European Journal of Cardiovascular Medicine

Diabetes is a multifactorial metabolic disorder resulting in raised blood sugar levels that affect multiple organs of the body, which majorly involves the cardiovascular system. Various studies have shown uncontrolled diabetes to be associated with many macro vascular complications like coronary artery disease, stroke & micro vascular complications like nephropathy, neuropathy, retinopathy etc ^[1-5]. Butsurgical stress results in hyperglycemia after all operations^[1]. Therefore, it is quite important to find the correlation of long term raise in blood sugar levels and its outcome in patients undergoing cardiac surgery. Therefore, one of the most reliable indicator for assessment of average level of blood sugar over the past 2 to 3 months is HbA1c and for management of diabetes mellitus it’s level is recommended to be less than 7 %.^[6]. As there are no prospective studies correlating HbA1C & outcomes in patients undergoing off pump coronary artery bypass grafting (CABG), so we hypothesized that HbA1C level influences the perioperative hemodynamics, regional perfusion, inotropic requirement, renal dysfunction and incidence of infections and arrhythmias in patients undergoing CABG off pump.

We have conducted a prospective observational single center study at our Institute from January 2017 to January 2019 after obtaining the approval from the ethical and the scientific committee (UNMICRC/ANESTH/2016/10). Informed consent and IRB approval have been obtained for all participants.

Sample size of 100 subjects in each group were selected. Patients aged 40-70 yrs. of either sex, scheduled for elective coronary artery bypass grafting (CABG) off pump were included. Patients with age less than 40yrs or more than 70yrs, having preoperative arrhythmias, preoperative renal failure, preoperative cerebrovascular stroke, preexisting infective focus, requiring emergency surgery, EF < 30 %, if procedure needs to be converted to CABG on CPB, with associated valvular pathology, LMCA pathology & those unwilling to give consent were excluded. The study was conducted under the supervision and permission of technical advisory committee & institutional ethical committee. HbA1C levels were done as a part of routine CABG workup for diabetic patients. Depending on HbA1C levels patients were divided into two groups. Group A (Study group): HbA1C > 7% & Group B (Control group): HbA1C < 7%. Random blood sugars were determined one day prior to the surgery, on the day of surgery and post operatively. In the preoperative period if the blood sugar levels were more than 180 mg/dl, patients were treated uniformly with human insulin according to sliding scale as per the institute’s protocol. Insulin infusion was continued intraoperatively to keep blood sugar levels less than 180mg/dl. Surgery was only planned when patient’s RBS levels were less than 180mg/dl on the day of surgery. In postoperative period blood sugar levels were monitored every hourly, and treated with insulin if RBS levels were more than 180 mg/dl; thus efforts were made to keep the blood sugar level less than 180mg/dl before, during and after the surgery in all patients.

A large bore peripheral venous cannula was inserted and a radial artery was cannulated with a 20G cannula before induction of anesthesia in all patients. Anesthesia was induced with midazolam 0.1 mg/kg, fentanyl 5-10 mcg/kg and vecuronium 0.2 mg/kg and patients were intubated with appropriate size endotracheal tube. Anesthesia was maintained with sevoflurane, vecuronium and fentanyl. The right internal jugular vein was cannulated with 7 French triple lumen central venous catheter before starting the operation. During surgery the patients were mechanically ventilated with 50% FiO2, volume control ventilation mode of ventilator with target tidal volume of 6-8ml/kg, SPO2 >98% and PaCO2 between 35-40 mmHg. Anesthesia was maintained with inhaled sevoflurane 0.4 to 1.5 MAC, vecuronium 0.02 to 0.06 mg/kg/hour and fentanyl 1 micrograms/kg/hour. On admission to the ICU, patients were sedated and mechanically ventilated until they reached extubation criteria (adequate neurologic response, sufficient muscle strength, hemodynamic stability with no need for high-dose ionotropic / vasoactive support, and a PaO2 >60 mmHg with an inspired oxygen fraction ≤ 40%).

The patients’ discharge from ICU to the intermediate care unit occurred if the patients fulfilled the discharge criteria (awake without neurologic deficit or agitation, had no need for inotropic/vasoactive support, a PO2 >60 mmHg with an inspired oxygen fraction ≤ 40%, a normal arterial PCO2 without metabolic or respiratory acidosis and regular kidney function with no need for renal replacement therapy or continuous infusion of loop diuretics). All demographic data, hemodynamic and all laboratory measurements were performed for data analysis. Under the preoperative demographic data and investigations following were recorded: age, sex, body surface area (BSA), body mass index (BMI), ejection fraction (EF %), duration of surgery, renal function test, total leucocyte count (TLC) & HbA1C levels & Random Blood Sugars (both by strips and ABG).

