Association of time in blood glucose range with outcomes following cardiac surgery
Association of time in blood glucose range with outcomes following cardiac surgery
Amr S Omar 0 1
Ahmed Salama 1 2
Mahmoud Allam 1 2
Yasser Elgohary 1
Shaban Mohammed 4
Alejandro Kohn Tuli 1
Rajvir Singh 3
0 Department of Critical Care Medicine, Beni Suef University , Beni Suef , Egypt
1 Department of Cardiothoracic Surgery/Cardiac Anaesthesia & ICU Section, Heart Hospital, Hamad Medical Corporation , Doha, PO: 3050 , Qatar
2 Department of Anesthesia, Al-Azhar University , Cairo , Egypt
3 Department of Medial Research, Hamad Medical Corporation , Doha , Qatar
4 Department of Clinical Pharmacy, Hamad Medical Corporation , Doha , Qatar
Background: The importance of optimal postoperative glycemic control in cardiac patients remains unclear. Various glycemic targets have been prescribed to reduce wound infection and overall mortality rates. Aim of the work: To assess glucose control, as determined by time in range (TIR), in patients with glycemic targets of 6.0 to 8.1 mmol/L, and to determine factors related to poor control. Methods: This prospective descriptive study evaluated 227 consecutive patients, 100 with and 127 without diabetes, after cardiac surgery. Patients received insulin to target glucose concentrations of 6.0 to 8.1 mmol/L. Data analyzed included patient age, gender, race, Euro score, cardiopulmonary bypass time (CPB), aortic cross clamp time (ACC), length of ventilation, stay in the intensive care unit (ICU) and stay in the hospital. Patients were divided into two groups, those who maintained > 80% and < 80% TIR. Outcome variables were compared in diabetics and non-diabetics. Results: Patients with >80% and <80% TIR were matched in age, sex, gender, and Euro score. Failure to maintain target glycemia was significantly more frequent in diabetics (p = 0.001), in patients with glycated hemoglobin (HbA1c) > 8% (p = 0.0001), and in patients taking dopamine (p = 0.04) and adrenaline (p = 0.05). Times of CPB and ACC, length of stay in the ICU and ventilation were significantly higher in patients with TIR <80% than >80%. Rates of hypoglycemia, acute kidney injury, and in-hospital mortality were similar in the two groups, although the incidence of wound infection was higher in patients with TIR <80%. Both diabetics and non-diabetics with low TIR had poorer outcomes, as shown by length of stay and POAF. No significant differences were found between the two ethnic groups (Arabs and Asians). Conclusion: Patients with >80% TIR, whether or not diabetics, had better outcomes than those with <80% TIR, as determined by wound infection, lengths of ventilation and ICU stay. Additionally, they were not subject to frequent hypoglycemic events. Preoperatively high HbA1C is likely a good predictor of poor glycemic control.
Glucose control; Outcome; Wound infection
Tracking adherence to insulin infusion protocols and the
use of standard metrics are key to maintaining glucose
control. Control practices after cardiac surgery were
shown to reduce mediastinitis . Poor perioperative
control of blood glucose concentration may be
associated with poorer outcomes in patients undergoing
cardiac surgery .
Tight glucose control has been reported to improve
acute outcomes in hospitalized diabetic patients, including
risks of infection and death [3,4]. Tight glucose control,
through continuous intravenous injection of insulin, was
also found to reduce mediastinitis and mortality rates, as
well as costs and length of hospital stay, in diabetic
patients after cardiac surgery [2-5]. Other advantages of tight
glucose control in cardiac surgery patients include
reductions in the rates of postoperative atrial fibrillation (POAF)
and ischemia .
Although maintaining normoglycemia between 4.4 and
6.1 mmol/L using intensive insulin therapy reduced
mortality in the surgical intensive care unit (ICU), as
well as organ complications associated with critical
illness, tight insulin control was also associated with
frequent hypoglycemic episodes . Moreover, a recent
study showed that intensive insulin therapy (6.18.3 mmol/
L) yielded superior outcomes when compared with less
intense control targeting higher glucose concentrations .
Cardiopulmonary bypass (CPB) has been shown to
affect glucose control, with controlling blood glucose
being difficult during cardiac surgery . Tight blood
glucose control during CPB was not easily achieved owing
to the exacerbation of insulin resistance. In addition ,
an investigation of blood glucose homeostasis
derangement showed that glucose levels were increased and
insulin levels decreased during hypothermic CPB .
