Patients are commonly extubated following open-heart surgery in the intensive care unit. Haemodynamic responses occur during laryngoscopy, intubation and extubation . In patients having coronary artery bypass graft (CABG) surgery, tachycardia and hypertension may occur resulting in silent myocardial ischaemia [2,3]. Esmolol, is a short acting, highly cardioselective β-adrenergic receptor antagonist which is rapidly metabolized to inactive metabolites by plasma esterases [4,5].
Magnesium (Mg) has been used to inhibit haemodynamic response to intubation, as it has been shown to inhibit catecholamine release from adrenal medulla and adrenergic nerve endings in in vitro studies [6,7]. Mg administration is also recommended since it causes coronary artery vasodilatation in addition to catecholamine inhibition [8-11].
In this study, we aimed to compare the effects of esmolol and Mg on haemodynamic response in the pre-extubation period in the intensive care unit following CABG surgery.
Following written informed consent by the patients and Trakya University Medical Faculty Local Ethics Committee, 120 consecutive cases undergoing CABG surgery which would be extubated in the intensive care unit were included in this double blind study. Patients received their routine medications before the operation. For premedication, diazepam (Diazem tablet, Deva, Istanbul, Turkey) 5-10 mg was orally administered the night before the operation, and diazepam (Diazem tablet, Deva) 5-10 mg with morphine (Morphine HCL, Galen, Istanbul, Turkey) 5-10 mg was administered intramuscularly 1 h prior to operation. Anaesthesia induction was performed with fentanyl (Fentanyl Citrate, USP, Abbott, Istanbul, Turkey) 10 μg kg−1 and pancuronium bromide (Pavulon, Organon, Istanbul, Turkey) 0.1 mg kg−1 intravenous. Controlled ventilation was undertaken with an oxygen-air mixture in order to maintain end tidal carbon dioxide tension between 30-35 mmHg. For maintenance of anaesthesia, sevoflurane (Sevorane, Abbott, Istanbul, Turkey) 2-3% with fentanyl 5 μg kg−1 and pancuronium bromide were used. Coronary revascularization was performed in all cases under cardiopulmonary bypass. After the operation, the patients were transferred to the intensive care unit where they were attached to a ventilator providing intermittent positive pressure ventilation.
Those patients who had a preoperative ejection fraction <40%, a history of asthma, were receiving vasodilatator and inotropic support by infusion or were allergic to the drugs used were excluded from the study. All patients were on treatment with a β-blocker agent until 8 h prior to operation. In accordance with the routine procedure of the clinic, the patients who were awake, had spontaneous respiration, adequate muscular strength and a rectal temperature of 36.5-37°C were randomly divided into three groups once the decision to extubate had been made. The drugs were prepared by one anaesthesiologist and administered by another who did not know its identity. Group I received esmolol (Brevibloc; Baxter, Deerfield, IL, USA) 1 mg kg−1, group II (n = 40) received Mg 30 mg kg−1 and Group III (n = 40) received normal saline. Each drug was diluted to 20 mL and administered over 5 min. Extubation was performed at the end of the infusion. Nitroglycerin (Perlinganit, Melusin, Istanbul, Turkey) infusion was available and administered at the dose of 0.5-5 μg kg−1min−1 if there was a more than 20% increase in heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) or mean arterial pressure (MAP) until the haemodynamic status turned to that prior to medication before extubation. HR, SAP, DAP, Peripheral Oxygen Saturation (SPO2), Central Venous Pressure (CVP) and side effects were recorded before medication (t1), before extubation (t2), during extubation (t3) and 1 min after extubation (t4).
Descriptive statistics, one-sample Kolmogorov-Smirnov test for normal distribution and one-way analysis of variance for continuous variables were used for comparison between the groups, Bonferroni test and Dunnett T3 test were applied as appropriate. For the qualitative data, Pearson χ2 analysis was done. The Kolmogorov-Smirnov test was applied to the ones with an expected value <5. For the other data, a Kruskal-Wallis variance analysis was used for comparisons between groups, Mann-Whitney U-test was applied to the ones with significant differences for binary comparison. For within-group comparisons, paired t-test was used where there was repeated continuous data, and for others Wilcoxon signed ranks test was used.
There was no significant difference in patient characteristics, operation time or anaesthesia time between groups (Table 1). There was a significant difference in HR between t3 (P < 0.001) and t4 (P < 0.05). Further analysis showed that the HR was significantly lower in Group I compared to Groups II (P < 0.05) or III (P < 0.001) and also that HR values were significantly lower in Group II compared to Group III (P < 0.05) at time t3. HR was significantly lower in Group I than in Group III (P < 0.05) at time t4. In the within-group comparisons, no difference was seen in Group I. A significant increase was found at t3 (P < 0.001) and at t4 (P < 0.05) compared to t1 in Group II. There was also a significant increase at t3 (P < 0.001) and t4 (P < 0.001) compared to t1 in Group III (Table 2; Fig. 1).
SAP was significantly lower in Group I than in Group II (P < 0.001) or III (P < 0.001) at time t3. In the within-group evaluation, no difference was seen in Group I. A significant increase was found in Group II and Group III in t3 and t4 measurements compared to t1 measurements (P < 0.001) (Table 2; Fig. 2).
With respect to DAP, a significant difference was detected at times t3 (P < 0.001) and t4 (P < 0.05). On further analysis, DAP was significantly higher in Group III than in Groups I (P < 0.001) and II (P < 0.001) at time t3 and also higher in Group III than in Groups I (P < 0.05) and II (P < 0.05) at time t4. In the within-group evaluations, no difference was detected in Group I. A significant increase was detected in t3 (P < 0.001) and t4 (P < 0.05) measurements compared to t1 in Group II; in t3 (<0.001) and t4 (P < 0.001) measurements compared to t1 measurements in Group III (Table 2; Fig. 3).
