Effects of Dexmedetomidine on Perioperative Glycemic Control in Adult Diabetic Patients Undergoing Cardiac Surgery

ABSTRACT

Background and Objective:

To study the effects of dexmedetomidine (DEX) on perioperative blood glucose levels in adult diabetes mellitus (DM) patients undergoing cardiac surgery.

Methods and Material:

A prospective, observational study was conducted on 100 adult diabetic patients aged between 18 and 75 years undergoing cardiac surgery with cardiopulmonary bypass (CPB). The patients were divided into two groups (group D and group C) of 50 each. Group D patients received DEX infusion, whereas the group C patients received 0.9% normal saline infusion.

Results:

The blood glucose levels, heart rate, mean arterial pressure, and serum potassium levels at different time points were comparable between the two groups (P > 0.05). The mean dose of insulin required in the combined population as well as in both controlled and uncontrolled DM patients was significantly less in group D than in group C (combined population - 36.03 ± 22.71 vs 47.82 ± 30.19 IU, P = 0.0297; uncontrolled DM - 37.36 ± 23.9 IU vs 48.16 ± 25.15 IU, P = 0.0301; controlled DM - 34.7 ± 21.5 IU vs 47.63 ± 35.25 IU, P = 0.0291). Duration of mechanical ventilation and VIS were comparable between the two groups. The incidence of arrhythmias (20% vs 46%, P = 0.0059) and delirium (6% vs 20%, P = 0.0384) was significantly less in group D than in group C. None of the patients in either group had stroke, myocardial ischemia, and mortality.

Conclusion:

The results suggested that DEX infusion during the intraoperative period was very effective for perioperative glycemic control and reduction of insulin requirement in DM patients undergoing cardiac surgery.

Diabetes mellitus (DM) is an important risk factor for cardiovascular diseases, and the prevalence of DM in patients undergoing coronary artery bypass (CABG) surgery is nearly 30–40%.[1] An increase in body of evidence showed that there was an association between perioperative hyperglycemia and adverse outcomes following cardiac surgery.[2] Surgical trauma induces a variety of stress responses and the use of cardiopulmonary bypass (CPB) further aggravates the perioperative inflammation.[3] Therefore, it is necessary to implement appropriate strategies during the perioperative period to modulate the surgical stress response and inflammation that would improve the clinical outcome. Dexmedetomidine (DEX) is a potent α2 adrenoreceptor agonist with a high α2/α1 ratio (1620:1), thereby avoiding any unwanted cardiovascular effects due to α1 activation.[4] Clinical studies have shown that DEX can suppress stress response and inflammation, and preserve the immunity of surgical patients.[5] DEX has been routinely used in cardiac surgery because it maintains hemodynamic stability and reduces the requirement for sedatives, opioids, and analgesics.[6] Perioperative administration of DEX has been shown to reduce mortality in patients undergoing CABG surgery.[7] Also, DEX has been found to attenuate the surgical stress response and neuroendocrine response better than morphine and propofol in adult cardiac surgery.[8] Studies have shown that intraoperative administration of DEX resulted in good glycemic control in patients undergoing noncardiac surgery.[9] Although DEX has been routinely used in cardiac anesthesia practice, there is plausibility of studies on its beneficial effects on perioperative glucose homeostasis. Therefore, through this study, we evaluated the effects of DEX on perioperative glycemic control in adult diabetic patients undergoing cardiac surgery. The primary objective of the study was to evaluate the effects of DEX infusion on perioperative blood glucose levels. The secondary objectives of the study were: (1) to evaluate the requirement of insulin, (2) to compare the glycemic control effects of DEX infusion between patients with controlled DM and uncontrolled DM, (3) to evaluate the hemodynamic effects of DEX at different time points in patients undergoing cardiac surgery, (4) to evaluate the effects of DEX infusion on duration of mechanical ventilation, vasoactive–inotropic score (VIS), and incidence of postoperative events like arrhythmias, stroke, myocardial ischemia, and postoperative delirium. Our hypothesis was that intraoperative DEX infusion would reduce the perioperative blood glucose levels and insulin requirements and maintain hemodynamic stability in DM patients undergoing cardiac surgery.

