Dexmedetomidine as an Anaesthetic Adjunct in Patients Undergoing Elective Off-Pump Coronary Artery Bypass Graft Surgery

Background: The aim of the present study was to study the hemodynamic profile of dexmedetomidine during induction and distal anastomosis of coronary arteries in patients undergoing OPCAB in comparison to the institutional practice of using midazolam.
Methods: In Group I, (n=25) patients were anaesthetised using fentanyl, pancuronium bromide, Isoflurane and midazolam. Group II (n=25) patients received a loading dose of dexmedetomidine infusion (1µg/Kg) over 10 minutes followed by an infusion of dexmedetomidine at the rate of 0.6 µg/Kg/hour, along with fentanyl, Pancuronium bromide and isoflurane. Heart rate (HR) mean arterial pressure (MAP), pulmonary artery (PA) catheter derived data and BIS were recorded at baseline, at 1 and 3 minutes after induction, at 1, 3 and 5 minutes after intubation, and at 5 and 30 minutes after protamine administration. MAP and HR were recorded every 10 min during the operation, except during distal anastomosis of the coronary arteries when it was recorded every 5 minutes after application of the Octopus tissue stabilising system.
Results: The intubation response by way of increase in HR was much less in group II and stabilized by 5 min after intubation. The accompanying hypotension at 1 minute after induction was more in group II, but it was clinically acceptable (81.68±21.74 mm Hg). During distal graft anastomoses HR was in the range of 68 beats/min to 85 beats/min in group II vs. 85 beats/min to 100 beats/min in Group I. The MAP was lower in this group during the distal anastomosis, but it was within clinically acceptable range (> 65 mm Hg).
Conclusion: Dexmedetomidine is a viable option as an anaesthetic adjunct in a loading dose of 1µg/Kg followed by an infusion of 0.6 µg/Kg. Future studies will be necessary to show if this provides any outcome benefits.

during cardiac surgery and they are a part of anaesthetic protocol at our institute. Dexmedetomidine, an α2 -adrenoreceptor agonist is an analgesic with additional beneficial effects such as a decrease in sympathetic tone with attenuation of hemodynamic and neuroendocrine response to stress [1,2]. It has been shown to reduce the anaesthetic and opioid requirement in patients undergoing CABG [3,4]. It has also proven to provide hemodynamic stability (in a dose of 2.64 µg/Kg), owing to its effect in controlling the adrenocortical as well as cardiac function in patients undergoing vascular surgery, a patient population, who have a high incidence of CAD [1]. In addition, it leads to a decrease in plasma levels of cortisol, epinephrine, norepinephrine and serotonin and provides cardioprotective effects [5,6]. It, thus, appears to be a useful agent during cardiac surgery.
The major drawbacks of dexmedetomidine are its propensity to cause bradycardia and hypotension [4]. There are a few reports of dexmedetomidine and its hemodynamic effects in patients undergoing OPCAB. The aim of the present study was to compare the hemodynamic profile of dexmedetomidine versus midazolam in patients undergoing OPCAB using Bi-spectral index (BIS) guided anaesthetic technique. As secondary efficacy variables, we also looked for untoward incidences such as bradycardia, hypotension and heart blocks.

