British Journal of Anaesthesia 85 (1): 80±90 (2000)

Anaesthetic management of patients with diabetes mellitus

G. R. McAnulty1, H. J. Robertshaw2 and G. M. Hall1*
1
Department of Anaesthesia and Intensive Care Medicine, St George's Hospital Medical School, London
SW17 0RE, UK. 2Department of Anaesthesia, Imperial College of Science, Technology and Medicine,
Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
*Corresponding author

Br J Anaesth 2000; 85: 80±90

Keywords: complications, diabetes; blood, glucose; hormones, insulin; metabolism,
hypoglycaemia

The prevalence of diabetes mellitus in both adults and
children has been steadily rising throughout the world for
the past 20±30 yr.29 55 97 Recent changes in diagnostic
criteria, if widely adopted, will probably also lead to more
patients being classi®ed as having diabetes.16 Inevitably,
diabetic patients presenting for incidental surgery, or
surgery related to their disease, will place an increasing
burden on anaesthetic services. Con¯ict will occur between
an economic need to minimize hospital stay and traditional
approaches to managing perioperative diabetic patients that
rely on a period of inpatient preoperative `stabilization'.
Better glycaemic control in diabetic patients undergoing
major surgery has been shown to improve perioperative
mortality and morbidity.44 90 Simple avoidance of hypogly-
caemia and gross hyperglycaemia are no longer adequate in
the light of this knowledge. While there can be little
argument about the management of diabetic patients
undergoing major procedures, their management for minor
surgery is an increasing dilemma. Under what circum-
stances are day-case anaesthesia and surgery appropriate?
Does admission on the day of surgery add to the risk for the
diabetic patient? What investigations, if any, are needed to
assess the cardiovascular system of an asymptomatic
diabetic who presents for major surgery? Unfortunately,
there are few data to provide answers to these questions. An
understanding of the pathophysiology of diabetes and of the
importance of recent research should improve the peri-
operative care of diabetic surgical patients. This review will
discuss some recent developments in the ®eld. It will not
provide `recipes' or algorithms for management. These can
be found in any of the standard texts.
Revised diagnostic criteria for diabetes
mellitus
Recently, both the American Diabetes Association (ADA)
and the World Health Organization (WHO) published
recommendations for new diagnostic criteria for diabetes
mellitus.1 106 Both bodies advise a reduction in the threshold
limit for fasting plasma glucose concentrations and reaf®rm
a more aetiologically based nomenclature. The terms type 1
(pancreatic B-cell destruction) and type 2 (defective insulin
secretion and, usually, insulin resistance) diabetes are
recommended to replace completely the frequently mis-
leading terms `insulin-dependent' and `non-insulin-depend-
ent' diabetes. The ADA has speci®ed that the diagnosis of
diabetes mellitus should be made if a `casual' (random)
plasma glucose value in an asymptomatic individual is
>11.1 mmol litre±1. If a fasting plasma glucose is >7.0 mmol
litre±1 (6.1 mmol litre±1 blood glucose) in an asymptomatic
individual, the test should be repeated on a different day and
a diagnosis made if the value remains above this limit. The
ADA de®nes fasting plasma glucose concentrations be-
tween 6.1 and 7.0 mmol litre±1 (5.6±6.1 mmol litre±1 blood
glucose) as representing `impaired fasting glycaemia'. The
WHO also recommends that a diagnosis of diabetes mellitus
be made if a random plasma glucose concentration is >11.1
mmol litre±1 (venous whole blood >10.0 mmol litre±1). It
can also be diagnosed with a fasting plasma glucose
concentration of >7.0 mmol litre±1 and a second similar
test or an oral glucose tolerance test producing a result in the
diabetic range.
The change in the fasting plasma glucose concentra-
tions used to de®ne diabetes and the role of a standard
oral glucose tolerance test may make it dif®cult to
compare epidemiological studies using these new criteria
with those using previous ones. Inevitably, some indi-
viduals will be diagnosed as having diabetes using
criteria based solely on (lower) fasting plasma glucose
concentrations who would not have been so diagnosed
under the earlier de®nitions. There will be others who
would have ful®lled the de®nition using an oral glucose
tolerance test but who will have acceptable fasting
values. Thus it is likely that the new de®nitions will

Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2000
 Diabetes mellitus
de®ne as diabetic a group of glucose intolerant individ-
uals.52
In addition to the two common types of diabetes, a
number of causes of glucose intolerance can be de®ned
according to a speci®c causal or pathological process.
Gestational diabetes is glucose intolerance which has its
onset in, or is ®rst diagnosed during, pregnancy. The
severity varies and the de®nition applies whether or not
insulin is administered in treatment. Women with diabetes
diagnosed before pregnancy are de®ned as having `diabetes
mellitus and pregnancy', not gestational diabetes.1 The
neonatal outcome of type 1 diabetic women who become
pregnant is poor. Their infants are approximately ®ve times
more likely to be stillborn and 10 times more likely to have
congenital malformations than those born to non-diabetic
mothers.10 Management in a specialist centre may improve
the incidence of perinatal mortality.34 Abnormally in-
creased membrane transport of glucose, even in mothers
whose diabetes is well controlled, may explain the continu-
ing high rates of congenital malformations (particularly
macrosomia) despite improved treatment.48 Increasing the
frequency of insulin administration from two to four times
daily during pregnancy can lead to better maternal
glycaemic control with a lower incidence of neonatal
hypoglycaemia and hyperbilirubinaemia without increasing
the risk of maternal hypoglycaemia.73
There is a number of rare genetic causes of glucose
intolerance. Among these are defects of B-cell function
(formerly called maturity-onset diabetes of the young, or
MODY) and defects in insulin action (formerly called type
A insulin resistance). Diffuse diseases of the exocrine
pancreas (such as pancreatitis), speci®c viral infections
which destroy pancreatic B cells (rubella, Coxsackie B,
cytomegalovirus, mumps and others) and immune-mediated
processes (insulin autoantibodies or insulin receptor anti-
bodies) can also lead to a `diabetic state'.1 Endocrinopathies
associated with excess secretion of counter-regulatory
hormones (such as growth hormone, cortisol, glucagon
and epinephrine) can lead to hyperglycaemia.
A number of drugs can induce glucose intolerance either
by inhibiting the secretion of insulin or by interfering with
the peripheral action of insulin.1 In anaesthesia, glucocorti-
coids and adrenergic agonists are most frequently impli-
cated. The new oral corticosteroid, de¯azacort, may be less
`diabetogenic' than prednisolone or betamethasone.2
`Metabolic syndrome' (also called syndrome X or insulin
resistance syndrome) is a non-causally linked cluster of
symptoms which carry a high risk of macrovascular disease.
The cluster includes impaired glucose tolerance or diabetes,
insulin resistance, raised arterial pressure, raised plasma
triglycerides, central obesity and microalbuminuria.1
Pathophysiology
Type 1 diabetics completely lack insulin secretion, making
them prone to lipolysis, proteolysis and ketogenesis. These
81
processes are inhibited by minimal levels of insulin
secretion and are rare in type 2 diabetics unless there is an
additional stress such as sepsis or dehydration.122
Obviously, both groups are subject to the effects of
hyperglycaemia.