When the MAP values were compared a significant difference was seen at t3 (P < 0.001) and t4 (P < 0.05). On further analysis, MAP was significantly lower in Group I than in Groups II (P < 0.001) and III (P < 0.001) and lower in Group II (P < 0.05) than in Group III at time t3 It was also lower in Group I than in Group III (P < 0.05) at time t4. In the within-group evaluations, no difference was found in Group I. A significant increase was found in t3 and t4 measurements compared to t1 measurements in Group II and III (P < 0.001) (Table 2; Fig. 4).
CVP values were lower in Group I than in Group III at t4 (P < 0.05). In the within-group evaluation, a significant increase was seen at t3 (P < 0.001) compared to t1 in Group I (Table 2). SPO2 was significantly lower at t4 in Group III than in Groups I (P < 0.05) and II (P < 0.05) (Table 2).
Nitroglycerin was needed in two patients in Group I, 13 patients in Group II and 27 patients in Group III (P < 0.001). Further analysis showed that it was significantly lower in Group I than in Groups II (P < 0.05) and III (P < 0.001), and significantly lower in Group II than in Group III (P < 0.05). No difference was found between the groups in terms of side effects and no hypotension or bradycardia related to esmolol was seen.
In this study, we have shown that esmolol and Mg decreased haemodynamic responses during extubation and that this was more prominent in the esmolol group. Esmolol is a β-adrenergic receptor antagonist with a very short duration of action and high cardio-selectivity. The reasons for preferring esmolol in this study are that it prevents postoperative myocardial ischaemia [12,13] and its short action depending on infusion speed. It has also been used to decrease cardiovascular responses during extubation .
Esmolol has been used in different doses in several studies [14-16]. Dyson and colleagues  administered esmolol over 30 s in 1, 1.5 and 2 mg kg−1 doses for extubation in patients having non-cardiac surgery. They determined that although tachycardia was prevented with 1 mg kg−1 of esmolol, systolic hypertension could not be adequately prevented. With a dose of 1.5 mg kg−1 the increase in the HR and systolic pressure was prevented and with 2 mg kg−1 both HR and systolic pressure increased when compared to the values gained before extubation. Kurian and colleagues  infused esmolol 0.5 mg kg−1 dL−1 before extubation following CABG and showed that esmolol decreases the incidence of myocardial ischaemia. In a similar study, Wang and colleagues  administered esmolol in doses of 0.5, 1, 1.5 and 2 mg kg−1 in order to suppress the haemodynamic response to extubation following elective cardiac surgery and reported that administration of esmolol in a dose of 1.5 mg kg−1 prevented the cardiovascular response to extubation without any side effects. In our study, esmolol was administered in a dose of 1 mg kg−1 to see if that would decrease haemodynamic responses to extubation without unwanted side effects such as bradycardia and hypotension.
Mg inhibits catecholamine responses and causes dilatation in the coronary circulation [8-11]. In anaesthetized dogs, a dose-dependent decrease in HR and systolic and diastolic pressures was observed after infusion of Mg . In human haemodynamic studies have shown a peripheral (predominantly arteriolar) vasodilator effect [18,19]. After the rapid infusion of a dose of 3 or 4 g of magnesium sulphate, a reduction of systolic arterial pressure occurred related to a decreased systemic vascular resistance. Positive inotropic and chronotropic effects compensated for the former by increasing the cardiac index, whereas pulmonary vascular resistance remained unchanged. In the study of Vigorito and colleagues  coronary vascular resistance decreased since coronary blood flow increased.
The stress of intubation and extubation is associated with catecholamine release. Mg reduces this release by an effect on the adrenal medulla and adrenergic nerve endings. In a comparative study, patients received thiopental and succinylcholine with or without Mg sulphate 60 mg kg-1 at anaesthesia induction. In the patients treated with Mg, a smaller increase in HR and systolic blood pressure was observed after intubation. Plasma concentrations of epinephrine and norepinephrine were markedly lower after intubation in the Mg-treated group .
In a prospective study concerning coronary patients, Puri and colleagues  compared haemodynamic changes during anaesthesia induction and intubation after infusion of Mg (50 mg kg−1) or lidocaine. The group treated with Mg showed a slight increase in mean arterial pressure and systemic vascular resistance and no decrease in cardiac output, as compared to the lidocaine group with equally good control of increased HR . In another study, the group treated with Mg showed a smaller hypertensive response during induction compared to placebo group, whereas early-reflex tachycardia was not controlled by Mg (60 mg kg−1) . Ashton and colleagues  found no increase in arterial pressure or HR but a moderate decrease in plasma catecholamine concentrations after intubation in a group treated with Mg (40 mg kg−1) alone before intubation. In all these studies, Mg administration before anaesthesia induction was associated with a good control of the adrenergic response during intubation.
In the previous studies, Mg was used in order to increase or prevent haemodynamic responses. The doses used in the previous studies were higher than 30 mg kg−1, the dose used in our study. The reason why we chose a lower dose was the fact that the haemodynamic response to extubation was considered to be less than the response to intubation. The low-dose Mg administration was found to decrease the haemodynamic responses better than the control group. A higher dose of Mg is recommended to inhibit haemodynamic responses.
In conclusion, we found haemodynamic responses to be decreased by the use of Mg and inhibited by the use of esmolol during extubation following CABG.
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