I Sample Size and Patient Selection
We were planning a study of continuous response variables from matched pairs of study subjects. Prior data indicated that the difference in the response of matched pairs is normally distributed with a standard deviation of 14. If the true difference in the mean response of matched pairs is 10, we will need to study 23 pairs of subjects to be able to reject the null hypothesis that this response difference is zero with probability (power) 0.9. The Type I error probability associated with this test of null hypothesis was 0.05. Therefore, in this prospective, randomized study 50 patients, undergoing elective OPCAB were divided into two groups. Exclusion criteria were age ≥ 70 years, left ventricular ejection fraction (EF) of < 40%, redo surgery, combined procedures, New York Heart Association (NYHA) class III and IV, any systemic diseases like chronic obstructive pulmonary disease and renal, hepatic or neurological disease. The patients were randomly allocated to two groups: Group I (Control, n=25) and Group II (dexmedetomidine, n=25) by computer generated randomization table. All the patients received premedication as per the institutional protocol with intramuscular morphine 0.2 mg/Kg and promethazine 0.5 mg/Kg, 30 minutes before surgery. In the operating room, taking aseptic precautions, a 23 G Y-cannula, intra-arterial cannula and pulmonary artery (PA) catheter were placed under local anaesthesia. Routine monitoring consisted of HR, invasive BP, BIS and peripheral oxygen saturation monitoring (SpO2).
In Group I, patients were anaesthetized by the standard institutional protocol using opioid (fentanyl 8-10 µg/Kg), muscle relaxant (pancuronium bromide 0.1mg/Kg) and midazolam (0.02mg/Kg). Anaesthesia was maintained with intermittent doses of fentanyl, pancuronium bromide, midazolam and isoflurane. Group II patients received a loading dose of dexmedetomidine (1µg/Kg) as an infusion over 10 minutes, fentanyl (8-10µg/Kg) and pancuronium bromide (0.1mg/Kg). Anaesthesia was maintained with intermittent fentanyl, pancuronium bromide and an infusion of dexmedetomidine at the rate of 0.6 µg/Kg/hour and isoflurane. The infusion of dexmedetomidine was discontinued at the end of surgery. A target BIS value of 40-60 was maintained in both the groups (by titrating Isoflurane) at all times during induction of anaesthesia and surgery. In both the groups, hemodynamics [HR, mean arterial pressure (MAP)], PA catheter derived data and BIS were recorded at baseline (soon after insertion of the PA catheter under local anaesthesia), at 1 and 3 minutes after induction of anaesthesia and again at 1, 3 and 5 minutes after endotracheal intubation. Thereafter, MAP and HR were recorded every 10 min during the operation, except during distal anastomosis of the native coronary artery [left anterior descending (LAD), obtuse marginal (OM) and right coronary (RCA)] when it was recorded every 5 minutes after application of the Octopus tissue stabilising system (OTSS). PA catheter derived data were also obtained at 5 and 30 minutes after protamine administration.
Patient outcome as regards, time to extubation, stay in intensive care unit (ICU), discharged/ expired, inotropic support and the use of intra-aortic balloon pump (IABP) were also noted. In both the groups, nitroglycerin was infused routinely at a rate of 0.3 µg/Kg/min continuously from the start of the procedure. Ringer's solution or succinylated gelatine was infused to maintain a sufficient preload and a CVP of 8-10 cm of H2O at the discretion of the attending anaesthesiologist. Body position was changed appropriately to aid the visualization during distal anastomosis, vasoactive drugs (Dopamine/Dobutamine/Adrenaline/Vasopressin/ or a combination/ IABP) were administered, if necessary, to maintain a MAP > 70 mm Hg. Nasopharyngeal temperature was maintained at 35-36⁰C. All OPCAB procedures were performed by any one of the two surgical teams. After surgery, dexmedetomidine infusion was discontinued and patients were transferred to the cardiac ICU where they were managed according to the institutional protocol.

II Statistical Methods
Data are presented as mean ± SD. Categorical data are presented as number of patients per category (n). Student's t-test was used to compare independent means. A chi-square test was used to compare categorical variables. P-values <0.05 were considered statistically significant.

Results
The two groups were similar with respect to age, weight, height, gender, body surface area (BSA) ( Table 1). Table 2 shows the PA catheter derived parameters in the two groups at various stages. The two groups were similar with respect to baseline PA catheter derived data. In Group I, the HR increased significantly at 1 min post-intubation and remained so throughout the study period. In Group II the HR increased significantly at 3 min after intubation but stabilised at 5 min post intubation. It again increased significantly at 5 min and 30 min after protamine administration. Comparison of HR between the two groups showed that although the HR was more in Group I at all points in time, it did not assume statistical significance. The MAP in Group I decreased significantly from baseline at 3 min post-induction and at 3 min postintubation and remained so throughout the study period. In Group II, the MAP decreased at 1 min post-induction and remained so throughout the study period. Between the groups comparison showed that the MAP was less in Group II at all times and became significantly less, 1 min postinduction. The stroke index (SI) decreased significantly in both the groups, 1 min post-induction and remained so throughout the study period, but it was not significantly different between the two groups. Likewise, the CI (cardiac index) decreased significantly from baseline in both the groups at 1 min post-induction and remained so throughout the study period. However, in Group II the CI recovered at 5 and 30 min after protamine administration. Although the CI was less in Group I at all-time points, it did not assume statistical significance.  The PCWP (pulmonary capillary wedge pressure) was significantly less in Group I at 5 and 30 min after protamine administration. There was no change in SVRI (systemic vascular resistance index) in the two groups. The PVRI (pulmonary vascular resistance index) decreased significantly in both the groups at 5 and 30 min after protamine administration. Comparison between the two groups showed that PVRI was significantly more in Group I at 1 min post-induction and at 1 min post-intubation.
The mixed venous oxygen saturation (SvO2) did not change significantly in both the groups when compared to baseline. The BIS value was maintained between 40 and 60 in both the groups at all times during the operative procedure. Tables 3-5 show the comparison of HR and MAP in the two groups during distal graft anastomosis of LAD, OM and RCA at 5 min intervals. The baseline was considered as the reading before induction of anaesthesia. In both the groups the HR increased and the MAP decreased significantly from the baseline at 5 min and remained so during the anastomosis. Comparison of the HR and MAP between the two groups showed that the HR was more in Group I becoming significant at 20 and 25 min and the MAP was less in Group II becoming significantly less 5 min after application of OTSS. Table 6 shows the comparison of intraoperative HR and MAP in the two groups after completion of the distal graft anastomoses till the patient was transferred to the cardiac ICU.    In Group I the HR was more than the baseline becoming significant at 10, 50, 60, 70, 80, 90, 110 and 120 min. in Group II the HR was more as compared to baseline but did not assume statistical significance except at 90 min. Between the Groups analysis showed that the HR was more in Group I at all times assuming statistical significance at 50 min only. The MAP was statistically less from 10 min throughout the study period in Group I as well as in Group II. Between group comparisons revealed that the MAP was significantly less in Group II at 40, 80 and 100 min. Table 7 shows the inotropic support required by the patients in the two groups. No inotropic support was required in 11 patients and 12 patients in Group I and Group II respectively. Seven patients in Group I and 5 patients in Group II required either Dopamine or Dobutamine. One patient in Group I and two patients in Group II required Adrenaline while six patients in both the groups required both Adrenaline and Dopamine as inotropic support. The mean number of days spent in ICU was 3.08±0.64 days in Group I and 3.36±1.25 days in Group II (Table 7, p=NS). One patient in Group II expired due to multi-organ failure following low cardiac output and one patient needed IABP support in Group II (p=NS). The time to extubation was not significantly different in the two groups.