Diabetics are at increased risk of myocardial ischaemia,
cerebrovascular infarction and renal ischaemia because of
their increased incidence of coronary artery disease,94
arterial atheroma51 and renal parenchymal disease.14
Increased mortality is found in all diabetics undergoing
surgery44 90 and type 1 diabetics are particularly at risk of
post-operative complications.111 Increased wound compli-
cations are associated with diabetes24 64 72 126 and
anastomotic healing is severely impaired when glycaemic
control is poor.118
The `stress response' to surgery is associated with
hyperglycaemia in non-diabetic patients as a result of
increased secretion of catabolic hormones in the presence of
a relative insulin de®ciency. This de®ciency arises from a
combination of reduced insulin secretion41 and insulin
resistance.109 Insulin resistance may result, in part, from the
increase in secretion of catecholamines, cortisol and growth
hormone42 and involves an alteration of post-receptor
binding of insulin and subsequent reduction of trans-
membrane glucose transport.79 Some, at least, of the
metabolic effects of the suppression of insulin secretion
are reversed by intraoperative insulin infusion37 and both
oral and i.v. perioperative administration of glucose
enhance postoperative glucose utilization rates.56 62 80
Adverse effects of hyperglycaemia
The consequences of a reduction in, or complete lack of,
insulin-mediated metabolic processes can be classi®ed
according to chronicity and to histopathological effects.
Acute consequences of untreated, or inadequately treated,
diabetes mellitus include dehydration (resulting from the
osmotic diuretic effect of glycosuria), acidaemia (because
of accumulation of lactic and/or ketoacids), fatigue, weight
loss and muscle wasting (because of lipolysis and
proteolysis in absolute insulin de®ciency). Ketoacidosis is
rare in type 2 diabetics but is frequently a presenting
symptom of type 1 disease. It is a medical emergency that
still carries a considerable mortality rate of up to 15%.4 49
The mortality of hyperosmolar non-ketotic hyperglycaemic
coma in type 2 diabetics may be even greater,63 probably
re¯ecting a more elderly population with a higher incidence
of co-existing disease.
Ketoacidosis is treated by rehydration and insulin
infusion with frequent measurements of serum electrolytes
and acid±base status. Sequential estimations of blood
b-hydroxybutyrate concentrations and concomitant con-
tinuation of intensive insulin therapy may expedite treat-
ment.124 Non-ketotic hyperglycaemic coma is frequently
precipitated by infection and is commonly associated with
 McAnulty et al.
multi-organ system dysfunction. Blood glucose concentra-
tions may be extremely high.33
Chronic effects of diabetes can be divided into micro-
vascular (including proliferative retinopathy and diabetic
nephropathy), neuropathic (autonomic and peripheral
neuropathies) and macrovascular complications (athero-
sclerotic disease). The incidence of microvascular and
neuropathic complications in types 1 and 2 diabetics is
similar when adjusted for duration of disease and quality of
glycaemic control. The cumulative lifetime incidence of
proliferative retinopathy, proteinuria and distal neuropathy
is roughly 50% for both type 1 and type 2 diabetics. This
implies that the primary cause of these complications is
hyperglycaemia itself, as the underlying metabolic path-
ology is different for type 1 and type 2 disease.31
Macrovascular complications (as measured by rates of
coronary artery, cerebrovascular and peripheral vascular
disease) are also similar for type 1 and 2 diabetics
(cardiovascular mortality is 30±54% for type 1 and 38±
41% for type 2 diabetes).31 In type 2 patients, at least,
abnormally high concentrations of plasminogen activator
inhibitor-1 (PAI-1) and, therefore, impaired ®brinolysis,
have been implicated in the accelerated rates of develop-
ment of atherosclerotic disease.83
Improved glycaemic control has a bene®cial effect on
microvascular and neuropathic complications in type 2
diabetes.114 Although there is probably no adverse effect,83
improvement in glycaemic control alone appears not to
improve the incidence of macrovascular disease in these
patients.114 However, tight control of blood pressure (with
an angiotensin-converting enzyme inhibitor or a b-blocker)
in patients with type 2 diabetes and hypertension reduces the
risk of diabetes-related death, including that secondary to
macrovascular complications, as well as the risk of other
diabetes-related complications and eye disease.115 116
Diabetic therapy
The problems of insulin replacement
Insulin is secreted into the bloodstream from pancreatic
B cells via the portal system so that there is normally a
portal±peripheral insulin concentration gradient which can-
not be mimicked by subcutaneous or i.v. insulin adminis-
tration. Additionally, even the most sophisticated arti®cial
insulin delivery systems cannot hope to replicate the
complex local interaction between the B cells and A, D
and PP cells of the islets of Langerhans (which secrete
glucagon, somatostatin and pancreatic polypeptide, respect-
ively) and the effects of the extrapancreatic neurohormonal
system. Insulin secretion in response to varying states of
feeding or starvation changes by 20- to 50-fold and
maintains a basal insulin secretion during the fasting state.
Insulin administered subcutaneously, even if timed opti-
mally, will inevitably have inadequate peak concentrations
for expected postprandial periods, and its duration of action
82
may be frequently too short to avoid periods of hypoinsu-
linaemia and subsequent risk of lipolysis and proteolysis in
patients with no endogenous insulin secretion.
Insulin is synthesized in the pancreas as part of a longer-
chain protein called proinsulin. This is cleaved by mem-
brane-bound proteases producing the polypeptides insulin
and C-peptide. These two polypeptides are secreted into the
circulation in equimolar amounts. C-peptide is useful
experimentally in determining native insulin production in
type 2 diabetic subjects receiving insulin. It was once
thought that C-peptide had no physiological role other than
facilitating the folding of the proinsulin molecule. However,
more recent studies point to a possible role for C-peptide in
glucose transport in skeletal muscle, renal tubular function
and in the prevention of autonomic neuropathy.119
Hypoglycaemic therapy
Type 1 diabetics require insulin. Type 2 diabetics may
require insulin but, in many cases, maintain reasonable
glycaemic control with an appropriate diet and often the use
of oral hypoglycaemic drugs.
Therapeutic insulin may be extracted from beef (now
rarely used) or pork pancreas, or synthesized using
recombinant DNA technology from Escherichia coli.6 The
amino acid sequences of insulin differ somewhat between
species; however, modifying porcine insulin can produce
human-sequence insulin. It was hoped that the replacement
of animal- by human-sequence insulins would reduce the
induction of antibodies and therefore insulin resistance, but
clinical trials have been disappointing.66
The three types of insulin preparation are classi®ed
according to their length of action. Soluble insulins have a
rapid onset and short duration of action (depending upon the
route of administration). When injected subcutaneously the
duration of action is from 30 min up to 8 h with a peak at
2±4 h. Human-sequence soluble insulin has a slightly
shorter onset time and duration of action. Insulin lispro, a
recently introduced recombinant human insulin analogue,
has an even shorter duration of action. Soluble insulin
injected i.v. has a half-life of approximately 5 min.6
Longer-acting insulin preparations are made with sus-
pensions of insulin with either protamine (`isophane insu-
lin') or zinc (`crystalline insulin') salts or both together.
They are often administered in combination with soluble
insulin to obtain rapid onset together with a long duration of
action.6 They are not suitable for i.v. use. Long-acting
insulins may act for up to 36 h for animal-91 and 24 h for
human-sequence preparations.47
There are four groups of oral hypoglycaemic agents: the
sulphonylureas, the biguanides, the (recently developed)
thiazolidinediones and modi®ers of glucose absorption from
the gut. In the main, sulphonylureas enhance the secretion of
insulin in response to glucose and increase sensitivity to its
peripheral actions. Biguanides (metformin is the only
compound in this group available in the UK) promote
 Diabetes mellitus
glucose utilization and reduce hepatic glucose production.