Insulin resistance has been associated with increased
levels of inflammatory cytokines in critically ill patients.
Concomitant insulin resistance plus hypothermia may
be aggravated by insulin adherence to the plastic
material included in the extracorporeal circuit, by glucose
administration in cardioplegia solution, and by the steroids
that may be used to reduce inflammatory responses to
CPB. Blood glucose concentrations tend to increase after
rewarming, as do levels of catecholamines, glucagon,
and growth hormone . The underlying molecular
mechanisms of this insulin resistance are not fully
understood, although transmembrane protein defects are
thought to play a role .
Ethnic differences in insulin sensitivity have been
associated with variations in body fat. South Asian
adolescents are more insulin resistant, with more body fat,
than white European adolescents, which may contribute
to the higher risk in the former of developing type 2
diabetes . Detrimental effects of hyperglycemia may
affect critically ill non-diabetic and diabetic patients. The
harmful effects of intensive hyperglycemic control are
still considered speculative , and the three domains
of glycemic control hyperglycemia, hypoglycemia and
glucose variability could affect outcomes in critically ill
patients . This study therefore evaluated patient
outcomes after implementation of a validated insulin
protocol , by assessing time in range (TIR) to investigate
factors related to poor glucose control.
This prospective, descriptive, single-center study with
purposive sampling evaluated 227 consecutive patients,
100 with and 127 without diabetes, after cardiac surgery.
Patients who received insulin for at least 12 h were
eligible. The study was performed from September 2012 to
August 2013 in the 12-bed cardiothoracic ICU of
Hamad Medical Corporation. The study was approved
by the ethics committee of Hamad Medical Corporation
(reference number 13156/13), which waived the
requirement for informed consent, since no specific
intervention was performed and blood sampling was
part of routine care to control blood glucose
Mean blood glucose (BG) concentration was measured
during infusion of 1.0 unit/mL of insulin at a rate
sufficient to maintain a target glucose concentration
of 6.08.1 mmol/L. Arterial blood was sampled every
1 h during the first 612 h after surgery, with capillary
blood samples obtained by finger stick thereafter. BG
concentrations were measured using the Accu-Check
Inform II point-of-care meters (Roche Diagnostics,
Indianapolis, IN). A quality control program was
maintained to assess nurses compliance with and
interpretation of the protocol. Nurses recorded BG
concentrations, measurement times and insulin
infusion rates on a daily ICU chart.
The main objective of this study was to investigate
glucose control, using TIR 80% as the threshold, and factors
associated with poor control. Total time of insulin
infusion (A) and the period of time being within the
target range (B) were measured in each patient during
insulin infusion, with TIR calculated as B/A*100. Patients
were divided into two groups based on successful
maintenance of TIR, with Groups I and II consisting of individuals
with TIRs >80% and <80%, respectively. Hypoglycemia was
defined as BG <4 mmol/L and severe hypoglycemia as
BG <2.2 mmol/L.
Factors assessed at admission to the ICU included
age, sex, race, medical diseases, drugs, type of surgery,
anesthesia time, CPB time, aortic cross clamp (ACC)
time, use of inotropes and vasopressors, Euro SCORE,
statin therapy, length of mechanical ventilation, and
stay in the ICU and the hospital. Complications and
outcomes, including acute kidney injury (AKI), POAF,
infection, stroke, wound infection, and death, were
recorded for each patient. Data were retrieved using
Dendrite Clinical Systems (London, UK). Outcomes
were compared in subgroups of diabetics and
nondiabetics, and factors associated with poor glycemic
control were analyzed. ICU stay was dichotomized
as 48 hours and >48 hours.
Normally distributed continuous variables are
reported as mean SD, non-normally distributed
continuous variables as median and range, and categorical
variables as frequency and percentage. Normally and
non-normally distributed continuous variables were
compared using Students t-tests and MannWhitney
U tests, respectively, and categorical variables using
Chi squared tests. A two-sided P-value <0.05 was
considered statistically significant. Variables influencing
TIR in our and previous analyses were assessed by
multivariate regression analysis. All statistical analyses
were performed using SPSS Version 16 software (SPSS
Inc. Chicago, IL, USA).
