British Journal of Anaesthesia 88 (4): 48995 (2002)

Glucose, insulin and potassium for heart protection during

cardiac surgery
S. Bruemmer-Smith1*, M. S. Avidan1, B. Harris2, S. Sudan1, R. Sherwood2, J. B. Desai3,
F. Sutherland3 and J. Ponte1
1
Department of Anaesthesia, 2Department of Biochemistry and 3Department of Cardiothoracic Surgery,
Kings College Hospital, London SE5 9RS, UK
*Corresponding author: 21 Stratheden Road, London SE3 7TH, UK

Background. Coronary artery bypass grafting with hypothermic cardiac arrest and cardiopul-
monary bypass (CPB) is associated with myocardial injury. Our study investigated whether an
infusion of glucose, insulin and potassium (GIK) during elective coronary artery bypass surgery
decreases myocardial cell death.
Methods. We measured cardiac troponin I (cTnI), a myobrillar structural protein, which is a
sensitive and specic indicator of myocytic injury. With ethics committee approval, 42 patients
were enrolled into a randomized, prospective, double-blinded study. In the GIK group, 500 ml
of 50% dextrose solution containing 100 IU insulin and potassium 80 mmol was infused at the
rate of 0.75 ml kg1 h1. Patients in the non-GIK group received 5% dextrose solution at the
same rate. Arterial blood samples were taken before induction of anaesthesia, after removal of
the aortic clamp and 6 and 12 h after CPB.
Results. In both groups there was an increase in cTnI concentration (P<0.05), which was
greatest about 6 h after CPB. At no time did the cTnI concentration differ between the two
groups.
Conclusion. The results suggest that GIK does not decrease the irreversible myocardial dam-
age associated with routine coronary artery bypass surgery.
Br J Anaesth 2002; 88: 48995
Keywords: surgery, cardiovascular; infusions, glucoseinsulinpotassium; heart, cardiac
troponin I; heart, myocyte protection
Accepted for publication: November 16, 2001

The use of glucoseinsulinpotassium (GIK) for cardiac
protection was rst described 25 yr ago.1 New interest in the
possible protective effect of GIK in patients with myocar-
dial infarcts followed the 1998 Estudios Cardiologicos
Latinoamerica (ECLA). In this multicentre study, a high-
dose regimen of GIK (25% glucose solution containing
insulin 100 IU and potassium 80 mmol per litre) infused at
1.5 ml kg1 h1 in patients with acute myocardial infarct
signicantly reduced mortality in patients given thrombo-
lytic therapy or angioplasty.2 The mechanism was not clear,
but one proposed mechanism was reduction in cell death
and infarct size.
During ischaemia, the heart has limited oxidative reserve
and energy-rich phosphates are steadily depleted. In
hypoxia, GIK may protect myocardial tissue by maintaining
normal carbohydrate and fatty acid metabolism and thus cell
function. The effects of GIK and its inuence on myocyte
metabolism, specically during ischaemia and reperfusion,
are complex. The protective effect of GIK on the functional
recovery of the heart has been investigated extensively.36
Cardiac troponin I (cTnI) is a myobrillar structural
protein, and the cardiac isomer is specic to heart muscle.
cTnI is a more reliable marker of irreversible myocardial
cell damage than creatine kinase MB.710 Surgery using
cardiopulmonary bypass (CPB) with hypothermic cardiac
arrest is associated with damage to the heart despite
improvements in surgery, anaesthesia and the technique of
CPB.11 12 We examined whether an intraoperative infusion
of GIK could reduce irreversible myocardial cell damage,
using cTnI as a marker of myocyte injury.

The Board of Management and Trustees of the British Journal of Anaesthesia 2002

Table 1 Patient characteristics. Values are mean (SD), number (%) or ratio
GIK group
(19 patients)
Age (yr) 64.3 (9.9)
Gender ratio (M:F) 19:0
Bypass time (min) 80.3 (22.3)
Cross-clamp time (min) 50.7 (13.7)
Hypertension 17 (90%)
Hypercholesterolaemia 14 (74%)
Preoperative ejection fraction <45% 9 (47%)
Previous myocardial infarction 10 (53%)
Methods
With local ethics committee approval and informed patient
consent, we conducted a double-blinded prospective
randomized study of 42 patients scheduled for elective
coronary artery bypass grafting. Three patients were
excluded from analysis, two because of incomplete sam-
pling and one because of missing randomization. All
patients who electively received at least two bypass grafts
were included in the study. Exclusion criteria were an
abnormal creatinine concentration and type 1 and type 2
diabetes. Assessment of ejection fraction was part of the
routine preoperative evaluation.