Thiazolidinediones, which are still under clinical evaluation
(and currently under a cloud because of reported hepato-
toxicity), enhance insulin action in the periphery and inhibit
hepatic gluconeogenesis, perhaps via a speci®c receptor
mechanism. The a-glucosidase inhibitor, acarbose, sup-
presses the breakdown of complex carbohydrates in the gut
and therefore delays the rise in postprandial blood glucose
concentrations.100
Intensive, effective glycaemic control of type 2 diabetes
results in a reduction of microvascular, but probably not
macrovascular, complications of the disease.31 114 Where
adequate control can be achieved (haemoglobin A1c
concentration 7±8%31) there is no clear advantage for any
therapeutic agent; oral hypoglycaemics and insulin have
similar effects.76 Metformin may be a better choice in obese
type 2 diabetics. It was associated with a lower incidence of
mortality and diabetes-related morbidity when used as a
®rst-line treatment compared with either sulphonylureas or
insulin in the recently-reported UK Prospective Diabetes
Study (UKPDS).113 However, addition of metformin to
patients receiving sulphonylureas in the UKPDS was
associated with a worrying increase in mortality. Despite
concerns about rare but potentially lethal lactic acidosis,
which may be more likely in the elderly,100 in association
with renal failure25 and hepatic failure and after surgery,71
metformin is well tolerated and less likely to cause
hypoglycaemia than sulphonylureas or insulin.28 113
Interest in the potassium channel-blocking effect of
sulphonylureas and, hence, interference with myocardial
ischaemic preconditioning, has increased recently.5
Glimepiride may not block potassium channels,58 but
angioplasty patients receiving sulphonylureas have greater
mortality and morbidity than those given insulin.30 The
general implications of this observation are not clear but,
until data from well-conducted studies are available, it
would seem prudent to convert patients taking sulphonyl-
ureas to insulin several days before cardiac or other major
surgery or procedures where myocardial perfusion may be
compromised.
Perioperative therapy
Type 2 diabetics not receiving insulin and undergoing minor
surgery usually can be managed satisfactorily without
insulin.108 However, diabetic patients scheduled for major
surgery, who are receiving hypoglycaemic medication or
who have poor glycaemic control, should be established on
insulin therapy preoperatively. Continuous i.v. infusion of
insulin is a better option than intermittent s.c. bolus
regimens11 and, at least in perioperative cardiac surgical
patients, may be associated with improved outcome.27
Although intermittent i.v. bolus regimens are still used,87
this approach is dif®cult to recommend.38 45
Adsorption of insulin on to the surface of syringes, i.v.
¯uid bags and i.v. giving sets is an unavoidable problem. In
83
solutions with a concentration of insulin of >400 ng ml±1
(~10 U litre±1) the effect is minimal.8 However, signi®cant
amounts of insulin may be adsorbed on to giving sets,
particularly if they have a relatively high surface area,
thereby reducing initial rates of insulin delivery if a high-
volume, low-insulin concentration regimen is used.69 More
consistent delivery can be achieved with more concentrated
solutions of lower volume administered from a syringe.92
When normal oral nutrition is not possible, parenteral
administration of carbohydrate is required to safeguard
against inadvertent hypoglycaemia and excessive catabo-
lism. Safety is always a concern when insulin infusions are
administered. Glucose±insulin±potassium (GIK) systems,
such as the Alberti regimen, are inherently safe because they
provide insulin and glucose in the same solution.107 With
separate glucose and insulin infusions one may be stopped
inadvertently with potentially disastrous consequences.
However, separate infusions were preferred by nursing
staff and resulted in marginally improved perioperative
glycaemic control when compared with a GIK system in one
randomized controlled trial of 58 surgical patients.101 Fifty
per cent glucose solutions containing 0.25 or 0.5 U insulin
ml±1 can provide amounts of glucose and insulin equivalent
to the more conventional systems using 10% glucose and
avoid the administration of large volumes of free water.68
However, the hypertonic 50% solution needs to be infused
into a central vein.
The metabolic challenge of surgery for the
diabetic patient
The immediate perioperative problems facing the diabetic
patient are: (i) surgical induction of the stress response with
catabolic hormone secretion; (ii) interruption of food intake,
which may be prolonged following gastrointestinal proced-
ures; (iii) altered consciousness, which masks the symptoms
of hypoglycaemia and necessitates frequent blood glucose
estimations; and (iv) circulatory disturbances associated
with anaesthesia and surgery, which may alter the absorp-
tion of subcutaneous insulin.
Surgery evokes the `stress response', that is, the secretion
of catecholamines, cortisol, growth hormone and, in some
cases, glucagon. These hormones oppose glucose homeo-
stasis, as they have `anti-insulin' and hyperglycaemic
effects. Gluconeogenesis is stimulated and peripheral glu-
cose uptake decreased. Although diabetics need increased
insulin during the perioperative period, requirements for
glucose and insulin in this period are unpredictable and
close monitoring is essential, especially in the unconscious
or sedated patient.
Diabetic patients established on longer-acting insulin are
at risk of hypoglycaemia if regular food intake is inter-
rupted, and of lipolysis and proteolysis if insulin therapy is
delayed. Postoperative wound healing and infection may be
 McAnulty et al.
in¯uenced by the adequacy of perioperative glycaemic
control.72 118
Options for the perioperative management of
diabetes
The main concern for the anaesthetist in the perioperative
management of diabetic patients has been the avoidance of
harmful hypoglycaemia; mild hyperglycaemia has tended to
be seen as acceptable. This has been attributed to the
dif®culties of measuring blood glucose when the reduced
level of consciousness perioperatively masks signs and
symptoms of hypoglycaemia. However, in the past decade
the availability of more accurate and easy-to-use glucose
monitors, with evidence that good glycaemic control
improves short-term outcome, makes the practice of
`permissive hyperglycaemia' unacceptable.
One survey of anaesthetic practice in the Oxford region of
the UK suggests that anaesthetists are likely to manage
hyperglycaemia in perioperative diabetic patients more
aggressively now than they did in 1985.22 However, of the
172 respondents in this survey, 22% still preferred to
maintain blood glucose at >10 mmol litre±1 in diabetic
patients and 2% preferred a value of >13 mmol litre±1. The
vast majority of respondents maintained glycaemic control
for type 1 diabetic patients undergoing major surgery with
glucose and insulin infusions, either separately or com-
bined. Nearly 90% of respondents did not consider it
necessary, in type 2 diabetics undergoing minor surgery, for
there to be any greater intervention than omitting the usual
hypoglycaemic therapy and avoidance of glucose-contain-
ing i.v. solutions. Surprisingly, 17% of senior anaesthetists
had the same approach to type 2 diabetics undergoing major
surgery. Cost and inconvenience may in¯uence decisions
about the intensity of blood glucose management and, until
recently, there has been little evidence to support strategies
aimed at tightening glycaemic control.35 Between the two
extremes of a diet-controlled stable type 2 diabetic
presenting for minor surgery and the `brittle' type 1 patient
undergoing major abdominal surgery, about whom there is
little argument, there remains considerable disagreement
about the ideal regimen for managing blood glucose.
Monitoring techniques
The advent of semi-automated devices has improved the
accuracy of measurement of blood and capillary glucose
concentrations in both the community and hospital.7 For
these machines to be effective they must be calibrated
regularly and people using them must be trained.
Recent work has suggested that measurement of circu-
lating b-hydroxybutyrate concentrations may be helpful in
treating acutely unstable diabetes70 124 and the development
of a bedside device will enable the usefulness of sequential
estimations of ketonaemia to be assessed.70
84
Glycosylated haemoglobin (HbAc1) measurement has no
value in the perioperative period but is a valuable guide to
long-term glycaemic control.31 If HbAc1 values have been
consistently >8% it is probable that microvascular compli-
cations of diabetes are present.