Under the intraoperative data following were recorded: blood sugar levels as random blood sugars, heart rate, mean arterial pressures, central venous pressure, lactates, pH, bicarbonate levels, ionotropic requirement (by Wernovsky inotropic score = Dobutamine (μg/kg/min) + Dopamine (μg/kg/min) + 100 X adrenaline (μg/kg/min) + 100 X nor adrenaline (μg/kg/min) + 10 X milrinone (μg/kg/min) + 10,000 X vasopressin dose (IU/kg/min),(17) & total insulin requirement during surgery.

Under the postoperative data i.e first 24 and 48 hrs. post-operatively following were recorded: Blood sugar levels, immediate postoperatively, at 6hrs,12hrs,18hrs & 24 hrs., heart rate, mean arterial pressures, central venous pressure, lactates, pH, bicarbonate levels, total ionotropic requirement postoperatively, total insulin requirement in postoperative day 1 and 2 &post-operative renal function test on 2nd postoperative day.

Under the Postoperative data 48 hrs. After the surgery till discharge from hospital following were recorded: any episode specifying infections, duration of ICU & hospital stay & any episodes of arrhythmias. Complications were defined as new arrhythmias, prolonged respiratory support (>48 h) or the need for continuous positive airway pressure breathing; renal complications were defined as patients with an increase of creatinine >1.5 mg/dl. Additional outcome parameters like hours of mechanical ventilation, any episode of infection including fever, positive cultures or antibiotic step up, length of ICU stay, length of hospital stay and any morbidity or mortality were recorded. Statically analysis was performed with SPSS 11th edition for windows. P value < 0.05 was considered as significant. 

Two hundred patients who were undergoing off pump CABG in our institute satisfying the inclusion & exclusion criteria were randomly included our study. After the informed consent based upon their HbA1C levels patients were grouped in to two groups: Group A: Study group: HbA1C > 7% &Group B: Control group: HbA1C < 7%.

There were no significant differences in demographic factors i.e age, height, weight, BSA, BMI and EF between patients in the two groups. Surgery duration was comparable in both the groups. (Table 1)

Table-1-Demographic variables

Heart Rate between the two groups measured preoperatively, at the beginning of the surgery, after 1 hour, after 2 hours, after 3 hours and at post operatively and were found to be significantly higher (p value<0.001) than the control group at all the time. (Table 2)

Table 2: Hemodynamic variables

Mean Arterial Pressure was lower in study group than the control group at all the times. But, the difference was insignificant for preoperative and baseline values, and significant after1 hr (p value 0.0038), after 2 hours (p value <0.001), after 3 hr. (p value 0.0003) and post operatively (p value<0.0001). (Table 2)

Central Venous Pressure was higher in the study group as compared to the control group. The difference was significant after 2 hr (p value <0.001), after 3 hr (p value 0.001), and post operatively (p value <0.0001). (Table 2)

Random blood sugar levels were found significantly higher for study group as compared to control group at all the time (except at the 3^rd of the surgery), with p value ranging from <0.001 to <0.0001. (Figure 1)

Figure 1: Random blood sugar

Insulin requirement to control the blood sugar levels was significantly higher for the study group at all the time with p value <0.0001. (Figure 2)

Figure 2: Insulin requirement

The difference of the ph remains insignificant at the start of the surgery and for the first 2 hrs.Of the surgery. But, the value starts to drops at 3^rdhr. of the surgery for the study the difference becomes statistically significant (p value 0.00015) and further decreases postoperatively (p value <0.0001). (Table 3)

Table 3: pH and Lactate

Serum Lactate concentration was significantly higher for the study group at the beginning of the surgery (p value 0.0004) and for first 3 hours of the surgery (p value 1hr: <0.001, p value 2hr: 0.0001, p value 3hr: 0.00002) & the difference becomes insignificant postoperatively. (Table 3)

Ionotropic requirement for the study group was significantly higher than the control group at both intraoperative (p value <0.0001) and postoperative period (p value <0.0001). (Figure 3)

Figure 3: Ionotropic score

The blood urea concentration was found to be significantly higher for the study group than the control group at both preoperative (p value <0.001) and postoperative periods (p value <0.0001). (Table 4)