Patients received either 50% glucose 500 ml containing
insulin 100 IU and potassium 80 mmol at a rate of 0.75
ml kg1 h1 (GIK group) or an equivalent rate of 5%
dextrose (non-GIK group), given into a central vein. The
infusion started immediately after induction of anaesthesia
and stopped at the end of surgery. Blood glucose was
measured hourly and insulin was given according to a
sliding scale to maintain blood glucose between 4 and 10
mmol litre1. Potassium was added to achieve a plasma
concentration of 46 mmol litre1. Peripheral arterial blood
samples were collected for cTnI analysis before induction of
anaesthesia, after removal of the aortic cross-clamp and 6
and 12 h after CPB.
Surgical and anaesthetic technique
A standardized anaesthetic technique was used for all
patients. Premedication consisted of oral temazepam 20 mg
and ranitidine 150 mg. Anaesthesia was induced with
fentanyl 1015 mg kg1 and propofol 2 mg kg 1. A single
dose of vecuronium 0.15 mg kg 1 was used for muscle
relaxation. Anaesthesia was maintained with 30% oxygen in
nitrous oxide and isourane before CPB. End-expiratory
isourane concentration was held between 0.6 and 0.8%.
Thereafter, a propofol infusion of 100350 mg h1 was used
to maintain anaesthesia until transfer to the recovery area.
Supplementary i.v. fentanyl was administered according to
the discretion of the anaesthetist up to a maximum of 500 mg.
Inotropic drugs were administered only when required to
facilitate separation from CPB.
Bruemmer-Smith et al.
The same surgeon operated on all patients.
Non-GIK group Cardiopulmonary bypass was achieved with a roller pump
(20 patients) and membrane oxygenator with mild hypothermia of 32C.
Multiple anterograde doses of St Thomas' cardioplegia
66.3 (10.4)
15:5
solution in cold (6C) oxygenated blood were infused for
69.5 (20.3) myocardial preservation. St Thomas' solution contains
45.2 (12.4) magnesium chloride BP 3.253 g, potassium chloride BP
18 (90%)
13 (65%)
1.193 g and procaine hydrochloride BP 272.8 mg in 20 ml.
3 (15%) CPB time, aortic cross-clamp time and reperfusion time
8 (40%) were noted. Mean arterial pressure was maintained between
50 and 60 mm Hg either by adjusting pump ow or with
small boluses of phenylephrine. Anticoagulation was with
heparin 300 IU kg1 and further doses to maintain an
activated clotting time greater than 480 s.
Blood sampling and laboratory analysis
Blood samples were taken into tubes without anticoagulant
and centrifuged at 2500 g for 20 min. The serum obtained
was then stored at 70C until analysis.
Quantitative cTnI analysis was performed using the
Bayer Immuno-1 assay (Bayer, Leverkusen, Germany), a
heterogeneous sandwich magnetic separation system using
mouse monoclonal and goat polyclonal anti-cTnI anti-
bodies. Both antibodies were directed to epitopes at the
centre of the cTnI molecule. The detection antibodies were
labelled with alkaline phosphatase and addition of substrate
subsequently gives a colour change directly proportional to
the cTnI concentration. The assay had a detection limit of
0.1 mg litre1 and an analytical range up to 200 mg litre1.
The interassay coefcient of variation was 6% at a
concentration of 0.2 mg litre1, which was the manu-
facturer's recommended clinical discriminatory level for
myocardial injury (cTnI >0.9 mg litre1 is considered
diagnostic of acute myocardial infarction).
Statistical analysis
A power analysis showed that 17 patients in each group
would be required to detect a mean difference of 0.9 (SD
0.8) mg litre1 in cTnI concentration between the two groups
at any of the time points with a power of 90% and a P value
of 0.05. The cTnI data were assessed with the ShapiroWilk
test of normality and were distributed asymmetrically. Non-
parametric statistical tests were therefore used for cTnI
analysis. The MannWhitney U-test was used to test for
differences in cTnI concentration between groups at each
time point. Changes in cTnI concentration over time within
groups were assessed by Friedman analysis of variance
(ANOVA) and the Wilcoxon signed ranks test. Fisher's
exact test was used to determine whether there was a
signicant difference in the proportion of patients with a
low ejection fraction (<45%) in the GIK group compared
with the non-GIK group. Other categorical data, including
all patient proportions (hypertension, hypercholesterolae-
mia, preoperative myocardial infarction, gender ratio), were
490
 GIK for heart protection
Fig 1 Glucose concentrations in the GIK group and non-GIK group.