Anaesthetic technique and the diabetic
patient
Anaesthetic techniques, particularly the use of spinal,
epidural, splanchnic or other regional blockade, may
modulate the secretion of the catabolic hormones and any
residual insulin secretion. The perioperative increase in
circulating glucose, epinephrine and cortisol concentrations
found in non-diabetic patients exposed to surgical stress
under general anaesthesia is blocked by epidural anaesthe-
sia.39 125 The perioperative infusion of phentolamine, a
competitive a-adrenergic receptor blocking drug, decreases
the glycaemic response to surgery by partially reversing the
suppression of insulin secretion.75 Interestingly, a small
study of non-diabetic patients showed preservation of the
insulin response to a bolus of glucose after the use of low,
but not high, spinal anaesthesia.40 This implies that basal
islet cell secretion is maintained by b-adrenergic stimula-
tion. Whether extensive spinal blockade is detrimental in
type 2 diabetics is not known. Cataract surgery in type 2
patients using local analgesia, when compared with general
anaesthesia, was associated with much less disruption of
glucose metabolism: blood glucose, lactate, b-hydroxybu-
tyrate, serum cortisol, insulin and plasma non-esteri®ed
fatty acid concentrations were measured perioperatively.3
Diabetic patients undergoing surgery with neural block-
ade will usually resume oral intake earlier than after general
anaesthesia. It is now common practice in cataract surgery
to allow normal oral intake and hypoglycaemic therapy
throughout the perioperative period. In a series of 12 000
cataract extractions under local anaesthesia, in which
patients were not starved, eight patients showed evidence
of brain stem anaesthesia, and one developed cerebral
spread of local anaesthetic solution. In only one patient was
surgery postponed because of persistent nausea.43 However,
the possibility of having to convert a regional technique to
general anaesthesia may militate against this practice in
other forms of surgery. At present, there is no evidence that
regional anaesthesia alone, or in combination with general
anaesthesia, confers any bene®t in the diabetic surgical
patient, in terms of mortality and major complications.
Regional anaesthesia may carry greater risks in the
diabetic patient with autonomic neuropathy. Profound
hypotension may occur with deleterious consequences in a
patient with co-existing coronary artery, cerebrovascular or
renovascular disease. The risks of infection and vascular
damage may be increased with the use of regional
techniques in diabetic patients; epidural abscesses occur
more commonly following spinal and epidural anaesthe-
 Diabetes mellitus
sia.54 77 Conversely, a diabetic peripheral neuropathy
presenting after epidural anaesthesia may be confused
with an anaesthetic complication of regional blockade.50
Anaesthetic agents and diabetes
Induction agents may affect glucose homeostasis periopera-
tively. Etomidate blocks adrenal steroidogenesis and hence
cortisol synthesis, by its action on 11b-hydroxylase and
cholesterol cleavage enzymes, and consequently decreases
the hyperglycaemic response to surgery by approximately 1
mmol litre±1 in non-diabetic subjects.26 The effects on
diabetic patients have not been established.
Benzodiazepines decrease the secretion of ACTH, and so
the production of cortisol, when used in high doses during
surgery.18 They reduce sympathetic stimulation but, para-
doxically, stimulate growth hormone secretion and result in
a decrease in the glycaemic response to surgery. These
effects are minimal when midazolam is given in usual
sedative doses, but may be relevant if the drug is given by
continuous i.v. infusion to patients in intensive care.
High-dose opiate anaesthetic techniques produce not only
haemodynamic, but also hormonal and metabolic stability.
These techniques effectively block the entire sympathetic
nervous system and the hypothalamic±pituitary axis, prob-
ably by a direct effect on the hypothalamus and higher
centres.36 Abolition of the catabolic hormonal response to
surgery will, therefore, abolish the hyperglycaemia seen in
normal patients and may be of bene®t in the diabetic
patient.59
Halothane, en¯urane and iso¯urane, in vitro, inhibit the
insulin response to glucose in a reversible and dose-
dependent manner.19 32 The effect of propofol on insulin
secretion is not known. Diabetic patients show a reduced
ability to clear lipids from the circulation.123 Although this
is unlikely to be relevant during short anaesthetics when
propofol is used for maintenance or as an induction agent
only, it may have implications for patients receiving
propofol for prolonged sedation in the intensive care unit.
Complications of diabetes
Microvascular, neuropathic and macrovascular complica-
tions of diabetes mellitus are of special concern for the
anaesthetist. Of particular importance are coronary heart
disease, diabetic nephropathy and autonomic neuropathy
because these may have a direct effect on the development
of perioperative complications. In addition, young patients
with long-standing type 1 diabetes and poor glycaemic
control were found to have signi®cantly decreased lung
volume, lung diffusing capacity and cardiac stroke index
during exercise when compared with patients treated with
intensive insulin therapy.78
Because of glycosylation of collagen in the cervical
joints, part of a generalized phenomenon called `stiff joint
syndrome',98 diabetic patients are more likely to present
85
with dif®cult laryngoscopy and intubation. Stiffness of the
fourth and ®fth interphalangeal joints is a common feature
and the resulting alteration in palm print may be a good
predictor of dif®cult intubation.74 However, in one retro-
spective review of the anaesthetic records of 725 patients
who underwent renal and/or pancreatic transplantation (of
whom 209 were diabetic), none were reported as having
`moderate to extreme dif®culty' of laryngoscopy. A total of
4.8% of the diabetics presented `minimal to moderate'
dif®culty for intubation compared with 1.0% of the non-
diabetics. All were intubated successfully although one was
intubated electively with the aid of a ®bre-optic ¯exible
laryngoscope.120
Coronary heart disease
Diabetic men are more than four times as likely, and women
®ve times as likely, to have coronary heart disease (CHD)
than non-diabetics.15 The annual cardiac event rate for
untreated patients is 2.5% and even treated patients have
more aggressive coronary disease and experience worse
outcomes at any stage of the disease.96 Some patients may
have signi®cant CHD causing myocardial ischaemia and
even suffer myocardial infarction without typical symp-
toms. This may result from autonomic neuropathy,67 but
such `silent ischaemia' is unlikely to occur without the co-
existence of multiple risk factors. However, even selective
screening targeted at patients with speci®c multiple risk
factors has been discouraged because there is no evidence to
support intervention (in the form of angioplasty or surgery)
for asymptomatic diabetic patients.99 What is the anaes-
thetist to do when presented with an asymptomatic diabetic
patient who has some or all of the other risk factors such as
advanced age, smoking, hyperlipidaemia and hypertension?
Perioperative management of such a patient may be altered
if it is known that there is a likelihood of myocardial
ischaemia even if intervention by coronary artery bypass
grafting or angioplasty (although perhaps not coronary
stenting) carries an unacceptable risk:bene®t ratio.81
Asymptomatic type 1 diabetics with severe nephropathy
scheduled for renal transplantation have been shown to
bene®t from preoperative screening and appropriate coron-
ary revascularization.65 A similar strategy may well be
appropriate for high-risk diabetics, particularly those with
`metabolic syndrome', about to undergo major, elective
non-cardiac surgery.
Diabetic patients have a worse outcome after coronary
artery bypass surgery96 and tend to stay in hospital longer.60
They are more likely to develop postoperative renal
failure13 and suffer delayed stroke.46 Deep sternal wound
infection rates are also higher than in the non-diabetic
population,126 but the incidence may be reduced by
improving diabetic control with continuous insulin infu-
sions.27 Mortality following coronary artery bypass surgery
in diabetics is generally reported as signi®cantly greater
than that in non-diabetics.110
 McAnulty et al.
