Year : 2009 | Volume
| Issue : 1 | Page : 7-14
Bis-guided evaluation of dexmedetomidine vs. midazolam as anaesthetic adjuncts in off-pump coronary artery bypass surgery (OPCAB)
Emad El-Din Mansour
Department of Anaesthesia, Faculty of Medicine, Ain Shams University, 24th Mohamad Al-Makreif Street, 6th zone, Nasr City, Cairo, Postal Code: 11371, Egypt
Emad El-Din Mansour
Department of Anaesthesia, Faculty of Medicine, Ain Shams University, 24th Mohamad Al-Makreif Street, 6th zone, Nasr City, Cairo, Postal Code: 11371
Source of Support: None, Conflict of Interest: None
|Date of Web Publication||18-Jul-2009|
| Abstract|| |
Background. To assess the efficacy of midazolam and dexmedetomidine as induction agents and adjuncts to anaesthesia during OPCAB surgery.
Patients and Methods. 107 patients scheduled for elective OPCAB surgery between 1st of January 2005 to 31 st of December 2007 were enrolled. Patients were randomly allocated into two groups Midazolam group (Group M, n=57) and Dexmedetomidine group (Group D, n=50). Patients in Group D (Dexmedetomidine group) received dexmedetomidine as initial i.v loading dose of 1 µg kg -1 over 1 minute (min) before induction of anaesthesia and 60 µg hr -1 continuous infusion thereafter until the end of surgery. Patients in group M (Midazolam group) received midazolam 0.1 mg kg -1 over 1 min before induction of anaesthesia and 2.5mg hr 1 continuous infusion thereafter until the end of surgery. Anaesthesia was maintained with continuous i.v infusion of sufentanil 0.2 µg kg -1 h -1 , study drug infusion at a rate of 10 ml h -1 , and rocuronium 0.5 mg kg-1 h -1 supplemented with sevoflurane as required. Induction doses as well as anaesthetic maintenance supplementation doses were guided by the BIS reading near 50. Data collection included haemodynamic parameters (HR, MAP, CI & SVR), BIS readings (T0-T7) and sevoflurane concentrations (T3-T7) were recorded at the following data points, T0= baseline pre-induction, T1= immediately post-induction T2= during laryngoscopy & intubation, T3= skin incision, T4= sternotomy, T5= during revascularization of the left anterior descending (LAD) artery, T6= during revascularization of the obtuse marginal (OM) artery, T7= with chest closure at conclusion of surgery.
Results. 5 patients in Group M and 3 patients in group D were excluded due to diversion to on pump technique. All baseline parameters were comparable among both groups. In group M (52 patients) SVR and BP had significantly decreased following induction (T1) compared to baseline (T0, p<0.0001), while HR and CI had significantly increased during T1 compared to baseline (T0, p<0.0001). Also parameters recorded thereafter were comparable to baseline values. In Group D (47 patients) all parameters recorded were comparable to baseline values with exception of HR that decreased significantly from T1-T7 compared to T0. BIS values recorded were comparable among both groups, however sevoflurane concentrations was significantly higher in Group M compared to group D (P<0.0001).
Conclusion. Midazolam can alter hemodynamic response following induction of anaesthesia; however such changes are reversible and returned to baseline. Dexmedetomidine is more haemodynamic stable and more potent anaesthetic adjuvant compared to midazolam in patients undergoing OPCAB surgery.