Serum Creatinine difference was insignificant preoperatively. But, at postoperative period the serum creatinine of study group was significantly higher than the control group (p value <0.0001). (Table 4)

Table 4: Blood Urea and Creatinine

Infection and Arrhythmia. The number of cases having postoperative infection was found to be significantly higher in study group as compared to the control group (p value 0.0038), similarly the number of cases having postoperative arrhythmias was found to be significantly higher in study group as compared to the control group (p value <0.0001). (Figure 4)

Figure 4: Postoperative complication

Duration of hospital stay, ICU stay and ventilation period. The duration of hospital stay, ICU stay and ventilation period for the study group was significantly higher than the control group (p value <0.0001). (Figure 5)

Figure 5: Postoperative observation

The objective of our study was to determine whether preoperative HbA1C levels could predict the probability of perioperative hyperglycaemia, regional hypoperfusion, increased inotropic requirement, post-operative renal dysfunction, increased incidence of infections and arrhythmias in the postoperative period, duration of stay in the ICU & hospital in patients undergoing Off Pump CABG. Many factors like surgical stress, inotropes, and insulin resistance predisposes both diabetic & non-diabetic patients for hyperglycemia. Various studies have shown that perioperative hyperglycemia & glucose variability is associated with prolonged ICU & hospital stay & increased mortality & morbidity during cardiac surgery. However, extent of perioperative hyperglycemia can only be determined afterwards, which limits their use as a clinical predictor. Identifying relevant patient characteristics that are connected to and could possibly predict intra- and postoperative hyperglycemia is an important step for improved medical management. The importance of preoperative HbA1C levels, whether surgery should be delayed in patients with higher values & optimization of HbA1C levels can be used to predict perioperative outcomes following off pump CABG is the basis of our study.

Demographic and clinical data of both the groups were comparable (Table 1).

HEMODYNAMIC PARAMETERS

The Mean Heart Rate at all the periods was significantly lower in group B (Table 2). Hence from our result we conclude that the heart rate throughout our observation was significantly less with no episodes of tachycardia or ventricular tachycardia (VT) in patients with HbA1c levels <7%. The Mean value of mean arterial pressure was significantly higher in group B at 1hour, 2hours and 3hours after start of surgery and also at immediately postoperative period (Table 2). Hence from our results we conclude that the blood pressure was more in patients with HbA1c <7%, and hence the regional and renal perfusion with less demand of ionotropic agents especially in postoperative period. The Mean value of central venous pressure was significantly lower in group B at 2hours and 3hours after start of surgery and also at immediate postoperative period (Table 2). Hence we can say that the central venous pressure was significantly lesser in latter half of surgery and especially in postoperative period in patients with HbA1c <7% , which along with more blood pressures comparatively might signify a better cardiac function in these patients however further studies are required to prove this.

THE RANDOM BLOOD SUGAR LEVELS & INSULIN REQUIREMENTS

The random blood sugar was targeted to be under 180mg/dl, with the use of regular insulin infusions because Furnary AP et al. concluded that continuous insulin infusions resulted in significantly lower mean glucose levels than could be obtained with intermittent subcutaneous insulin therapy ^[7]. The target levels were less than or equal to 180mg/dl as Finfer S et al^[8]. & Harold L. Lazar et al. ^[9]. found that intensive glucose control increased mortality among adults in the ICU and a blood glucose target of 180 mg or less per deciliter resulted in lower mortality. The Mean value of random blood sugars at all the periods except three hours after start of surgery was significantly lower in group B. At 6hours, 12 hours, 18 hours and 24 hours after shifting to ICU the RBS levels were well controlled in group B as compared to group A in which all the values were crossing the set limit and mandating correction. Hence from these results we conclude that random blood sugars in patients with HbA1c >7% crossed our set limit of 180mg/dl at 1 hour after start of surgery and were continuously raised till 24 hours after shifting the patient to ICU mandating correction (Figure 1).In a similar study Dr Dinesh Kumar and Dr. Thomas Koshy concluded that preoperative HbA1C levels predict the degree of perioperative hyperglycaemia, insulin requirement perioperatively & duration of stay in the hospital^[10]. In this subset of patients surgery may be delayed until the blood sugars are controlled for a better outcome^[10]. Supporting our study was a study by Moitra VK et al. concluding that HbA1C values may serve as biomarkers for glucose control during the immediate perioperative period in patients with type 2diabetes undergoing elective surgery ^[11]. Hudson CC et al. found that Patients with elevated HbA1C had higher fasting and peak intraoperative blood glucose values ^[12].Their findings suggested that HbA1C might have value as a screening tool to identify high-risk non-diabetic cardiac surgery patients ^[12].The comparative analysis for insulin requirement between control group and study group was done for intaoperative period and 2 days postoperatively and it revealed that amount of insulin required in control group was significantly lower than the that in the study group both intraoperatively as well as in postoperative day 1 and postoperative day 2. Hence we can conclude that patients with HbA1c levels<7% have much less insulin requirements in both intra and post-operative periods (Figure 2) as was in a study by Dr. Dinesh Kumar and Dr. Thomas Koshy ^[10], the authors concluded that preoperative HbA1C levels predict the degree of perioperative hyperglycaemia, insulin requirement perioperatively & duration of stay in the hospital. In this subset of patients surgery may be delayed until the blood sugars are controlled for a better outcome. (10)