Diabetic nephropathy
In most countries, the leading causes of end-stage renal
failure are hypertension and diabetes mellitus. In the USA,
30±40% of patients with type 1 diabetes will develop
diabetic nephropathy and end-stage renal failure.93 There is
now substantial evidence that angiotensin-converting en-
zyme (ACE) inhibitors have a renal protective effect in
patients with type 1 diabetes.61 This may also be the case in
type 2 diabetes, but the evidence is less convincing. No
agent has been shown to be renoprotective in the
perioperative period and some of the traditional drugs
used for this purpose may be harmful.17 105 Ensuring
adequate renal perfusion by expanding the extracellular
space (salt loading) or, more speci®cally, the intravascular
space with appropriate haemodynamic monitoring may
reduce the risk of postoperative renal dysfunction.
Hydration with 0.45% sodium chloride solution alone
provides better protection against radiocontrast medium-
induced renal failure in at-risk subjects than saline with the
addition of furosemide or mannitol.102
Autonomic neuropathy
Diabetic patients frequently develop neuropathy, most
commonly a distal symmetrical sensory or sensorimotor
polyneuropathy with a variable degree of autonomic
involvement.12 Autonomic dysfunction, which is of par-
ticular importance to the anaesthetist, is detectable in up to
40% of type 121 and 17% of type 2 diabetic patients.23 Only
a small proportion of these patients are symptomatic, with
signs and symptoms such as gastroparesis, postural
hypotension, gustatory sweating, diabetic diarrhoea and
bladder paresis.121 Many pathogenic mechanisms have been
suggested for diabetic autonomic neuropathy, including
local ischaemia,112 tissue accumulation of sorbitol,20 altered
function of neuronal Na+/K+-ATPase pump activity103 and
immunologically mediated damage.21
The cardiovascular effects of insulin are paradoxical in
autonomic neuropathy patients. In normal subjects, i.v. or
s.c. insulin administration activates the sympathetic nervous
system, causing an increase in circulating norepinephrine,
supine arterial pressure and peripheral vascular resistance.85
At the supraphysiological concentrations often used in the
treatment of diabetes, vasodilation occurs with decreased
peripheral vascular resistance and increased ¯ow.85 These
observations suggest that insulin has dual effects, namely a
vasoconstrictor effect mediated by the sympathetic nervous
system at low insulin concentrations, and a vasodilator
effect, perhaps mediated by nitric oxide release at higher
concentrations. In patients with autonomic neuropathy,
insulin causes a decrease in supine arterial pressure and
exacerbates postural hypotension.
Detection of autonomic neuropathy in patients without
symptoms has relied on methods such as assessment of heart
rate variability (HRV).104 In diabetic autonomic neuro-
86
pathy, there is loss of HRV. The severe impairment of HRV
in patients with end-stage diabetic nephropathy probably
results from autonomic neuropathy and partly from co-
existing heart disease.57 The loss of HRV may be a
contributory risk factor for ventricular arrhythmias and
sudden death in these patients.57 The presence of autonomic
dysfunction in diabetics undergoing coronary artery surgery
is not, however, automatically associated with haemody-
namic instability during induction and the cardiovascular
responses in non-diabetic and diabetic patients were very
similar.53
Diabetic gastroparesis is characterized by a delay in
gastric emptying without any gastric outlet obstruction.117
The increased amount of gastric contents enhances the risk
of acid aspiration during the induction of anaesthesia.82
These patients are often asymptomatic and unpredictable
dif®culties in tracheal intubation increase even further the
risk of aspiration.88 Studies have shown little effect of pro-
kinetic agents, such as cisapride, in reducing the volume of
gastric contents in diabetics.89
Postoperative respiratory arrest seems to be more com-
mon in diabetic patients. Acute, unexpected respiratory
problems in the recovery room are more common in men, in
those aged >60 years, and in obese or diabetic patients.95
Wound healing and infection
It has long been recognized that wound healing is impaired
in diabetic patients.9 44 This observation has been repeated
in animal models where it has been shown that pre- and
postoperative glycaemic control with insulin, not post-
operative alone, can restore normal anastomotic healing.118
Recent work suggests that better glycaemic control with
insulin infusions may reduce the incidence of deep sternal
wound infections in diabetic patients who have undergone
cardiac surgery.27 This observation is supported by a study
demonstrating better preservation of neutrophil function
with `aggressive' glycaemic control using an insulin
infusion, compared with intermittent therapy, in diabetic
cardiac surgical patients.86 Interestingly, high-dose insulin
and glucose infusions, aimed at maintaining supranormal
plasma insulin concentrations and euglycaemia in non-
diabetic burns patients, signi®cantly decreased donor-site
healing time after skin grafting.84
Conclusion
It is well known that diabetic patients are at greater risk of
perioperative mortality and morbidity after major surgery
and have a higher incidence of co-existing disease. Over
recent years evidence has accumulated that improving
glycaemic control in both the short and long term improves
outcome. Attention to detail in the day-to-day management
of the disease itself and associated conditions, such as
hypertension, reduces the devastating consequences of
microvascular and macrovascular complications. In add-
 Diabetes mellitus
ition, a more aggressive approach to glycaemic control in
the perioperative period results in better wound healing,
lower morbidity and shorter hospital stays. Gone are the
days when anaesthetists could tolerate `permissive hyper-
glycaemia' with the idea that this approach was in the
patient's best interest. Tight metabolic control in the
perioperative period is imperative and is a goal which is
attainable in most patients.
References
1 Alberti KGMM, Zimmet PZ for the WHO Consultation.
De®nition, diagnosis and classi®cation of diabetes mellitus and
its complications. Part 1: diagnosis and classi®cation of diabetes
mellitus. Provisional report of a WHO consultation. Diabet Med
1998; 15: 539±53
2 Anon. De¯azacortÐan alternative to prednisolone? Drug Ther
Bull 1999; 37: 57±8
3 Barker JP, Robinson PN, Va®dis GC, Burrin JM, Sapsed-Byrne S,
Hall GM. Metabolic control of non-insulin-dependent diabetic
patients undergoing cataract surgery: comparison of local and
general anaesthesia. Br J Anaesth 1995; 74: 500±5
4 Basu A, Close CE, Jenkins D, Krentz AJ, Nattrass M, Wright AD.
Persisting mortality in diabetic ketoacidosis. Diabet Med 1993;
10: 282±4
5 Bijlstra PJ, den Arend JA, Lutterman JA, Russel FG, Thien T, Smits
P. Blockade of ATP-sensitive potassium channels reduces the
vasodilator response to ischaemia in humans. Diabetologia 1996;
39: 1562±8
6 British National Formulary. London: British Medical Association,
Royal Pharmaceutical Society of Great Britain, 1999: 302±6
7 Brunner GA, Ellmerer M, Sendlhofer G et al. Validation of home
blood glucose meters with respect to clinical and analytical
approaches. Diabetes Care 1998; 21: 585±90
8 Canivet B, Berre A, Macchi P, Grimaud D, Maestracci P, Freychet
P. Adsorption de l'insuline introduite directement dans les
¯acons de perfusion. Sem Hop Paris 1983; 59: 1405±8
9 Casey J, Flinn WR, Yao JS, Fahey V, Pawlowski J. Correlation of
immune and nutritional status with wound complications in
patients undergoing vascular operations. Surgery 1983; 93: 822±7
10 Casson IF, Clarke CA, Howard CV et al. Outcomes of pregnancy
in insulin dependent diabetic women: results of a ®ve year
population cohort study. Br Med J 1997; 315: 275±8
11 Christiansen CL, Schurizek BA, Malling B, Knudsen L, Alberti
KG, Hermansen K. Insulin treatment of the insulin-dependent
diabetic patient undergoing minor surgery. Continuous
intravenous infusion compared with subcutaneous
administration. Anaesthesia 1988; 43: 533±7
12 Comi G, Corbo M. Metabolic neuropathies. Curr Opin Neurol
1998; 11: 523±9
13 Conolon PJ, Stafford-Smith M, White WD et al. Acute renal
failure following cardiac surgery. Nephrol Dialysis Transplant 1999;
14: 1158±62
14 Culleton BF, Larson MG, Evans JC et al. Prevalence and
correlates of elevated serum creatinine levels: the Framingham
Heart Study. Arch Intern Med 1999; 159: 1785±90
15 Curry CJ, Morgan CL, Peters JR. Patterns and costs of hospital
care for coronary heart disease related and not related to
diabetes. Heart 1997; 78: 544±9
16 DECODE Study Group, on behalf of the European Diabetes
Epidemiology Study Group. Will new diagnostic criteria for
diabetes mellitus change phenotype of patients with diabetes?