Keywords: OPCAB, Dexmedetomidine, midazolam, BIS and hemodynamics.
|How to cite this article:|
Mansour EE. Bis-guided evaluation of dexmedetomidine vs. midazolam as anaesthetic adjuncts in off-pump coronary artery bypass surgery (OPCAB). Saudi J Anaesth 2009;3:7-14
|How to cite this URL:|
Mansour EE. Bis-guided evaluation of dexmedetomidine vs. midazolam as anaesthetic adjuncts in off-pump coronary artery bypass surgery (OPCAB). Saudi J Anaesth [serial online] 2009 [cited 2019 Jul 17];3:7-14. Available from: http://www.saudija.org/text.asp?2009/3/1/7/51828
| Introduction|| |
The impact of OPCAB surgery on patient outcome, as judged by the end-points of mortality and morbidity, is still debated. However, if compared with on-pump revascularization, OPCAB surgery shows a slight trend towards fewer cardiac events for up to 3 years of follow-up  . The course of patients in the early postoperative period is usually improved with OPCAB surgery compared with on-pump surgery. The duration of ventilatory support, ICU length of stay, and hospital length of stay are significantly diminished in many studies  . During beating-heart surgery, the surgeon must displace the heart; compress the ventricular wall to obtain an adequate exposure of the anastomosis site. Thus, the anaesthetist must be prepared to handle severe haemodynamic alterations, transient deterioration of cardiac pump function, and acute intraoperative myocardial ischaemia. The team must be prepared for conversion to CPB in case of sustained ventricular fibrillation or cardiovascular collapse.
It is well appreciated that volatile anaesthetics possess dose-dependant myocardial depressant properties, moreover awareness during cardiac surgery is not uncommon due to opioid-based anaesthetic regimens  . Thus anaesthetists should balance between myocardial depressant effects of anaesthetics as well as possibility of awareness, rendering delivery of anaesthesia in such patient population a great challenge. In October 1996, bispectral index (BIS) achieved approval by the Food and Drug Administration as the first electroencephalogram (EEG)-based monitor of anaesthetic effect. BIS reduces complex EEG processing to a simple number ranging from 100 to 0. BIS decreases with increasing depth of anaesthesia and adequate level of anaesthesia is achieved with BIS ranging from 40 to 60 .
Recently adjuncts to anaesthetics in patients undergoing cardiac surgery are frequently used during cardiac surgery in an attempt to maintain adequate depth of anaesthesia and at the same time maintain haemodynamic stability specially in critical periods (intubation, skin incision, sternotomy, cardiac manupilations..etc). α2-adrenergic agonists decrease sympathetic tone, induce sedation, and decrease blood pressure (BP) and heart rate (HR) ,. Dexmedetomidine is a more specific and selective α2 agonist with 10-fold greater α2/α1- receptor selectivity and has a shorter duration of action than clonidine . It produces dosedependent sedation and analgesia. These properties make it theoretically a suitable agent for use as a part of an anaesthetic regimen. In patients having non cardiac surgery, perioperative administration of dexmedetomidine decreases the need for anaesthetics and induces sympatholysis with ensuing haemodynamic and neuroendocrine stability .
Midazolam is an agonist at the benzodiazepine receptor-a subunit of the central neuroinhibitory yaminobutyric acid-A receptors. Midazolam can be administered as an intravenous (i.v) bolus or as a continuous infusion, and its desirable clinical effects range from anxiolytic to hypnotic depending on the percentage of receptor occupancy rather than plasma concentrations of the drug . The sedative, hypnotic, and amnestic properties of benzodiazepines have been used as an adjunct to opioids during cardiac surgery. The interaction between some benzodiazepines and high-dose opioids has various effects on haemodynamic variables . Some reported advantages from the haemodynamic effects of midazolam in conjunction with an opioid include reduced opioid use and decreased stress responses during cardiac surgery.