METHODS

This was a prospective observational study conducted at a tertiary referral hospital after obtaining approval from the institutional ethics committee (No. SCT/IEC/1480/Jan 2020). Written informed consent was obtained from all the study participants. One hundred adult diabetic patients aged between 18 and 75 years who were scheduled to undergo elective cardiac surgery using CPB were divided into two groups (group D and group C) of 50 patients. The group distribution was performed by the principal investigator by assigning consecutive participants alternatively to each group. Exclusion criteria were patients not consenting to participate in the study, patients with severe left ventricular dysfunction, patients with other end-organ dysfunction like renal dysfunction, and hepatic dysfunction, history of known allergy to alpha-2 agonists drugs, patients with heart block and low heart rate (<50/min), emergency and redo cardiac surgeries. Patients who were on diabetic medications and with glycated hemoglobin (HbA1C levels) ≤7% were classified as controlled DM, and patients with HbA1C levels >7% were classified as uncontrolled DM.[10] A data safety monitoring board was established to monitor and document any adverse event or unexpected worsening of clinical status in the participants.

All patients were educated regarding the effects of the study drug (DEX) during the preoperative anesthetic checkup. Patients were advised to discontinue all oral hypoglycemic agents from the night before surgery, whereas metformin was discontinued 48 h before surgery. Patients who were on long-acting insulin therapy were changed to a regular insulin regimen and were advised to discontinue on the day of surgery.[11] Blood glucose was monitored and any rise in blood glucose levels (>110 mg/dl) was treated with regular insulin.[11] All patients were premedicated with oral diazepam 5 mg on the night before surgery and the morning of surgery. All patients were kept nil per oral as per the American Society of Anesthesiologists (ASA) recommendations before providing anesthesia.

In the operation room, immediately after securing peripheral venous access, group C patients received a placebo infusion of 0.9% normal saline at 3 ml/h, while group D patients received the DEX infusion at 0.5 mcg/kg/h. The DEX infusion was prepared for all patients to receive at a rate of 3 ml/h. Subsequently, general anesthesia was induced in all patients in both groups with 2 mcg/kg fentanyl, 1 to 2 mg/kg propofol, and the trachea was intubated after giving 0.12 mg/kg vecuronium. Anesthesia was maintained with sevoflurane, intermittent boluses of fentanyl and vecuronium, and morphine infusion at 20 mcg/kg/h throughout the surgery. The total dose of fentanyl was restricted to 6 mcg/kg in all patients in both groups. After administration of heparin (400 units/kg) and achieving target activated clotted time of more than 480 s, CPB was initiated with aortic and venous cannulations. An aortic cross-clamp was applied, and the heart was arrested in diastole using blood cardioplegia. A roller CPB pump was used, and the flow rate of the pump was maintained between 2 and 2.4 L/m²/min. The mean arterial pressure during CPB was maintained between 60 and 80 mm Hg. Patients were subjected to mild-to-moderate hypothermia (temperature of 30 to 33°C) during CPB. After the completion of the surgical procedure, rewarming and deairing (during intracardiac procedures) of the cardiac chambers was done and the aortic cross-clamp was released. During CPB, sevoflurane was administered in the oxygenator circuit through a dedicated plenum vaporizer. Depth of anesthesia was monitored using the bispectral index (BIS) and the BIS values were maintained between 40 and 60. The DEX infusion in group D was continued till tracheal extubation. Intraoperative blood glucose levels were maintained below 180 mg/dl using regular insulin as per the regimen suggested by Duggan et al.[11] Inotropes and vasopressors were administered to the patients after weaning from CPB to maintain the mean arterial pressure (MAP) >65 mmHg. The vasoactive inotropic score (VIS) was calculated using the following formula: (VIS = dopamine dose [μg/kg/min] + dobutamine dose [μg/kg/min] +100 * epinephrine dose [μg/kg/min] +100 * norepinephrine dose [μg/kg/min] +50 * levosimendan dose [μg/kg/min] +10 * milrinone dose [μg/kg/min] +10000 * vasopressin [IU/kg/min]).[12]

The following observations were recorded by an independent observer during the study period: (1) heart rate (HR), MAP, blood glucose level, and serum potassium level were noted at six different time points: before induction of anesthesia (T0), after sternotomy (T1), after establishment of CPB (T2), after the termination of CPB (T3), after transferring the patient to the intensive care unit (T4) and at 6^th hour of the postoperative period (T5), (2) total insulin dose required to maintain the blood glucose levels <180 mg/dl during the study period, (3) hyperglycemia episodes (blood glucose levels >180 mg/dl), (4) duration of mechanical ventilation, (5) VIS score, (6) incidence of postoperative arrhythmias and delirium till 72 hours after extubation, and (7) incidence of stroke, myocardial ischemia, and mortality till discharge from hospital.