Signicant differences between groups are represented by asterisks
(P<0.05). The graphs show mean concentrations and standard deviations
(error bars). BL=baseline; 1 h=1 h after anaesthetic induction; XC=aortic
cross-clamp; ICU=intensive care unit; 3, 6 and 12 h=3, 6 and 12 h after
CPB.
also assessed with Fisher's exact test. The MannWhitney
U-test was used to determine whether cTnI concentrations
were greater in patients with low ejection fractions. The
relationship between cross-clamp time and cTnI concentra-
tion was evaluated by Spearman correlation analysis.
Patient age, CPB time, aortic cross-clamp time and blood
glucose and blood potassium concentrations were normally
distributed and were assessed with parametric statistical
tests. Differences in these variables between the GIK and
non-GIK groups were assessed with the unpaired t-test.
Changes in potassium and glucose concentrations over time
within groups were examined by ANOVA and paired t-tests.
P<0.05 was regarded as signicant for all tests. All
statistical tests were carried out with Analyse-it software
(Analyse-it, Leeds, UK).
Results
The groups were well matched for age and number of
bypass grafts (Table 1). Four patients in group 1 and three
patients in group 2 each had four grafts, and four in each
group each received two grafts. All other patients had three
coronary artery grafts with at least one internal mammary
artery graft.
Randomization did not give an equal distribution of male
and female patients. Ten patients (53%) in the GIK group
and eight (40%) in the non-GIK group had suffered a
previous myocardial infarct. Nine out of 19 patients (47%)
in the GIK group had an ejection fraction less than 45%,
compared with only three out of 20 (15%) in the non-GIK
group (P=0.06). Mean operation times, cross-clamp times
and CPB times did not differ between the two groups
(Table 1).
491
Fig 2 Potassium concentrations in the GIK group and non-GIK group.
Signicant differences between groups are represented by asterisks
(P<0.05). The graphs show mean concentrations and standard deviations
(error bars). BL=baseline; 1 h=1 h after anaesthetic induction; XC=aortic
cross-clamp; ICU=intensive care unit; 3, 6 and 12 h=3, 6 and 12 h after
CPB.
Before operation, all patients were on beta-blockers and
aspirin; the latter was stopped 5 days before surgery. A large
number were also taking cholesterol-lowering medications
and angiotensin-converting enzyme inhibitors.
Inotropic support
In the GIK group, two patients received an epinephrine
infusion and two patients required ventricular pacing to
facilitate weaning from CPB. In the non-GIK group, one
patient received epinephrine, one patient received dopamine
2 mg kg1 min1 and one patient needed ventricular pacing.
No patient developed ECG changes after surgery that were
suggestive of acute myocardial infarction.
Blood glucose concentration
None of the patients in the non-GIK group needed insulin to
maintain blood sugar within the normal range. Twelve
patients in the GIK group required additional doses of
insulin. Blood glucose concentrations in the recovery phase
were within the normal range in both groups (Figs 1 and 2).
There were signicant changes in blood concentrations in
both the GIK and the non-GIK group over time (P<0.05).
Glucose concentrations were greater in the GIK than in the
non-GIK group during the entire intraoperative period
(P<0.05). Three hours and 12 h after CPB, the blood glucose
concentration was slightly lower in the GIK than in the non-
GIK group (P<0.05).
There were signicant changes in blood potassium
concentration in both the GIK and the non-GIK group
over time (P<0.05). Potassium concentration was lower in
the GIK than in the non-GIK group from 1 h after induction
of anaesthesia until the time of arrival in the intensive care
unit (P<0.05) (Fig. 1).
 Bruemmer-Smith et al.