The aim of this study is to evaluate the haemodynamic profile and the efficacy of dexmedetomidine in maintaining anaesthesia in patients undergoing OPCAB surgery compared with midazolam and guided by BIS monitoring.
| Patients and Methods|| |
Following institutional Ethics Committee approval and obtaining written informed consents, all patients aged 40-70 years, scheduled for elective OPCAB between 1st of January 2005 till 31 st of December 2007 were enrolled in this prospective, randomized double-blinded study. Exclusion criteria were myocardial infarction (MI) < 7 days prior to surgery, left ventricular ejection fraction (LVEF) < 35 %, left main coronary artery stenosis greater than 50 %, significant valvular dysfunction (over I/IV), severe insulin-dependent diabetes mellitus characterized by glycosylated haemoglobin >10 %, uncontrolled hypertension defined as mean arterial blood pressure >150 mmHg , hepatic dysfunction (patients Child B or C or evidence of cirrhosis by ultrasound), renal dysfunction (creatinine clearance <50ml/min), respiratory disorder (FVC <50% of expected values) , preoperative medication with clonidine or a-methyldopa and patients who were converted to on-pump CABG.
Patients were randomly allocated into two groups (randomization was performed with the help of a computer-generated random number sequence program). Patients in Group D (Dexmedetomidine group) received dexmedetomidine as initial i.v loading dose of 1 µg kg -1 over 1 minute (min) before induction of anaesthesia and 60µg hr -1 continuous infusion thereafter until the end of surgery. Patients in group M (Midazolam group) received midazolam 0.1 mg kg -1 over 1 min before induction of anaesthesia and 2.5 mg hr -1 continuous infusion thereafter until the end of surgery.
To ensure proper blinding, the studied drugs were prepared by the pharmacy, delivered to the operating room (OR) on the morning of surgery and identified as either loading dose 1( D group) or loading dose 2 (M group) and labeled by the patient name and medical record in a 10 ml syringe containing either dexmedetomidine in group D (1 µg kg -1 ), or midazolam in group M (0.1 mg kg -1 ) and was administered over 1 min by anaesthetist in charge who was blinded to the experimental protocol, and the infusion dose were also prepared by the pharmacy and identified as either infusion 1( D group) or infusion 2 (M group) and labeled by the patient name and medical record in a 50 ml syringe containing 300 µg dexmedetomidine in group D, 12.5 mg midazolam in group M and were infused by syringe pump at a rate of 10 ml h -1 (Dexmedetomidine or midazolam) both drugs exhibits clear appearance.
All patients received premedication in the form of lorazepam 2 mg orally at night of the operation and intramuscular morphine sulphate 0.1 mg kg -1 one hour prior to transfer to the OR. All patients were transferred to the OR receiving O2 via face mask at a flow rate of 5 L m-1 Before induction of anaesthesia, a large-bore peripheral venous line was inserted and five-lead ECG, pulse oximetry, and invasive arterial blood pressure monitoring via radial arterial line together with BIS electrode were connected. A Fiber-optic pulmonary artery catheter (7F, Baxter, Irvine, CA) was inserted under local infiltration anaesthesia for continuous monitoring of the cardiac output (CO) and mixed venous oxygen saturation (MVO2) as well as other derived parameters. Pre-induction baseline values of the HR, mean arterial blood pressure (MAP), cardiac index (CI), and systemic vascular resistance (SVR) were collected, then the loading dose of the studied drug was given. Anaesthesia was induced by sufentanil 1.5 µg kg -1 and intubation of the trachea was facilitated by rocuronium 0.9 mg kg -1 . Direct laryngoscopy was not performed unless achieving a BIS reading in the range of 40-60. The lungs were ventilated with a tidal volume of 8 ml/kg and FiO2 of 50% in air mixture while ventilatory rate adjusted to maintain PaCO2 of 32-36 mmHg.
Anaesthesia was maintained with continuous i.v infusion of sufentanil 0.2 µg kg -1 h -1 , study drug infusion at a rate of 10 ml h -1 , and rocuronium 0.5 mg kg -1 h -1 supplemented with sevoflurane as required. Induction doses as well as anaesthetic maintenance supplementation doses were guided by the BIS reading near 50. We chose BIS value 50 relying on previous work that demonstrated adequate depth of anaesthesia as well as haemodynamic stability at such value  .