87
Reanalysis of European epidemiological data. Br Med J 1998; 317:
371±5
17 Denton MD, Chertow, GM, Brady HR. `Renal-dose' dopamine
for the treatment of acute renal failure: Scienti®c rationale,
experimental studies and clinical trials. Kidney Int 1996; 49: 4±14
18 Desborough JP, Hall GM, Hart GR, Burrin JP. Midazolam
modi®es pancreatic and anterior pituitary secretion during
upper abdominal surgery. Br J Anaesth 1991; 67: 390±96
19 Desborough JP, Jones PM, Persaud SJ, Landon MJ, Howell SL.
Iso¯urane inhibits insulin secretion in isolated rat pancreatic
islets of Langerhans. Br J Anaesth 1993; 71: 873±6
20 Dyck P, Zimmerman B, Vilen T. Nerve glucose, fructose, sorbitol
and myoinositol, and ®ber degeneration and regeneration in
diabetic neuropathy. New Engl J Med 1988; 319: 542
21 Ejskaer NT, Zanone MM, Peakman M. Autoimmunity in diabetic
autonomic neuropathy: Does the immune system get on your
nerves? Diabet Med 1998; 15: 723±9
22 Eldridge AJ, Sear JW. Peri-operative management of diabetic
patients: any changes for the better since 1985? Anaesthesia 1996;
51: 45±51
23 Flynn MD, O'Brien IA, Corrall RJ. The prevalence of autonomic
and peripheral neuropathy in insulin-treated diabetic subjects.
Diabet Med 1995; 12: 310±3
24 Folk JW, Starr AJ, Early JS. Early wound complications of
operative treatment of calcaneus fractures: analysis of 190
fractures. J Orthop Trauma 1999; 13: 369±72
25 de Fronzo RA, Goodman AM. Multicentre Metformin Study
Group: ef®cacy of metformin in patients with non-insulin-
dependent diabetes mellitus. New Engl J Med 1995; 333: 541±9
26 Fragen RJ, Shanks CA, Molteni A, Avram MJ. Effects of etomidate
on hormonal responses to surgical stress. Anesthesiology 1984;
61: 652±6
27 Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous
intravenous insulin infusion reduces the incidence of deep sternal
wound infection in diabetic patients after cardiac surgical
procedures. Ann Thorac Surg 1999; 67: 352±60
28 Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Ef®cacy
of metformin in type II diabetes: results of a double-blind,
placebo-controlled, dose-response trial. Am J Med 1997; 103:
491±7
29 Gardner SG, Bingley PJ, Sawtell PA, Weeks S, Gale EAM. Rising
incidence of insulin dependent diabetes in children aged under 5
years in the Oxford region: time trend analysis. Br Med J 1997;
315: 713±17
30 Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes
DR Jr. Sulfonylurea drugs increase early mortality in patients
with diabetes mellitus after direct angioplasty for acute
myocardial infarction. J Am Coll Cardiol 1999; 33: 119±24
31 Gaster B, Hirsch IB. The effects of improved glycemic control on
complications in type 2 diabetes. Arch Intern Med 1998; 158:
134±40
32 Gingerich R, Wright PH, Paradise RR. Inhibition by halothane of
glucose-stimulated insulin secretion in isolated pieces of rat
pancreas. Anesthesiology 1974; 40: 449±52
33 Gupta S, Prabhu MR, Gupta MS, Niblett D. Severe non-ketotic
hyperosmolar comaÐintensive care management. Eur J
Anaesthesiol 1998 15: 603±6
34 Hadden DR. How to improve prognosis in type 1 diabetic
pregnancy. Old problems, new concepts. Diabetes Care 1999; 22
(suppl. 2): B104±8
35 Hall GM, Desborough JP. Diabetes and anaesthesia: slow
progress? Anaesthesia 1988; 43: 531±2
36 Hall GM, Lacoumenta S, Hart GR, Burrin JP. Site of action of
 McAnulty et al.
fentanyl in inhibiting the pituitary-adrenal response to surgery in
man. Br J Anaesth 1990; 65: 251±3
37 Hall GM, Walsh ES, Paterson JL, Mashiter K. Low-dose insulin
infusion and substrate mobilisation during surgery. Br J Anaesth
1983; 55: 939±45
38 Hall GM. Insulin administration in diabetic patients: return of the
bolus? Br J Anaesth 1994: 72: 1±2
39 Hall GM. The anaesthetic modi®cation of the endocrine and
metabolic response to surgery. Ann R Coll Surg Engl 1985; 67: 25±9
40 Halter JB, P¯ug AE. Effect of sympathetic blockade by spinal
anesthesia on pancreatic islet cell function in man. Am J Physiol
1980; 239: E150±5
41 Halter JB, P¯ug AE. Effects of anesthesia and surgical stress on
insulin secretion in man. Metabolism 1980; 29 (suppl. 1): 1124±7
42 Halter JB, P¯ug AE. Relationship of impaired insulin secretion
during surgical stress to anesthesia and catecholamine release. J
Clin Endocrinol Metab 1980; 51: 1093±8
43 Hamilton RC, Gimbel HV, Strunin L. Regional anaesthesia for
12,000 cataract extraction and intraocular lens implantation
procedures. Can J Anaesth 1988; 35: 615±23
44 Hickman MS, Schwesinger WH, Page CP. Acute cholecystitis in
the diabetic. A case±control study of outcome. Arch Surg 1988;
123: 409±11
45 Hirsch IB, McGill JB, Cryer PE, White PF. Perioperative
management of surgical patients with diabetes mellitus.
Anesthesiology 1991; 74: 346±59
46 Hogue CW, Murphy SF, Schechtman KB, Davila-Roman VG. Risk
factors for early or delayed stroke after cardiac surgery.