Of the 260 patients screened, 227 were enrolled; the
remaining 33 patients were excluded because they were
infused with insulin for < 12 h. The study population
consisted mostly of males and had a mean age of 54.3
10.8 years (Table 1); in addition, 43.1% of the patients
were diabetics, and 59.3% were hypertensive. There was
a higher proportion of Asians than Arabs in the studied
population. The majority of patients underwent CABG
surgery (Tables 1 and 2).
Patients were divided into two groups based on their
success in maintaining target BG concentration. Group I
consisted of patients with TIR >80% and Group II of
patients with TIR < 80% (Table 3). The two groups were
well matched in age, gender, BMI, association with
hypertension, and Euro score. Non-diabetics showed
better BG control than diabetics (Table 3). There were
no significant differences between ethnic groups. Basal
creatinine and EF% were similar in Groups I and II.
HbA1C was significantly higher in Group II. Patients
taking dopamine and adrenaline had poorer BG control,
as were patients who underwent CABG. In contrast,
patients who underwent valvular surgeries were more
likely to have better BG control.
Table 4 summarizes the clinical outcomes in these
patients. ACC and total anesthesia time were significantly
higher in Group II, as were lengths of ICU and hospital
stay and duration of mechanical ventilation. The
percentages of patients with new POAF and wound
infection were significantly higher in Group II, as was the
rate of overall in-hospital mortality. Multivariate analysis
Table 1 Demographic and clinical characteristics of the
Number Minimum Maximum Mean SD
Table 2 Comparative characteristics of the included patients
Additive Euro score 222
CPB time (minutes)
ACC time (minutes)
BMI, body mass index; EF, ejection fraction; HgA1C, glycated hemoglobin; CPB,
cardiopulmonary bypass; ACC, aortic cross clamp; WBCs, white blood cells;
LOV, length of mechanical ventilation, LOShosp, length of hospital stay.
showed that diabetes was the only independent
predicator of poor glycemic control (Table 5). Variables
affecting TIR were included in the multivariate model
(Table 6). Comparisons of outcome variables in
subgroups of diabetics and non-diabetics showed that TIR
<80% was associated with longer lengths of stay and
higher POAF frequency in both diabetics and
nondiabetics (Tables 7 and 8). Moreover, multivariate
analysis showed that TIR <80% was significantly associated
with longer ICU stay (Table 9).
The main findings of this study were that patients with
higher TIR had better postoperative outcomes, whether
they were non-diabetics or diabetics, and that a BG
range of 6.08.1 mmol/L was safe in the studied
population. In addition, HbA1C was found to predict poor
glycemic control, ethnicity was unrelated to poor control
and hourly sampling of BG after cardiac surgery is useful
in patient monitoring.
Adverse outcomes in surgical patients may be due to
hyperglycemia [16,17], and insulin therapy in the ICU
has yielded diverse outcomes [6,18]. Based on mortality,
Table 3 Clinical and laboratory variables of patients in
Groups I (TIR >80%) and II (TIR <80%)
Table 4 Clinical outcomes of patients in Groups I
(TIR >80%) and II (TIR <80%)
CPB time (minutes)
ACC time (minutes)
Anesthesia time (minutes)
Basal creatinine (micromole/L) 88.6 25.3
IDDM, insulin dependent diabetes mellitus; NIDDM, non insulin dependent
diabetes mellitus; BMI, body mass index; HbA1C, glycated hemoglobin;
EF, ejection fraction; CABG, coronary artery bypass graft.
morbidity, and long-term survival benefits, the
guidelines of the Society of Thoracic Surgeons recommended
a glycemic control target of 6.18.0 mmol/L glucose after
cardiac surgery . More recently, moderate glycemic
control after cardiac surgery showed better outcomes ,
and the literature relating to intensity of BG control in CV
surgery patients is somewhat conflicted .
Diabetics comprised 43.1% of the patients in our study,
compared with 13% and 20% in the Leuven and
NICESUGAR studies, respectively. Diabetes is highly prevalent
in populations, along with greater insulin resistance .
Using TIR to classify patients, we found that maintaining
target TIR was more difficult in diabetics than in
nondiabetics, confirming previous results showing that out
of range glycemia was more prevalent in diabetics .
Although we hypothesized that poor control would be
related to ethnicity, we found that both Asians and
Arabs were equally distributed in both TIR groups.