All patients were operated on according to a standardized surgical protocol. After full midline sternotomy, the left internal mammary artery (LIMA) was harvested, together with an additional graft material (saphenous vein and/or left radial artery). Stabilization of the beating heart during distal vascular anastomosis was established with the Octopus 4® tissue stabilizer (Medtronic Inc., Minneapolis, MN, USA). After harvesting the LIMA, i.v heparin was administered at dose of 0.8- 1.0 mg kg -1 to achieve systemic anticoagulation during surgery. Intraoperatively, activated clotting time (ACT) was adjusted to a target of 250-280. The routine use of protamine after the procedure at a dose of 1 mg protamine per 100 units of heparin was standardized in all patients.
Data collection included haemodynamic parameters (HR, MAP, CI & SVR), BIS readings (T0-T7) and sevoflurane concentrations (T3-T7) were recorded at the following data points, T0 = baseline pre-induction, T1 = immediately post- induction T2 = during laryngoscopy & intubation, T3 = skin incision, T4 = sternotomy, T5 = during revascularization of the left anterior descending (LAD) artery, T6 = during revascularization of the obtuse marginal (OM) artery, T7 = with chest closure at conclusion of surgery. Total vasopressor (phenylephrine) dosage given as well as the need of inotropic support (epinephrine) was recorded. At the end of surgery, the total duration of surgery was also recorded.
Data are presented as mean ± SD, or number (percentage) as appropriate. The comparisons of haemodynamic variables (HR, MABP, and CI & SVR) and BIS at each time point between the two groups were done using repeated measure ANOVA where haemodynamics and BIS values are the dependant variables while Groups D and M were the independent variables. If statistical significance was reached, Tukey post hoc test was used to identify level of significance. Numerical demographic data, sevoflurane concentrations were compared using independent student's t-test, while categorical data were compared using Chi-square test or Fisher's exact test as appropriate. P < 0.05 was considered as statistically significant. Statistical software package (GraphPad InStat® version 3.00 for Windows, GraphPad Software Inc., San Diego, California, USA) was used for data analysis.
| Results|| |
During the study period 107 patients were enrolled, 57 patients in the midazolam group (Group M, n=57), while 50 patients in the dexmedetomidine group (Group D, n=50). During surgery, five patients in midazolam group, three patients in dexmedetomidine group, developed severe hypotension during distal vascular anastomosis unresponsive neither to phenylephrine nor to i.v fluid boluses necessitating conversion into on-pump CABG, and were excluded from the study. Thus, 52 patients in midazolam group versus 47 patients in dexmedetomidine group had completed the experimental protocol. Both groups were comparable regarding demographic data, preoperative and intraoperative variables [Table 1].
The pre-induction baseline variables were comparable among both groups. Following induction of anaesthesia (T1) MAP in the midazolam group was significantly lower compared to all values in the same group and also significantly lower at all time points to the other group (group D from T0-T7) p<0.0001. However, MAP values in the dexmedetomidine were comparable to all study points in the same group (T0-T7) and other group (group M) except at T1 [Figure 1]. Heart rate values were comparable at all study points among midazolam group (group M) with the exception of T1 where heart rate was significantly higher compared to all study points within the same group and also to the other group (group D) p<0.0001. In dexmedetomidine group (group D) heart rate was significantly lower from T1-T7 compared to T0 (p<0.0001), however heart rate values were comparable from T1-T7. Also heart rate was significantly lower from T1-T7 compared to midazolam group (group M), p<0.0001 [Figure 2]. Systemic vascular resistance index (SVR) in the midazolam group decreased significantly following induction (T1) compared to baseline (p<0.0001) and was also significantly lower than all values recorded after (T2-T7, p<0.0001). Additionally cardiac index following induction increased significantly compared to baseline (p<0.0001) and was also significantly higher than all values recorded after (T2-T7, p<0.0001).