In both the groups, during the pre-CPB and CPB period, hypotension (defined as MAP <65 mm Hg) was treated with boluses of fluid or phenylephrine (0.5 to 1 mcg/kg), and any incidence of bradycardia (HR <50/min) was treated with intravenous atropine (0.01 mg/kg). The attending anesthesiologist would discontinue the DEX infusion if there was severe hypotension (MAP <50 mmHg) or severe bradycardia (HR <40/min) and the study participant was considered to be dropped out and would not be included in the analysis.

Statistical analysis

Based on a previous study,[9] a sample size of 40 was required in each group to detect a difference of 20 mg/dl in the blood glucose level between the two groups to obtain a power of 80% and an alpha error of 0.05. We included 50 patients in each group considering a dropout of 20% due to discontinuation of the drug. Statistical analyses were performed using SPSS, version 22.0 for Windows (IBM Corp, Armonk, NY, USA). All baseline variables, and primary and secondary outcome variables were compared between the groups to document the efficacy and safety of the study drug. The Kolmogorov–Smirnov test was used to test the normality of the distribution of data. The mean and standard deviation of normally distributed quantitative variables were compared between the groups using the Student’s t test. The median and interquartile range of the nonnormally distributed data were compared using the Mann–Whitney test. The qualitative variables were compared between the groups using the Chi-square test/Fischer’s exact test. For comparing the percentages between the two groups, a two-sample t test was performed. A P- value of <0.05 was statistically significant.

RESULTS

A total of 126 patients were enrolled in this study, among which 26 patients were excluded based on the exclusion criteria [Figure 1]. The remaining 100 patients were divided into two groups of 50 each, with no additional exclusion from data analysis. The demographic profile, type of surgery, and diabetic profile were comparable between the two groups [Table 1]. There was a significant difference in the HbA1C levels between the controlled and uncontrolled diabetic patients (6.12 ± 0.78 vs 8.01 ± 0.67; P < 0.0001). The hemodynamic data, blood glucose, and serum potassium levels at different time points were comparable between the two groups [Table 2]. In group D, the blood sugar levels of patients with controlled DM were significantly lower than the patients with uncontrolled DM at different time points of the study period [Table 3]. The mean dose of insulin requirement in the combined population as well as in both uncontrolled and controlled DM subgroups was significantly lower in group D than the group C [Table 4]. In group D, 22 (46%) patients had episodes of hyperglycemia, whereas in group C, it was 36 (72%) patients (P = 0.0048). Also, the number of hyperglycemic episodes was higher in group C than in group D (63 vs 31). The intraoperative surgical data, total fluids administered, VIS, and duration of mechanical ventilation were comparable between the two groups [Table 4]. The incidence of arrythmias and postoperative delirium was significantly higher in group C in comparison with group D [Table 4]. None of the patients in either group had stroke, myocardial ischemia, and in-hospital mortality.

Figure 1.

Flow chart of the study design

Table 1.

Comparison of demographic data, type of surgeries, and diabetic profile between the two groups

Demographic variable	Group D (n=50)	Group C (n=50)	P
Age (years)	61.6±6.5	62.2±7.7	0.6747
Sex (male/female)	34/16	37/13	0.6598
Weight (kg)	65.78±9.23	68.12±7.95	0.1775
Height (cm)	160.54±8.29	162.05±7.96	0.3552
Type of surgeries
CABG	25 (50%)	27 (54%)	0.6904
MVR	11 (22%)	10 (20%)	0.8070
MV repair	7 (14%)	5 (10%)	0.5403
AVR	7 (14%)	8 (16%)	0.7805
Diabetic profile
Controlled DM	24 (48%)	27 (54%)	0.5504
Uncontrolled DM	26 (52%)	23 (46%)	0.5309

Note: Values are expressed as mean±standard deviation or number (proportion). P<0.05 was considered statistically significant. CABG, coronary artery bypass surgery; MV, mitral valve; MVR, mitral valve replacement; AVR, aortic valve replacement

Table 2.