Circulation 1999; 100: 642±7
47 Holman RR, Steemson J, Darling P, Reeves WG, Turner RC.
Human ultralente insulin. Br Med J 1984; 288: 665±8
48 Jansson T, Wennergren M, Powell TL. Placental glucose
transport and GLUT 1 expression in insulin-dependent
diabetes. Am J Obstet Gynaecol 1999; 180: 163±8
49 Japan and Pittsburgh Childhood Diabetes Research Groups.
Coma at the onset of young insulin-dependent-diabetes in Japan:
the results of a nationwide survey. Diabetes 1985; 34: 1241±6
50 Kahn L. Neuropathies masquerading as an epidural complication.
Can J Anaesth 1997; 44: 313±16
51 Keen H, Jarrett RJ, Fuller JH, McCartney P. Hyperglycemia and
arterial disease. Diabetes 1981; 30 (suppl. 2): 49±53
52 Keen H. Impact of new criteria for diabetes on pattern of
disease. Lancet 1998; 352: 1000±1
53 Keyl C, Lemberger P, Palitzsch KD, Hochmuth K, Liebold A,
Hobbhahn J. Cardiovascular autonomic dysfunction and
hemodynamic response to anesthetic induction in patients with
coronary artery disease and diabetes mellitus. Anesth Analg 1999;
88: 985±91
54 Kindler CH, Seeberger MD, Staender SE. Epidural abscess
complicating epidural anesthesia and analgesia. An analysis of the
literature. Acta Anaesthesiol Scand 1998; 42: 614±20
55 King H, Rewers M. Global estimates for prevalence of diabetes
mellitus and impaired glucose tolerance in adults. Diabetes Care
1993; 16: 157±77
56 Kingston WJ, Livingston JN, Moxley RT. Enhancement of insulin
action after oral glucose ingestion. J Clin Invest 1986; 77: 1153±62
57 Kirvela M, Salmela K, Toivonen L, Koivusalo A-M, Lindgren L.
Heart rate variability in diabetic and non-diabetic renal transplant
patients. Acta Anaesthesiol Scand 1996; 40: 804±8
58 Klepzig H, Kober G, Matter C et al. Sulfonylureas and ischaemic
preconditioning; a double-blind, placebo-controlled evaluation of
glimepiride and glibenclamide. Eur Heart J 1999; 20: 439±46
59 Klingstedt C, Giesecke K, Hamberger B, Jarnberg PO. High and
low dose fentanyl anaesthesia: circulatory and plasma
88
catecholamine responses during cholecystectomy. Br J Anaesth
1987; 59: 184±8
60 Lazar HL, Fitzgerald C, Gross S, Heeren T, Aldea GS, Shemin RJ.
Determinants of length of stay after coronary artery bypass graft
surgery. Circulation 1995; 92 (suppl II): 20±4
61 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the
Collaborative Study Group: The effect of angiotensin-
converting-enzyme inhibition on diabetic nephropathy. New
Engl J Med 1993; 329: 1456±62
62 Ljungqvist O, Thorell A, Gutniak M, Haggmark T, Efendic S.
Glucose infusion instead of preoperative fasting reduces
postoperative insulin resistance. J Am Coll Surg 1994; 178: 329±6
63 Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med
Clin North Am 1995; 79: 39±52
64 Maher M, Singh HP, Dias S, Street J, Aherne T. Coronary artery
bypass surgery in the diabetic patient. Ir J Med Sci 1995; 164:
136±8
65 Manske CL, Wang Y, Rector T, Wilson RF, White CW.
Coronary revascularisation in insulin-dependent diabetic
patients with chronic renal failure. Lancet 1992; 340: 998±1002
66 Maran A, Lomas J, Archibald H, Macdonald IA, Gale EA, Amiel
SA. Double blind clinical and laboratory study of hypoglycaemia
with human and porcine insulin in diabetic patients reporting
hypoglycaemia unawareness after transferring to human insulin.
Br Med J 1993; 306: 167±71
67 Marchant B, Umachandran V, Stevenson R, Kopelman PG,
Timmis AD. Silent myocardial ischaemia with and without
diabetes. J Am Coll Cardiol 1993; 22: 1433±7
68 McAnulty GR, Robertshaw HJ, Berge D, Barnardo P, Hall GM.
Insulin concentrations from stored glucose±insulin±potassium
(`GIK') solutions: an improved system. Br J Anaesth 1999; 82
(suppl. 1): 129
69 McAnulty GR, Robertshaw HJ, Hall GM. Insulin concentrations in
samples from stored glucose±insulin±potassium (`GIK') bags. Br J
Anaesth 1998; 80 (suppl. 1): 91±2
70 McBride MO, Smye M, Nesbit GS, Hadden DR. Bedside blood
ketone monitoring. Diabet Med 1991; 8: 688±90
71 Merckner SK, Maier C, Neumann G, Wulf H. Lactic acidosis as a
serious complication of antidiabetic biguanide medication with
metformin. Anesthesiology 1997; 87: 1003±5
72 Mossad SB, Serkey JM, Longworth DL, Cosgrove DM, Gordon
SM. Coagulase-negative staphylococcal sternal wound infections
after open-heart operations. Ann Thorac Surg 1997; 63: 395±401
73 Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus
four times daily insulin regimens for diabetes in pregnancy:
randomised controlled trial. Br Med J 1999; 319: 1223±7
74 Nadal JLY, Fernandez BG, Escobar IC, Black M, Rosenblatt WH.
The palm print as a sensitive predictor of dif®cult laryngoscopy in
diabetics. Acta Anaesthesiol Scand 1998; 42: 199±203
75 Nakao K, Miyata M. The in¯uence of phentolamine, an
adrenergic blocking agent, on insulin secretion during surgery.
Eur J Clin Invest 1977; 7: 41±5
76 Nathan DM. Some answers, more controversy, from UKPDS.
Lancet 1998; 352: 832±3
77 Nikolajsen L, Ilkjaer S, Christensen JH, Krùner K, Jensen TS.
Randomised trial of epidural bupivacaine and morphine in
prevention of stump and phantom limb pain in lower-limb
amputation. Lancet 1997; 350: 1353±7
78 Niranjan V, McBrayer DG, Ramirez LC, Raskin P, Hsia CCW.
Glycemic control and cardiopulmonary function in patients with
insulin-dependent diabetes mellitus. Am J Med 1997; 103: 504±13
79 Nordenstrom J, Sonnen®eld T, Arner P. Characterization of
insulin resistance after surgery. Surgery 1989; 105: 28±35
80 Nygren J, Soop M, Thorell A, Efendic S, Nair KS, Ljungqvist O.
 Diabetes mellitus
Preoperative oral carbohydrate administration reduces
postoperative insulin resistance. Clin Nutr 1998; 17: 65±71
81 O'Neill WW. Multivessel balloon angioplasty should be
abandoned in diabetic patients! J Am Coll Cardiol 1998; 31: 20±2
82 Olsson GL, Hallen B, Hambraeus-Jonzon K. Aspiration during
anaesthesia: a computer-aided study of 185,358 anaesthetics.
Acta Anaesthesiol Scand 1986; 30: 84±92
83 Panahloo A, Yudkin JS. Diminished ®brinolysis in diabetes
mellitus and its implication for diabetic vascular disease. J
Cardiovasc Risk 1997; 4: 91±9
84 Pierre EJ, Barrow RE, Hawkins HK et al. Effects of insulin on
wound healing. J Trauma 1998; 44: 342±5
85 Porcellati F, Fanelli C, Bottini P et al. Mechanisms of arterial
hypotension after therapeutic dose of subcutaneous insulin in
diabetic autonomic neuropathy. Diabetes 1993; 42: 1055±64
86 Rassias AJ, Marrin CA, Arruda J, Whalen PK, Beach M, Yeager
MP. Insulin infusion improves neutrophil function in diabetic
cardiac surgery patients. Anesth Analg 1999; 88: 1011±6
87 Raucoules-Aime M, Labib Y, Levraut J, Gastaud P, Dolisi C,
Grimaud D. Use of i.v. insulin in well-controlled non-insulin-
dependent diabetics undergoing major surgery. Br J Anaesth 1996;