In dexmedetomidine group (group D) SVR and CI were comparable among all study points. SVR recorded in T1 in the midazolam group (group M) was significantly lower to all values recorded in the dexmedetomidine group (p<0.0001). Otherwise, all values were comparable among dexmedetomidine and midazolam groups. Similarly CI recorded in T1 in midazolam group (Group M) was significantly higher to all values recorded in dexmedetomidine group (p<0.0001). Otherwise, all values were comparable among dexmedetomidine and midazolam groups.
Bispectral index (BIS %) was comparable among both groups at all study points [Figure 3]. Sevoflurane concentrations used were comparable within the same group from T3-T7 in both midazolam group (Group M) and dexmedetomidine group (Group D). However Sevoflurane concentrations used were significantly lower in dexmedetomidine group compared to midazolam group.
The total doses of phenylephrine used among both groups were comparable (487.5 ± 50.3 versus 463.5 ± 94.0 µg, p= 0.12) for Groups D and M, respectively. From T0-T4 none of patients among both groups required infusion of epinephrine.
However, From T5-T7 infusions of epinephrine among both groups were comparable in regard to number of patients and doses of epinephrine used.
| Discussion|| |
The main findings in the current study, were that both dexmedetomidine and midazolam anaesthesia during off pump coronary artery bypass surgeries are comparable in most circumstances with the exception of : 1) midazolam had more cardio-suppressive effect than dexmedetomidine immediately following induction of anaesthesia, 2) such effect was transient and returned to baseline thereafter, 3) dexmedetomidine based anaesthesia produces relative bradycardia compared to midazolam based anaesthesia, 4) anaesthetic requirements are decreased with dexmedetomidine based anaesthesia compared to midazolam anaesthesia.
Midazolam and sufentanil anaesthetic technique is common during cardiac surgery the use of such combination arise from potential sustained haemodynamic response following administration and maintenance . However such concept is not always true as results from earlier studies are conflicting, however most reports admits that hemodynamic changes are minimal and limited. Heikkila et al compared two doses of midazolam 0.075 mg and 0.15 mg kg -1 are either injected following high dose fentanyl (75µg kg -1 ) versus high dose fentanyl alone . They found that injection of midazolam during the induction of high-dose fentanyl anaesthesia seems to be followed by rapidly increased venous pooling and a moderately to severely decreased systemic arterial pressure (2432% MAP) compared to those of baseline. In our study, mean arterial blood pressure had dropped around 6% from that of baseline. Raza et al used a reverse technique in injecting midazolam (prior to sufentanil injection) and demonstrated that injection of midazolam per se had significantly decreased both systolic and diastolic blood pressure and SVR in 15 patients scheduled for elective CABG using conventional CPB . Similarly, our work not only had demonstrated such findings but also demonstrated increase in both heart rate and CI. Such moderate increase in heart rate had been demonstrated in other trials ,.
Slight increase in cardiac index was observed, such finding contradicts most of studies that reported rather decrease in cardiac output. Depression of cardiac output is multifactorial and attributed to decreased venous return (pooling of blood) or direct inhibition, evidenced by reduction in left ventricular stroke work index . We can not conclude with confidence, the main patho-physiological mechanism responsible for such finding; however we can suggest that such increase in CI may be attributed to increased heart rate. Another explanation may be that volume status of patient may play a role as haemodynamic response vary widely accordingly. Adams et al demonstrated in animal model that midazolam caused a significant decrease in systolic blood pressure (SBP) and an increase in heart rate (HR) during normovolaemia, but produced significant decreases in SBP, diastolic blood pressure (DBP), and mean arterial pressure (MAP) only during hypovolaemia .
Despite decrease in SVR, MAP and increase in heart rate and CI, such changes were transient and self limited and values recorded thereafter were comparable to baseline with efficient blunted response to laryngoscopy, intubation & surgical stimulation, and decrease in the incidence of tachycardia throughout the whole operation. These findings are supported by Jain et al in their multicenter study on 152 patients undergoing CABG under sufentanil-midazolam anaesthesia demonstrated that the haemodynamic responses to laryngoscopy & intubation, skin incision, and sternotomy were blunted .