Comparison of hemodynamic data, blood glucose levels, and serum potassium levels at various time points between the two groups

Time points	Group D (n=50)	Group C (n=50)	P
Mean arterial pressure (mmHg)
T0	93.4±16.7	92.2±14	0.6978
T1	81.9±10.7	85.2±9.8	0.1110
T2	76.7±10.4	79.7±9.4	0.1334
T3	79.6±10.3	80.5±8.4	0.6331
T4	78.6±8.8	81.9±10.6	0.0935
T5	79.8±8.7	79.2±8.4	0.7256
Heart rate (beats/min)
T0	67.8±14.3	64.8±12.6	0.2684
T1	61.3±9.1	64.2±11.8	0.1719
T2	60.2±7.3	63.1±10.3	0.1075
T3	69.9±13.6	73.9±14.7	0.1610
T4	74.1±13.4	76.6±15.9	0.3973
T5	74.4±13	78.5±15.5	0.2113
Blood glucose levels (mg/dl)
T0	134.1±42.7	145.2±39.8	0.1819
T1	139.2±37	150.1±37.2	0.1450
T2	154.5±39	162.3±37.9	0.3130
T3	171.9±29.2	178.1±30.1	0.2984
T4	164.8±30.4	173.8±39.5	0.2047
T5	159.9±38.6	165.7±34.2	0.4284
Serum potassium levels (meq/L)
T0	3.9±0.3	3.8±0.6	0.2944
T1	4.1±0.3	4.2±0.2	0.0527
T2	4.2±0.4	4.3±0.6	0.3292
T3	3.9±0.4	4.1±0.7	0.0825
T4	3.7±0.3	3.8±0.3	0.0988
T5	4.0±0.6	3.9±0.2	0.2663

Note : Values are expressed as mean±standard deviation. P<0.05 was considered statistically significant. Time points: T0, before induction of anesthesia; T1, after sternotomy; T2, after establishment of CPB; T3, after termination of CPB; T4, after transferring the patient to the intensive care unit; T5, 6th hour of postoperative period

Table 3.

Comparison of blood glucose levels at different time points between the controlled DM and uncontrolled DM of group D

Group D—Blood glucose levels (mg/dL)
Time points	Controlled DM (n=24)	Uncontrolled DM (n=26)	P
T0	132.65±33.58	159. 71±42.57	0.0157
T1	139. 37±30.93	162. 35±42.45	0.0327
T2	150.87±42.18	175.35±30.54	0.0239
T3	167.25±26.71	193.21±30.02	0.0022
T4	149.5±31.17	167.21±24.29	0.0290
T5	157. 25±26.20	177.78±37.67	0.0312

Note: Values are expressed as mean±standard deviation. P<0.05 was considered statistically significant. Abbreviations: DM, diabetes mellitus. Time points: T0, before induction of anesthesia; T1, after sternotomy; T2, after establishment of CPB; T3, after termination of CPB; T4, after transferring the patient to the intensive care unit; T5, 6th hour of postoperative period

Table 4.

Comparison of insulin requirement, intraoperative surgical data, fluids administered, VIS, duration of mechanical ventilation, and postoperative complications between the two groups

	Group D (n=50)	Group C (n=50)	P
Insulin requirement in combined population (IU)	36.03±22.71	47.82±30.19	0.0297
Insulin requirement in uncontrolled DM (IU)	37.36±23.9	48.16±25.15	0.0301
Insulin requirement in controlled DM (IU)	34.7±21.5	47.63±35.25	0.0291
CPB time (min)	115.9±24.8	111.7±25.2	0.4030
ACC time (min)	64.8±18.9	62.8±23.4	0.6393
Duration of surgery (hours)	5.48±0.85	5.41±1	0.7069
Total fluids administered (ml)	2290±493.6	2210±660.9	0.4945
VIS	8.3±3.5	7.6±3.4	0.3129
Duration of mechanical ventilation (hours)	13.5±3.8	14.7±3.5	0.1037
Arrhythmias	10 (20%)	23 (46%)	0.0059
1. Atrial fibrillation	5 (10%)	10 (20%)	0.0291
2. Atrial ectopics	2 (4%)	7 (14%)	0.0821
3. Ventricular ectopics	3 (6%)	6 (12%)	0.2969
Delirium	3 (6%)	10 (20%)	0.0384