ACIDOSIS & LACTATES

The mean value of pH was found to be in physiological limits throughout in group B but it was slightly lower than physiological limit at 3 hours after start of surgery in group A. At immediate postoperative period it was found to be acidotic in group A. Hence we conclude that in last hours of surgery and the postoperative period the patients with HbA1c >7% turned acidotic. (Table 3)The mean value of lactate levels at beginning of surgery was found to be lower in group B but in physiological limits in both the groups. At one, two & three hours after start of surgery it was in physiological limits in group B but above the limit in group A. At immediate postoperative period both groups had mean value of lactate levels slightly above the physiological limit (Table 3). Hence from the results we conclude that the intraoperative lactate levels were significantly higher in patients with HbA1c >7% and the lactates crossed 2 mmol/L , that is signifying minimal regional hypoperfusion , 1 hour after start of surgery and continued till the postoperative period.

IONOTROPIC REQUIREMENTS

The requirement of ionotrops during the surgery as well as in postoperative period came out to be significantly lower in control group than in study group which indicates that the patients with HbA1C>7mg/dl required more inotropes during as well as after the surgery while those with HbA₁C <7mg/dl required significantly lower amounts of iontropes during and after the surgery (Figure 3).  In a study by Dr Dinesh Kumar and Dr. Thomas Koshy ^[10], the authors concluded that patients with higher HbA1C levels have an increased risk of infections & require higher inotropic support. In patients with higher HbA1C levels preoperatively, the risk benefit ratio to be considered before taking for surgery. In this subset of patients surgery may be delayed until the blood sugars are controlled for a better outcome ^[10].

BLOOD UREA & SERUM CREATININE

The preoperative mean blood urea value for control group was lower than for study group and so were the postoperative values, thus it can be said that the blood urea value for study group is significantly higher than the control group in both pre and postoperative periods (Table 4). In preoperative period the mean serum creatinine value difference between the two is insignificant, however as we can see the value in study group is slightly higher than that in control group. When measured postoperatively the mean serum creatinine value was significantly higher in study group than the control group (Table 4). Hence, we can conclude that although in physiological range the creatinine value which was similar in both the groups preoperatively increased significantly postoperatively in study group (HbA1c>7%) predisposing them to renal dysfunction. However, the urea levels which were already high in preoperative period in study group raised to a highly significant value postoperatively, again predisposing the uncontrolled diabetic group to renal dysfunction. Salomon et al in their study found that the incidence of renal insufficiency was significantly greater in the diabetic group. Halkos ME et al. concluded that HbA1C greater than 8.6% was associated with a 4-fold increase in mortality, renal failure, cerebrovascular accident, and deep sternal wound infection, and was strongly associated with adverse events after coronary artery bypass grafting^[13]. In a study by Hudson et al. the author found that an elevated HbA1C level was independently associated with increased 30-day mortality &acute kidney injury ^[12].

INFECTION & ARRHYTHMIAS

In postoperative period both the groups were observed for any episode of infection that includes fever, positive cultures and chest X ray suggestive of any foci or any change in electro cardio gram rhythm and it was found that both infection and arrhythmias were significantly higher in the study group (Figure 4). In a study by Dr Dinesh Kumar and Dr. Thomas Koshy ^[10], the authors concluded that the patients with higher HbA1C levels have an increased risk of infections. Salomon et al ^[1] in their study found that the incidences of sternotomy complications were significantly greater in the diabetic group.A study in relation to heart rate was done by Tran et al^[14] and found that patients with hyperglycemia were at increased risk for developing VT. The presence of hyperglycemia was significantly associated with early but not with late VT. They concluded efforts should be made to closely monitor and treat patients who develop hyperglycemia, especially early after hospital admission, to reduce their risk of VT.