Additionally, dexmedetomidine maintained the pump function & SVR after induction of anaesthesia while in midazolam treated patients, SVR decreased significantly with subsequent increase in CI compared to dexmedetomidine and to the pre- induction baseline values. These findings are consistent with the study of Jalonen et al who found that dexmedetomidine prevented the increase in CI and the decrease of SVR that were observed in the placebo-treated patients during anaesthesia induction and differ from those studies of patients having CABG and who received clonidine, in which either no effect on CI or SVR was seen or CI was decreased and SVR was increased during induction of anaesthesia compared with placebo .
An important finding in this trial is that dexmedetomidine anaesthesia produced significant and sustained decrease in heart rate, while all other haemodynamic variables were maintained. Such finding is of great interest as, tight heart rate control is an important factor that demonstrated reduced myocardial ischemia and Troponin T release in high risk patients undergoing vascular surgery . In a recent meta-analysis, dexmedetomidine use had showed a trend towards improved cardiac outcomes in non-cardiac surgery relying primarily on tight heart control . In the current study, patients receiving dexmedetomidine infusion had demonstrated significant and sustained decrease in heart rate from baseline values. Moreover; variations in heart rate were minimal with dexmedetomidine infusion among the 47 patients enrolled (Minimum heart rate was 62 and maximum was 72 beat/min from T1-T7).
Another important finding in the current study is that dexmedetomidine reduced sevoflurane anaesthetic requirements. This finding is supported by other reports in which the use of dexmedetomidine has been shown to decrease isoflurane requirements to maintain haemodynamic parameters within predetermined limits . while other investigators found that it reduces halothane requirements by up to 90% in rats . The adjuvant anaesthetic effect of dexmedetomidine is well appreciated, and had been investigated in diversity of patient populations and most studies rendered consistent results that dexmedetomidine decrease anaesthetic requirements .
BIS is now considered to have a reliable predictive power of adequate anaesthetic depth, thus could guard against the occurrence of major haemodynamic events during the induction period . In the current study, BIS readings of adequate anaesthetic depth were achieved among both groups at all time points of data collection [Figure 3]. In the current study, sufentanil infusion and test drug (dexmedetomidine in group D and midazolam in group M) were standardized among both groups and the target BIS value was solely achieved by manipulations of end tidal sevoflurane concentration. Thus the adjuvant anaesthetic effect of dexmedetomidine can be considered superior to that of midazolam, as BIS values achieved with dexmedetomidine were comparable to those of midazolam but at lower sevoflurane concentrations.
Results of the current study showed that the MAP & SVR were comparable among both groups during distal vascular anastomosis of the graft materials to the native LAD and OM territories indicating haemodynamic stability in both groups while the heart is being displaced. Thus, both anaesthetic techniques possess a safe and efficient approach to patients undergoing off pump procedures. However, dexmedetomidine can be considered superior to midazolam as anaesthetic adjuvant during off pump procedure, in the context of tight heart rate control and less inhalational anaesthesia requirements. The beneficial effects of tight heart rate control had been demonstrated, also the deleterious effects of inhalational anaesthetics on haemodynamics and myocardial function are well appreciated. Up to date there is no solid evidence whether reduction in the use of inhalational anaesthesia can have potential benefit on outcome.
In conclusion, dexmedetomidine and midazolam are useful adjuncts to anaesthesia for patients undergoing OPCAB surgery. The main drawback of midazolam is that following induction of anaesthesia non-fatal transient haemodynamic changes can occur that are usually self limited. Dexmedetomidine provided sustained haemodynamic stability regardless of surgical phase, with potential tight heart control and less utilization of volatile anaesthetics.
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[Figure 1], [Figure 2], [Figure 3]