Note: Values are expressed as mean±standard deviation or number (proportion). P<0.05 was considered statistically significant. ACC, aortic cross clamp; BG, blood glucose; CPB, cardiopulmonary bypass; DM, diabetes mellitus; IU—international units; VIS—vasoactive inotropic score

DISCUSSION

Stress response to cardiac surgery and anesthesia induces a variety of metabolic, immunological, and neurohormonal effects.[5] Dexmedetomidine, an α2 agonist, is a well-known drug in cardiac anesthesia practice due to its beneficial effects.[6,7,8] Although previously published studies revealed the beneficial effects of DEX in terms of reduction of stress hormones release and better hemodynamics,[7] the valuable effects of DEX in the perioperative management of hyperglycemia during cardiac surgery are not well studied.

Cortisol released during an acute stress condition like surgery enhances neo-glucogenesis from amino acids and fats and produces a state of insulin resistance which may be associated with increased blood glucose levels of 50% above the normal level.[13] Exposure of the patient to the CPB circuit may further aggravate this stress response.[14] Studies have shown that estimation of blood glucose levels can be a reliable indicator of stress response after surgery.[15] Insulin resistance increases rapidly during surgery, persists in the early postoperative period, and shows a rapid decline in the late postoperative period.[16] In cardiac surgical patients, after the removal of CPB stress, the elevated blood glucose levels continue to fall and normalize within the first six hours of the postoperative period.[17] Conversely, the continued use of inotropes in the postoperative period after cardiac surgery may mask the recovery of insulin resistance and results in persistent hyperglycemia during the postoperative period.[18] In our study, during the postoperative period, patients in group D showed lower blood glucose levels in comparison with the patients in group C and the difference was statistically significant. In spite of inotropes administration in the postoperative period, DEX is known to modulate the stress response after cardiac surgery, and therefore, the degree of hyperglycemia was less in group D.[15] Apart from the surgical stress, hypothermia and the addition of glucose to cardioplegia solutions could be the contributing factors for rising blood glucose levels after cardiac surgery.[19] A subgroup analysis of group D showed that the blood glucose levels were significantly higher in uncontrolled DM patients in comparison with patients with controlled DM. Younger age, duration of diabetes, and compliance with antidiabetic medications are the factors known to be associated with poor glycemic control.[20] This could be the explanation for the high blood glucose levels during the perioperative period in group D patients with uncontrolled DM.

Studies have shown that the perioperative insulin requirement would be higher in patients with high preoperative HbA1C levels.[21] In our study, we found that blood glucose levels in group D were significantly lower than in group C at different time points of the perioperative period. Consequently, the total insulin requirement was also significantly lower in both controlled and uncontrolled DM patients of group D in comparison with patients of group C. Insulin administration may be associated with the risk of the development of hypoglycemia, which if not monitored, may lead to neurological complications.[22] Under general anesthesia, the symptoms of hypoglycemia may be masked, and therefore, frequent monitoring of blood glucose levels is required during insulin administration. Since the DEX administration significantly reduces the insulin requirement, the risk of development of hypoglycemic episodes and the need for frequent blood glucose monitoring may be reduced.