ICU STAY, HOSPITAL STAY & VENTILATION PERIOD

Duration of ICU stay, hospital stay & ventilation period in control group was significantly lower than that of the study group, which is in accordance with the other studies (Figure 5). In a study by Dr Dinesh Kumar and Dr. Thomas Koshy ^[10], the authors concluded that preoperative HbA1C levels predict the duration of stay in the hospital. In patients with higher HbA1C levels preoperatively, the risk benefit ratio to be considered before taking for surgery. In this subset of patients surgery may be delayed until the blood sugars are controlled for a better outcome.^[10] Salomon et al ^[1] in their study found that the total number of hospital days were greater in diabetic groups.(1) Thourani et al ^[2] in their study concluded that Diabetics have a worse hospital and long term outcome after coronary artery bypass grafting.^[2] Anderson and coworkers ^[4]studied effects of cardio-pulmonary bypass on glucose homeostasis after coronary artery bypass surgery and strongly suggested that increased fasting glucose levels prior to surgery, and persistently elevated glucose levels during and immediately after cardiac surgery, are predictive of increased perioperative morbidity and mortality inpatients with and without diabetes & influences the early & late outcomes after coronary artery bypass surgery^[4].In a study by Gandhi GY et al^[5].The authors concluded that it is not just postoperative hyperglycemia butintraoperative hyperglycemia is also an independent risk factor for complications, including death, after cardiac surgery ^[5].

In a study Halkos ME et al^[13].Concluded that HbA1C greater than 8.6% was associated with a 4-fold increase in mortality. For each unit increase in HbA1C, there was a significantly increased risk of myocardial infarction and deep sternal wound infection, renal failure, cerebrovascular accident, and deep sternal wound infection occurred more commonly in patients with elevated HbA1C. Elevated HbA1C level was strongly associated with adverse events after coronary artery bypass grafting. Preoperative HbA1C testing may allow for more accurate risk stratification in patients undergoing coronary artery bypass grafting ^[13]. Furnary AP et.al^[15].also concluded that 3-blood glucose or “3-BG,” consisting of the average of all glucose values obtained on the day of surgery and the first and second postoperative days was an independent predictor of perioperative mortality, incidence of deep sternal wound infections, hospital length of stay, blood transfusions, new onset atrial fibrillation, and low cardiac output syndrome ^[17]And finally in the study by Lazar HL et al ^[16]. the glucose insulin– potassium-treated patients achieved significantly better glycemic control immediately prior to cardiopulmonary bypass (169 mg/dL vs. 209mg/dL), and after 12 hours in the ICU (134mg/dL vs. 266 mg/dL). Patients treated with tight glycemic control had significantly higher cardiac indices and less need for inotropic support and pacing. Tighter glycemic control also resulted in a lower incidence of infections and atrial fibrillation. All this contributed to a shorter hospital length of stay. After 5 years, the Kaplan-Meier curves showed a significant survival advantage for patients receiving better glycemic control. They had a significantly lower incidence of recurrent ischemia and wound infections, and were able to maintain a lower angina class^{[ 16]}.

Limitation of the study

HbA1c is a reliable indicator of diabetic control except in situations where the average RBC lifespan is significantly less than120 days which will give false low HbA1c results because 50% of glycation occurs in 90-120 days. Common causes include: increase in red cell turnover (blood loss, haemolysis, haemoglobinopathies and red cell disorders, myelodysplastic disease) and interference with the test (persistent fetal hemoglobin, hemoglobin variants &carbamylated hemoglobin as in uraemic patients). As per The Society of Thoracic Surgeons Practice Guideline Series, Annals of Thoracic Surgery 2009; 87: 663–669. HbA1C Results may be unreliable in circumstances like blood loss; blood transfusion, anemia & high erythrocyte turn over.

We conclude that patients with  HbA1C levels >7%  have increased risk of intraoperative tachycardia, acidosis and high lactates, perioperative and postoperative hyperglycemia and increased insulin requirements, higher inotropic support requirements in both intra-operative and postoperative periods, raised creatinine levels postoperatively predisposing to renal dysfunction, infections and arrhythmias postoperatively & having a longer ICU stay, hospital stay and ventilation period. Thus in patients with higher HbA1C levels preoperatively, the risk benefit ratio to be considered before taking for surgery and in these patients surgery may be delayed until the blood sugars are controlled with a HbA1c level<7% for a better outcome.

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