CPB, cardiopulmonary bypass; ACC, aortic cross clamp; LOV, length of
mechanical ventilation; LOSICU, length of ICU stay; LOShosp, length of hospital
stay; AF, atrial fibrillation; AKI, acute kidney injury; VAP ventilator
Our finding, that use of dopamine or adrenaline was
associated with poor glycemic control, is in good
agreement with findings showing that higher BG levels were
associated with adrenaline use . Intensive glycemic
management may be required in non-diabetic patients
infused with high doses of catecholamines .
However, catecholamine infusion may be responsible for
hyperglycemia in ICU patients .
We found that the frequency of poor glycemic control
was higher in patients who underwent CABG than in
those who underwent valvular surgery, a finding that
may be due to the higher preoperative rate of diabetes in
CABG patients. CABG was found to be more closely
associated with hyperglycemia than was valvular
surgery, as were wound infections (93% versus 4%) .
We found, however, that the acute nature of surgery
was similar in both groups.
Prediction of poor glycemic control
Although potential predictors of poor glycemic control,
such as baseline creatinine concentration and EF%, were
similar in our patient groups, HbA1C concentration was
significantly higher in Group II. High HbA1c after
CABG may be associated with higher short- and
longterm mortality rates .
Table 5 Multivariate logistic regression analysis for low
TIR less than 80%
CABG coronary artery bypass graft, HbA1C glycated hemoglobin, LOV length
of mechanical ventilation, LOSICU ICU length of stay, LOShosp Hospital length of
stay, ACC aortic cross clamp time, AF atrial fibrillation.
Hyperglycemia associated with CPB may be due to the
insulin resistance that accompanies surgical intervention,
resulting in poorer patient outcomes . Although we
found that CPB time was higher in Group II, the
difference was not statistically significant. In contrast, ACC
and total anesthesia time were significantly higher in
Group II. Although insulin secretion is not impaired
during cardiac surgery, insulin signaling cascade in
target organs is reduced, and inotropes needed during
weaning from CPB affect glucose levels . CPB has
been shown to affect glucose control , with increases
in inflammatory cytokines during cardiac surgery
enhancing insulin resistance .
Postoperative parameters and complications
Lengths of stay in the ICU and hospital, as well as
duration of mechanical ventilation, were all significantly
higher in Group II, as well as in both non-diabetics and
diabetics with low TIR. These results were consistent
with findings showing that moderate glycemic control
(6.610.0 mmol/L) in diabetic CABG patients was
associated with minimal morbidity and mortality .
Table 6 Glycemic changes in Groups I (TIR >80%) and II
Total hours of insulin infusion
Moderate glycemic control (6.18.0 mmol/L) after
cardiac surgery was found to reduce the duration of
ventilation . A 3-mmol/L increase in BG was found to be
an independent predictor of deep sternal wound
infection, length of stay in the hospital and mortality rate. In
addition, new POAF events, blood transfusion and low
cardiac output syndrome were found to correlate significantly
, suggesting that reducing BG below 10 mmol/L
appears to be an ideal goal. Maintaining BG below this
concentration was associated with reductions in mortality
and morbidity, whereas aggressive glycemic control (4.4
6.1 mmol/L) did not offer a superior advantage .
Complications related to poor glycemic control are
challenging for health care practitioners. For example,
we found that the occurrence of acute kidney injury
(AKI) tended to be higher in Group II, similar to results
showing that glycemic control after cardiac surgery was
significantly associated with a reduced risk of AKI .
The rate of POAF events was also significantly higher in
Group II, similar to findings showing that proper
glycemic control could reduce the incidence of POAF after
CABG, from 30% to 18% (39% risk reduction; p = 0.042)
, and may reduce the rate of POAF-associated
mortality . In addition, a prospective randomized study
found no differences in the rates of POAF events and
wound infection between aggressive (5.06.6 mmol/L)
and moderate (6.610.0 mmol/L) glycemic control .
We found that the rate of wound infection was
significantly higher in Group II, similar to findings showing
that the rate of wound infection was reduced from 2.6%
to 1.0% following glycemic control for 18 months .