The risk factors for postoperative arrhythmias after cardiac surgery have been attributed to hypoxia, ischemia, tissue trauma, catecholamine release, and electrolyte abnormalities. DEX is known to have a beneficial effect on all these factors as it suppresses the electrical activity of the sinus node and atrioventricular node through vagal stimulation.[23] This could have led to a lower incidence of atrial arrhythmias in group D. These findings were like the study results of El Amrousy et al.,[24] who reported a significantly lower incidence of arrhythmias with the prophylactic use of DEX. However, the study was conducted in children undergoing cardiac surgery who have a noticeably different risk profile than the adults.[24] Postoperative atrial fibrillation (POAF) after cardiac surgery is the most common and thoroughly investigated atrial tachyarrhythmia. Although different pharmacological agents have been proposed for the treatment of POAF, it remains unclear whether these drugs have definitive beneficial effects. Also, there is conflicting evidence in the literature on the effects of DEX in the management of on POAF.[25] In our study, we observed that the incidence of POAF was significantly reduced in group D in comparison with group C. Additionally, increasing age and prolonged cross-clamp duration are well-known risk factors for the development of POAF after cardiac surgery. In our study, the mean age and aortic cross-clamp time were statistically insignificant between the two groups, thereby avoiding the influence of these risk factors on the incidence of POAF. Studies have shown that the administration of DEX has significantly reduced the incidence of ventricular arrhythmia due to its vagolytic and beta-blocking properties.[26] We had found similar results in our study, where the incidence of ventricular ectopics was lower in group D than in group C, albeit statistically insignificant.

The incidence of postoperative delirium was significantly lower in group D in comparison with group C. The development of delirium after cardiac surgery has been attributed to the collaborative effect of hypoperfusion, microemboli, and rapid rewarming during CPB. Studies have shown that the possibility of delirium is increased with the amount of disruption of neurotransmitter pathways.[27] Increased plasma levels of free-MHPG (3-methoxy-4-hydrophenylglycol) concentration due to disruption of the noradrenergic system have been defined as the potential causative factor for the occurrence of delirium.[27] DEX acts in the presynaptic noradrenergic transmission and produces sedative effects by blocking the norepinephrine neurotransmitter by binding to the potent α2 adrenoreceptor.[4] Also, DEX administration reduces the requirement of opioids and other GABAergic agents like propofol and midazolam, all of which have a direct relationship with the development of delirium due to various mechanisms.[28,29]

Studies have shown that administration of DEX as an anesthetic attenuated the hemodynamic response to endotracheal intubation, skin incision, and sternotomy in patients undergoing cardiac surgery.[30] Although the MAP and HR were lower at different time points in group D than in group C, the difference was not statistically significant in our study. Administration of loading dose of DEX prior to infusion could have significantly attenuated the hemodynamic response to intubation and surgical stimulation.[30] The higher postoperative VIS scores in group D could be explained by the sympatholytic effects of DEX infusion. Contrarily, a study by El Amrousy et al.[24] showed a low VIS with DEX infusion in pediatric patients undergoing cardiac surgery. It was stated that the incidence of junctional ectopic tachycardia was significantly lower with DEX infusion which reduced the requirement of inotropes and vasopressors.[24]

We acknowledge that there are certain limitations in our study. First, our study involves a small sample size which might be the reason for the insignificant differences observed in the blood glucose levels at different time points between the two groups. However, we do not rule out the possibility of widening these differences in a larger cohort of patients. Second, we did not standardize the preoperative dietary intake of both controlled and uncontrolled diabetic patients, as the recent trends suggest reduced fasting for clear fluids and promoting the intake of carbohydrate-rich fluids before surgery. Third, sampling time intervals for blood glucose analysis were selected randomly based on the observation from previously available data and experience. Fourth, we did not analyzed the impact of opioids on stress response and blood glucose levels as the administration of opioids could have reduced the release of stress hormones and blood glucose levels. Finally, the duration of diabetes was not considered during data analysis, which might have been a significant factor for the degree of hyperglycemia in uncontrolled diabetic patients. A future randomized trial with larger sample size and more blood glucose analysis in the postoperative period may provide more information on the effects of DEX on perioperative blood glucose levels to add more strength to the literature.

CONCLUSIONS

DEX administration reduced the requirement of insulin in both controlled and uncontrolled diabetic patients undergoing cardiac surgery using CPB. In addition, the blood glucose levels were significantly less in the controlled DM patients than in the uncontrolled DM patients. Also, the incidence of arrhythmias and postoperative delirium was significantly reduced with DEX infusion. These results suggested that DEX can be an effective drug for perioperative glycemic control and reduction of postoperative arrhythmias and delirium in DM patients undergoing cardiac surgery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.