Fig 3 Box and whisker plots showing cTnI concentrations in the GIK (G)
and non-GIK (nG) groups at four time points: 1=baseline; 2=after aortic
clamp removal; 3=6 h after CPB; 4=12 h after CPB. The boxes depict
median values with interquartile ranges and the whiskers show the full
ranges. In both groups, there was a signicant (P<0.05) increase in cTnI
concentration, with a peak concentration at time point 3. There was no
signicant difference in cTnl concentration between groups at any time.
cTnI concentration (Fig. 3)
No patient had a signicantly raised baseline cTnI concen-
tration. In both groups there was an increase in cTnI
concentration (P<0.05), in keeping with myocardial cell
injury after cardiac surgery, which peaked about 6 h after
CPB. At no time was there a signicant difference in cTnI
between the two groups (P>0.05) (Fig. 3). There was also no
difference in cTnI concentration at any time point between
patients with low and those with normal ejection fractions
(P>0.05). There was a strong correlation between cross-
clamp time and peak cTnI concentration (rS=0.57, P<0.001)
(Fig. 4).
Discussion
Cardiac surgery with hypothermic cardioplegic arrest
causes some myocardial cell death, even in patients with
no ECG changes and uneventful recovery.13 Perioperative
myocardial infarction is a clinically recognizable form of
such damage and has an adverse effect on outcome.12
There is reason to believe that GIK infusion should aid
recovery of the heart and decrease ischaemic injury during
cardiac surgery using bypass. The possible benets of GIK
include the following.
(i) A glycogen-sparing effect by the supply of substrate to
the cells during ischaemia.4 5
(ii) Increased ATP synthesis. During hypoxia there is
depletion of energy-rich phosphates such as ATP, and
glycolysis is important in the maintenance of myocardial
viability.14 ATP produced by oxidative phosphorylation is
used preferentially to support myocyte contractile activity
by supplying energy to the actinmyosin-ATPase.15 Under
normal circumstances, oxidative metabolism of free fatty
acids is the predominant energy source for the myocardium.
After reperfusion, oxidative metabolism of free fatty acids
resumes but seems to be reduced after ischaemia.6 14 16
492
Fig 4 Correlation of cTnl concentration 6 h after CPB with cross-clamp
time.
Bunger and colleagues showed that, during the change from
anaerobic to aerobic metabolism, glycolytic activity is
critical for functional recovery of the heart and GIK could
serve as a substrate.17
(iii) Maintenance of sarcoplasmic reticulum function and
calcium homeostasis. Another explanation for a protective
role of GIK is a possible compartmentation of glycolytic
and oxidative ATPase.15 18 This renders ATP derived from
glycolysis vital for the recovery of the sarcoplasmic
reticulum (SR) function after hypoxia. In a study conducted
by Xu and colleagues,15 sarcoplasmic reticulum vesicles
from skeletal and cardiac muscle were isolated to investi-
gate whether the energy derived from glycolysis was
functionally coupled to active calcium transport in the SR.
They found that the entire chain of glycolytic enzymes was
associated with SR vesicles producing the ATP that was
needed to maintain calcium pump function and thus SR
membrane integrity. This suggests that there is functional
coupling of glycolytic ATP to calcium transport and thus
cell homeostasis.
(iv) Free radical scavenging activity.19
(v) Reduction in free fatty acid concentration. This is an
insulin-related effect. Free fatty acids can harm cell
membranes under hypoxic conditions, causing calcium
overload, arrhythmias and cell death.5 6
(vi) Decreased coronary artery resistance leading to
increased myocardial perfusion.3 4
We studied whether GIK decreases the amount of
irreversible myocytic injury during coronary artery bypass
grafting, in contrast to other studies, which assessed
functional recovery of the heart.
To quantify the amount of myocardial damage periopera-
tively, we used cTnI, a sensitive and reliable marker for the
detection of perioperative myocardial infarction.11 The
maximum value can be used to quantify the extent of
myocardial cell death.11 20 cTnI is accepted as a marker of
perioperative risk stratication in cardiac risk patients
 GIK for heart protection
undergoing non-cardiac surgery21 and in patients undergo-
ing coronary bypass grafting, because its concentration is
related to the amount of irreversible cell injury. Higher
perioperative concentrations are associated with more
postoperative complications.22 It has also been used to
indicate underlying cardiac injury in intensive care
patients23 24 and to examine the benet of different solutions
and temperatures of cardioplegia.25 The heart is most likely
to sustain ischaemic injury when the aortic cross-clamp is
applied. This is supported by our nding of a correlation
between cross-clamp time and peak cTnI concentration.