76: 198±202
88 Reissell E, Orko R, Maunuksela E.-L, Lindgren L. Predictability of
dif®cult laryngoscopy in patients with long-term diabetes
mellitus. Anaesthesia 1990; 45: 1024±7
89 Reissell E, Taskinen M.-R, Orko R, Lindgren L. Increased volume
of gastric contents in diabetic patients undergoing renal
transplantation: lack of effect with cisapride. Acta Anaesthesiol
Scand 1992; 36: 736±40
90 Risum O, Abdelnoor M, Svennevig JL et al. Diabetes mellitus and
morbidity and mortality risks after coronary artery bypass
surgery. Scand J Thorac Cardiovasc Surg 1996; 30: 71±5
91 Rizza RA, O'Brien PC, Service FJ. Use of beef ultralente for basal
insulin delivery: plasma insulin concentrations after chronic
ultralente administration in patients with IDDM. Diabetes Care
1986; 9: 120±23
92 Robertshaw HJ, McAnulty GR, Berge D, Barnardo P, Hall GM.
Pre-prepared glucose-insulin-potassium (`GIK') syringes: a
practical alternative alternative to `GIK' bags. Br J Anaesth
1999; 82 (suppl. 1): 129
93 Rodby RA, Firth LA, Lewis EJ for the Collaborative Study Group.
An economic analysis of captopril in the treatment of diabetic
nephropathy. Diabetes Care 1996; 19: 1051±61
94 Rodriguez BL, Lau N, Burch®el CM et al. Glucose intolerance and
23-year risk of coronary heart disease and total mortality: the
Honolulu Heart Program. Diabetes Care 1999; 22: 1262±5
95 Rose DK, Cohen MM, Wigglesworth DF, DeBoer DP. Critical
respiratory events in the postanesthesia care unit. Anesthesiology
1994; 81: 410±8
96 Rutter MK, Marshall SM, McComb JM. Coronary artery disease
and diabetes. Heart 1997; 78: 527±8
97 Ruwaard D, Hirasing RA, Reeser HM et al. Increasing incidence
of type I diabetes in The Netherlands. The second nationwide
study among children under 20 years of age. Diabetes Care 1994;
17: 599±601
98 Salzarulo HH, Taylor LA. Diabetic "stiff joint syndrome" as a
cause of dif®cult intubation. Anesthesiology 1986; 64: 366±8
99 Sayer JW, Timmis AD. Investigation of coronary artery disease in
diabetes: is screening of asymptomatic patients necessary? Heart
1997; 78: 525±6
100 Scheen AJ, LefeÁbvre PJ. Oral antidiabetic agents: a guide to
selection. Drugs 1998; 55: 225±36
101 Simmons D, Morton K, Laughton SJ, Scott DJ. A comparison of
two intravenous insulin regimens among surgical patients with
89
insulin-dependent diabetes mellitus. Diabetes Education 1994; 20:
422±7
102 Solomon R, Werner C, Mann D, D'Elia J, Silva P. Effects of saline,
mannitol, and furosemide to prevent acute decreases in renal
function induced by radiocontrast agents. New Engl J Med 1994;
331: 1416±20
103 Stevens MJ. Nitric oxide as a potential bridge between the
metabolic and vascular hypotheses of diabetic neuropathy. Diabet
Med 1995; 12: 292±5
104 Stys A, Stys T. Current clinical applications of heart rate
variability. Clin Cardiol 1998; 21: 719±24
105 Tang AT, El-Gamel A, Keevil B, Yonan N, Deiraniya AK. The
effect of `renal-dose' dopamine on renal tubular function
following cardiac surgery: assessed by measuring retinol
binding protein (RBP). Eur J Cardiothorac Surg 1999; 15:
717±21
106 The Expert Committee on the Diagnosis and Classi®cation of
Diabetes Mellitus. Report of the expert committee on the
diagnosis and classi®cation of diabetes mellitus. Diabetes Care
1997; 20: 1183±97
107 Thomas DJ, Platt HS, Alberti KG. Insulin-dependent diabetes
during the peri-operative period. An assessment of continuous
glucose±insulin±potassium infusion, and traditional treatment.
Anaesthesia 1984; 39: 629±37
108 Thompson J, Husband DJ, Thai AC, Alberti KG. Metabolic
changes in the non-insulin-dependent diabetic undergoing minor
surgery: effect of glucose±insulin±potassium infusion. Br J Surg
1986; 73: 301±4
109 Thorell A, Nygren J, Hirshman MF et al. Surgery-induced insulin
resistance in human patients: relation to glucose transport and
utilization. Am J Physiol 1999; 276: E754±61
110 Thourani VH, Weintraub WS, Stein B, Gebhart SS, Craver JM,
Jones EL, Guyton RA. In¯uence of diabetes on early and late
outcome after coronary artery bypass grafting. Ann Thorac Surg
1999; 67: 1045±52
111 Treiman GS, Treiman RL, Foran RF et al. The in¯uence of
diabetes mellitus on the risk of abdominal aortic surgery. Am
Surg 1994; 60: 436±40
112 Tuck RR, Schmelzer J, Low P. Endoneurial blood ¯ow and
oxygen tension in the sciatic nerves of rats with experimental
diabetic neuropathy. Brain 1984; 107: 935±50
113 UK Prospective Diabetes Study (UKPDS) Group. Effect of
intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes
(UKPDS 34). Lancet 1998; 352: 854±65
114 UK Prospective Diabetes Study (UKPDS) Group. Intensive
blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients
with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837±53
115 UK Prospective Diabetes Study Group. Ef®cacy of atenolol and
captopril in reducing macrovascular and microvascular
complications in type 2 diabetes: UKPDS 39. Br Med J 1998;
317: 713±20
116 UK Prospective Diabetes Study Group. Tight blood pressure
control and risk of macrovascular and microvascular
complications in type 2 diabetes UKPDS 38. Br Med J 1998;
317: 703±12
117 Varis K. Diabetic gastroparesis. Scand J Gastroenterol 1989; 24:
897±903
118 Verhofstad HJ, Hendriks T. Complete prevention of impaired
anastomotic healing in diabetic rats requires preoperative blood
glucose control. Br J Surg 1996; 83: 1717±21
119 Wahren J, Johansson B-L, Wallberg-Henriksson H. Does C-
 McAnulty et al.
peptide have a physiological role? Diabetologia 1994; 37 (suppl.
2): S99±107
120 Warner ME, Contreras MG, Warner MA, Schroeder DR, Munn
SR, Maxson PM. Diabetes mellitus and dif®cult laryngoscopy in
renal and pancreatic transplant patients. Anesth Analg 1998; 86:
516±19
121 Watkins PJ. Clinical observations and experiments in diabetic
neuropathy. Diabetologia 1992; 35: 2±11
122 Westphal SA. The occurrence of diabetic ketoacidosis in non-
insulin-dependent diabetics and newly diagnosed diabetic adults.
Am J Med 1996; 101: 19±24
123 Wicklmayr M, Rett K, Dietz G, Mehnert H. Comparison of
90
metabolic clearance rates of MCT/LCT and LCT emulsions in
diabetics. J Parenteral Enteral Nutr 1988; 12: 68±71
124 Wiggam MI, O'Kane MJ, Harper R et al. Treatment of diabetic
ketoacidosis using normalization of blood 3-hydroxybutyrate
concentration as the endpoint of emergency management.
Diabetes Care 1997; 20: 1347±52
125 Wolf AR, Eyres RL, Laussen PC et al. Effect of extradural
analgesia on stress responses to abdominal surgery in infants. Br J
Anaesth 1993; 70: 654±60
126 Zacharias AZ, Habib RH. Factors predisposing to median
sternotomy complications. Chest 1996; 110: 1173±8