Discussion
The results of the present study show that the HR and MAP were generally on the lower side in the group II throughout the study period but assumed statistical significance only during distal and proximal graft anastomosis. In particular, the intubation response by way of increase in HR was much less in group II and stabilized by 5 min after intubation. The accompanying hypotension at 1 minute after induction was more in group II, but it was clinically acceptable (82 mm Hg). The patients undergoing OPCAB are especially susceptible to develop hemodynamic changes during distal anastomosis of the coronary arteries. In the present study hemodynamic parameters during distal anastomosis of individual vessels is being reported. Comparison of the HR between the two groups during various distal graft anastomoses showed that the HR was in the range of 68 beats/min to 85 beats/min in group II vs. 85 beats/min to 100 beats/min in Group I. Considering the desirable HR of 70-80 beats / min during distal graft anastomosis in OPCAB group II patients maintained a much better HR [7]. The MAP was lower in this group during the distal anastomosis, but it was within the acceptable range (> 65 mm Hg). Despite maintaining lower HR and MAP in group II, there was no significant difference in the inotropic requirements or outcome (the length of stay in ICU or mortality).
In patients with CAD, mild myocardial depression (lower HR and MAP) is desirable and beneficial as it decreases the myocardial oxygen demand [8]. In this respect, the observed effects of dexmedetomidine in the present study can be considered as beneficial. However, extreme bradycardia and hypotension can be dangerous. This can be relevant in patients undergoing OPCAB, where the surgeon needs to manipulate the heart during distal anastomosis. Although with the improvements in the technology (suction-based stabilizers, apical positioners) and surgical expertise, the hemodynamic alterations are much less, they are not unknown [9,10]. Similar results (obtundation in the increase in HR and BP in response to intubation and skin incision, decrease in the variability of systolic arterial pressure and decrease in the incidence of hypertension and tachycardia during operation, before and after bypass) have been reported with dexmedetomidine in patients undergoing on pump CABG [4,[11][12][13]. After all the distal anastomoses, MAP was significantly lower but in the clinically acceptable range (>70 mm Hg) in group II at 40 min, 80 min, 110 min and 120 min. This time period represented the performance of proximal anastomosis with side biting aortic clamp in place. During this time, a lower systolic BP and HR is desirable as it is convenient for the surgeon to perform the anastomosis as well as to provide protection against dissection of the aorta.
Opioid-based anaesthetic technique along with benzodiazepines and inhalational agents have been largely used during OPCAB. It is well known that volatile anaesthetics possess dose-dependent myocardial depressant properties. Therefore, as a part of balanced anaesthesia technique, the sedative, hypnotic and amnestic properties of benzodiazepines have been used as an adjunct to opioids during cardiac surgery [14,15]. Dexmedetomidine is a more specific and selective alpha 2 agonist, producing dose-dependent sedation and analgesia. Although, dexmedetomidine-based anaesthesia has been found to produce relative bradycardia compared to midazolam-based anaesthesia, it has been shown to decrease isoflurane requirements to maintain hemodynamic parameters within predetermined limits and thus, dexmedetomidine is well appreciated as an anaesthetic adjunct with consistent results that it reduces anaesthetic requirements [11-13, 16, 17]. Use of dexmedetomidine has also shown a trend towards improved cardiac outcomes (decrease in the release of Troponin T in high-risk patients undergoing vascular surgery and decreased level of serum cardiac troponin I and creatine kinase MB in patients undergoing OPCAB relying primarily on tight control of heart rates [6,18]. BIS is now considered to have a reliable predictive power of adequate anaesthetic depth, thus could guard against the occurrence of major hemodynamic events during the induction period [19,20]. In the present study BIS values were maintained in a range of 48-58 in the patients who received dexmedetomidine infusion. This was comparable with the control group (BIS 49-62), in which patients received midazolam. The present study demonstrates that when used under-regulated doses using BIS monitoring, dexmedetomidine caused only mild (beneficial) effects on the HR and MAP and no extreme effects as reported in some of the earlier studies [21,22]. Future studies will be necessary to show if this provides any outcome benefits.

Conclusion
Dexmedetomidine is a viable option as an anaesthetic adjunct in a loading dose of 1µg/Kg followed by an infusion of 0.6 µg/Kg. However, one should be watchful and be prepared to deal with extreme bradycardia and hypotension.

Conflicts of Interest
None.

Funding
None.

Permission
None.