In this study, despite the theoretical protective effects of
GIK listed above and the reliability of cTnI as a marker of
myocardial cell damage, no cardioprotective effect of GIK
was observed. We did not nd a signicant difference in
cTnI concentration between the two groups. The median
values of both groups (Fig. 3) after 6 and 12 h showed that
some myocardial death had occurred during surgery,
supporting the ndings of other studies,13 but there was no
difference between GIK- and non-GIK-treated patients.
Before concluding that GIK confers no protective effect on
the myocardium during CABG surgery, other possible
reasons for our negative ndings should be considered.
We used a high dose of GIK, as recommended in other
studies,16 26 but this was only given during surgery. It might
be of more benet if started before surgery and continued
for 1248 h after surgery, as suggested by other studies.
Oldeld and colleagues examined the effect of GIK on
complications of mitral valve replacement and demon-
strated an increased myocardial glycogen content after an
infusion of GIK 12 h before the operation.27 This reduced
complications after surgery, such as hypothermia and
arrhythmia. Lazar and colleagues28 found better cardiac
performance and faster recovery from urgent coronary
bypass grafting in patients with unstable angina given GIK
infusion for 12 h after operation. These patients had greater
cardiac output, a signicantly lower incidence of atrial
brillation (13.3 vs 53.3%; P=0.02) and a shorter stay in
intensive care.
GIK might be benecial in patients with decreased
cardiac reserve, poor left ventricular function and/or
cardiogenic shock. Patients with a high risk of death may
be more likely to benet from metabolic therapy.29 Patients
with insulin-dependent diabetes might benet particularly
from GIK, as shown in the DIGAMI study for patients with
myocardial infarct.30 A recent study by Lazar and col-
leagues found better cardiac performance and faster recov-
ery after coronary bypass grafting in a group of 40 diabetic
patients.31 Postoperative GIK infusion for 48 h is of benet
in patients with refractory cardiac failure after hypothermic
cardiac arrest for bypass grafting.32 33
Limitations of our study
It is possible that our study was too small and the
groups too poorly matched to reveal the benet of GIK.
493
The different proportions of male and female patients in
the GIK and non-GIK groups is unlikely to have
inuenced the results, but this possibility cannot be
excluded. The possible inuence of the ejection fraction
was analysed retrospectively. Nine out of 19 patients in
our GIK group and only three in the non-GIK group
had an ejection fraction of less than 45% (P=0.06). The
importance of the ejection fraction as a confounding
factor is uncertain as there was no signicant difference
in cTnI concentration at any time point between patients
with low and those with normal ejection fractions. It
remains speculative whether those patients in the GIK
group with poor cardiac function would have had higher
cTnI concentrations without GIK infusion. Differences in
preoperative ventricular function can affect postoperative
recovery but not necessarily the postoperative cTnI
concentration, which specically indicates myocardial
cell death. It would be useful to conduct a larger study
in diabetic patients or patients with decreased left
ventricular function,34 testing for an even smaller
difference in cTn concentrations, and to relate cTnI to
functional recovery of the heart. One problem with a
high-concentration glucose infusion is hyperglycaemia
during CPB, which could damage the brain and worsen
neurological outcome. Hyperglycaemia may aggravate
ischaemic brain injury35 and be harmful after acute head
injury.36 The critical glucose concentration at which
treatment should be initiated is not known.37 A
confounding factor is that high glucose concentrations
may indicate severe head injury, as hyperglycaemia is a
general stress response.38 However, there is consensus
that the blood glucose concentration should be main-
tained within the normal range.37 38 Measuring glucose
and potassium concentrations regularly is necessary.
Blood glucose concentrations were higher in the GIK
group implying that, in future studies, more insulin
should be added to the glucose solution. Another
concern is that increasing glycolysis can increase the
concentrations of end-products such as lactate. Lactate
accumulation is associated with inhibition of glycolysis
and mitochondrial changes leading to cell damage, but
in an animal study treatment with glucose did not affect
the lactate concentration.39
Conclusion
We did not nd that the use of GIK infusion during surgery
reduced myocardial cell damage associated with cardiac
surgery and CPB. However, it was associated with increased
hyperglycaemia. As hyperglycaemia may worsen the
neurological outcome, routine GIK infusions cannot be
recommended until studies have been performed that
demonstrate the value of this practice and determine
which patients are most likely to benet.
 Bruemmer-Smith et al.
Acknowledgement
The troponin analysis was funded from educational grants within the
Department of Cardiothoracic Surgery, King's College Hospital.
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