intake and
mobilisation: key tenets of ERAS.
There remains much scope for rigorously designed or
multicentre trials to better define the role of carbohydrate
loading in the perioperative period. Future studies should
also investigate the effects of supplemental immunonutrients
and metabolic conditioning agents such as glutamine and
citrulline.
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