Wound infections after cardiac surgery may be
reduced by antimicrobial prophylaxis, control of
preoperative BG concentration, and staple avoidance in patients
with a normal BMI . Preoperative screening for
diabetes may reduce the rates of these postoperative
morbidities associated with surgical site infections . We
found that the rates of hypoglycemic events were
similarly low in both groups, with two patients in each group
The overall in-hospital mortality rate was higher in
Group II than in Group I (3.7% versus 1.2%). Outcomes
may be improved by enhancing TIR in ICU settings,
especially when hypoglycemia can be avoided. We found
that both diabetics and non-diabetics with low TIR had
similar outcomes, suggesting that diabetics with greater
numbers of comorbidities may have poorer outcomes.
Moreover, diabetics may benefit from higher target
glucose concentrations .
Strengths and limitations
Utilization of the TIR as a distinguishing factor may
have clinical advantages. The relatively low rate of
hypoglycemia in our study may have been due to the
LOSICU median (hours)
LOShosp median (days)
LOV median (minutes)
TIR less than 80%
Table 7 Outcome variables in non-diabetics in both
Table 9 Multivariate analysis for favorable ICU length of
stay (=or < 48 hours)
LOV length of mechanical ventilation, LOSICU ICU length of stay, LOShosp
Hospital length of stay, AF atrial fibrillation, AKI acute kidney injury.
frequency of blood sampling (hourly during the first
6 h). This high sampling rate should not confer an extra
burden on the nursing staff, as arterial sampling is
required for early assessment of these patients. The
optimum sampling frequency has not yet been
determined, although sampling every 12 h is common in
many studies [15,37]. The early postoperative period is
usually associated with stress from the use of inotropes,
as well as bleeding, predisposing to early difficulties in
glucose control. This study was limited by being
performed at a single center, as well as by an inability to
occlude the glucose variability.
Patients with >80% TIR 6.0-8.1 mmol/L, whether
diabetics or non-diabetics, had better outcomes than those
with <80% TIR 6.0-8.1 mmol/L. The former group had a
Table 8 Outcome variables in diabetics in Groups I
(TIR >80%) and II (TIR <80%)
LOSICU median (hours)
LOShosp median (days)
LOV median (minutes)
LOV, length of mechanical ventilation; LOSICU, length of ICU stay; LOShosp,
length of hospital stay; AF, atrial fibrillation; AKI, acute kidney injury.
CABG coronary artery bypass graft, ACC aortic cross clamp time, AF atrial
fibrillation, TIR time in range.
lower rate of wound infection, shorter duration of
ventilation and shorter stay in the ICU. Moreover, strict
glycemic control did not increase the occurrence of
hypoglycemic events. Preoperatively high HbA1C
appears a more likely predictor of poor glycemic control.
Ethnicity had no effect on glucose control.
Recommendations and future directions
1) Attempt to enhance TIR in ICU population
2) HbA1C screening for all patients before cardiac surgeries.
3) Hourly sampling of blood glucose
4) Considering glucose variability in similar studies Key messages
1) Power of TIR to predict outcome after cardiac surgeries.
2) Safety of 6.0-8.1 mmol/L target BG.
3) Reduced complication in the adequately controlled group
4) Power of HbA1C to predict poor control
5) Ethnicity is not predictive of poor control among the studied population
6) Value of hourly sampling of BG soon after cardiac surgery
The ethics review panel waived informed consent for all
patients enrolled in the study. However, all study data
were maintained anonymously.
ACC: Aortic cross clamp; AKI: Acute kidney injury; BG: Blood glucose;
CABG: Coronary artery bypass graft; CAD: Coronary artery disease;
CPB: Cardiopulmonary bypass; HbA1c: Glycated hemoglobin;
POAF: Postoperative atrial fibrillation; TIR: Time in range.
The authors declare that they have no competing interests.
ASO wrote the manuscript, designed the study and submitted the
manuscript. AS, MA and YE collected data. SM provided support in the initial
study design and in writing the manuscript. RS performed statistical analyses.
AKT, as chair of the intensive care department, provided general support.
All authors read and approved the final manuscript.
This work would not have been possible without the kind support and help
of many individuals and our organization. The authors thank all members of
the Cardiothoracic surgery department, Heart Hospital, of Hamad Medical
Corporation, Qatar, for providing necessary information regarding the
project and for support. The authors also thank the members of the medical
research department of Hamad Medical Corporation for their support
throughout this project.
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