Efficacy of Combination of Esmolol and Diltiazem for Attenuating Hemodynamic Response to Laryngoscopy and Intubation: A Prospective Randomized Study.

BACKGROUND: Laryngoscopy and tracheal intubation (LTI) are known to release catecholamines resulting in rise in heart rate (HR) and blood pressure. Various drugs have been studied till date to attenuate the sympathomimetic effects of laryngoscopy and intubation. AIMS: The aim is to study the effect and safety of esmolol, diltiazem, and their combination on pressor response of laryngoscopy and intubation. SETTING AND
DESIGN: This prospective, randomized double-blind study was designed to assess the efficacy of the combination of esmolol and diltiazem and compare it with esmolol and diltiazem when used alone, for attenuating the pressor response to laryngoscopy and intubation.
MATERIALS AND METHODS: One hundred twenty-four adult patients of physical status American Society of Anesthesiologists Classes I and II posted for elective surgery under general anesthesia requiring endotracheal intubation were randomly allocated (using computer-generated random numbers) into four groups of 31 each, in a double-blind fashion, to receive the test drug, i.e., saline (control), diltiazem (0.2 mg/kg), esmolol (1.5 mg/kg), or a combination (diltiazem [0.1 mg/kg] and esmolol [0.75 mg/kg]). The test drug was administered intravenously as a bolus after 1 min of injecting the muscle relaxant. LTI was performed after 2 min of the test drug. Hemodynamic data - HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) - were recorded at 1 min intervals after induction, until laryngoscopy and intubation, and at 1, 2, 3, 4, 5, and 10 min thereafter. STATISTICAL ANALYSIS: Statistical analysis was performed using one-way analysis of variance (ANOVA) for comparison among and between the groups. The Bonferroni's correction was applied when a significant difference was found between groups after applying ANOVA. Results were considered statistically significant at P ≤ 0.05.
RESULTS: In the control and diltiazem groups, a significant increase in HR (P ≤ 0.05) was observed after laryngoscopy. Esmolol and combination groups were associated with a significant fall in HR after administration of the test drug, and no significant rise was noted after laryngoscopy. HR was significantly less in the combination and esmolol groups as compared to the control till 5 min after LTI. As compared with the control, all the other groups were associated with a fall in SBP after the test dose, and this lasted for 5 min (P < 0.001) after laryngoscopy in the esmolol and combination groups and for 1 min (P < 0.001) in the diltiazem group. All groups were associated with a significant rise in DBP and MAP for 1-2 min after LTI (P < 0.001), except the combination group in which no change was noted. DBP and MAP were significantly less in the combination group as compared to the control, from 1 min after giving the test dose till 5 min (P < 0.001) after LTI.
CONCLUSION: Although esmolol and combination groups were both effective in controlling the increase in HR and SBP, only the combination group was effective in controlling the rise in DBP and MAP after LTI. HR, SBP, DBP, and MAP were significantly less in the combination group as compared to the control till 5 min after LTI. We recommend a combination of esmolol and diltiazem in appropriate doses for effectively attenuating the rise in HR and blood pressure responses during LTI.

INTRODUCTION

Laryngoscopy and tracheal intubation (LTI) may lead to an undesirable stress response, particularly in hypertensive patients.[12] Various techniques which are recommended to prevent the stress response include increasing the depth of anesthesia, limiting the duration of laryngoscopy to <15 s, and the use of various pharmacological agents such as intravenous (IV) and topical lignocaine, opioids, beta-blockers such as esmolol, calcium channel blockers such as verapamil, diltiazem, and nicardipine, and other agents such as magnesium sulfate, labetalol, nitroprusside, and nitroglycerine.[34567] None of the agents used so far has been completely satisfactory and the quest for an ideal agent to attenuate the stress response continues.

Diltiazem is a calcium channel blocker with a rapid onset of action. It effectively decreases the rise in blood pressure, but not the increase in heart rate (HR) associated with stress response.[7] Esmolol has been used as both bolus and infusion and is effective in controlling HR and arrhythmias. It is not as effective in controlling the rise in blood pressure.[8910] Atlee et al.[11] reported that when a combination of esmolol (1.0 mg/kg) and nicardipine (30 μg/kg) is used in half the doses, it is more effective in blunting the peak increase in blood pressure, resulting from laryngoscopy and intubation, than when either drug is used alone. We, therefore, hypothesized that a combination of esmolol and diltiazem would more predictably blunt the hemodynamic changes associated with laryngoscopy and intubation, than when either drug is used alone. Hence, this prospective, randomized double-blind study was designed to assess the efficacy of the combination of esmolol and diltiazem and compare it with esmolol and diltiazem when used alone, for blunting the rise in HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) after LTI.

MATERIALS AND METHODS

This prospective, randomized double-blind study was conducted in the Department of Anesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, after written informed patient consent and approval from the hospital ethics committee.

One hundred twenty-four normotensive adult patients in the age group of 20–60 years, of either gender, American Society of Anesthesiologists physical status classification I–II, scheduled for elective surgery under general anesthesia requiring endotracheal intubation, were included in the study. Exclusion criteria included patients with coexisting cardiorespiratory illness, with contraindication for beta-blockers or calcium channel blockers, and anticipated difficulty in intubation.

Using a computer-generated random number table, the patients were randomly allocated into four groups of 31 each to receive the test drug, i.e., Group A: IV saline (control group), Group D: IV diltiazem (0.2 mg/kg), Group E: IV esmolol (1.5 mg/kg), and Group C: combination of IV diltiazem (0.1 mg/kg) and IV esmolol (0.75 mg/kg). The patients were randomly assigned to one of the groups using computer-generated random numbers which were contained in a sealed envelope. Another anesthesiologist not involved in the study diluted the test drug to a volume of 10 ml in an unlabeled sterile syringe. Patient assessment and observations were recorded by the second author who was unaware of the test drug being administered.

All patients received oral alprazolam 0.25 mg the night before surgery. After arrival in the operating room, pulse oximetry, electrocardiography, and noninvasive blood pressure monitoring – SBP, DBP, and MAP – were established, and baseline values were obtained. Patients were induced with fentanyl (1 μg/kg) and thiopentone (5 mg/kg), and loss of eyelash was confirmed. Vecuronium (0.1 mg/kg) was administered to produce neuromuscular blockade, and intermittent positive pressure ventilation was instituted with oxygen in nitrous oxide (50:50) and isoflurane 0.4%. After 1 min of administration of the muscle relaxant, the test drug was administered IV as a bolus (in 10 ml saline), and after 2 min of the test drug, LTI was performed. All intubations were performed by an experienced anesthesiologist and accomplished within 15 s. Any kind of surgical stimulus was avoided for 10 min postintubation. Hemodynamic parameters were recorded preoperatively, i.e., baseline (B), postinduction (I), after giving the test drug (AT), 1 min after injection of test drug (AT1), and at 1, 2, 3, 4, 5, and 10 min after intubation (L1, L2, L3, L4, L5, and L10).

Anesthesia was maintained with oxygen, nitrous oxide, and isoflurane; muscle relaxation was achieved with intermittent doses of vecuronium bromide; and additional fentanyl was administered for analgesia. At the end of surgery, neuromuscular blockade was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 8 μg.kg-1, and trachea was extubated.

Statistical analysis

Power analysis based on the difference of 20% between the control and test groups (α = 0.05 and β = 0.1) for peak SBP and HR suggested that a sample size of 31 would be adequate in each group. Data are expressed as mean ± standard deviation. Demographic profile including age, weight, and doses of thiopentone and fentanyl was evaluated using Chi-square test. Statistical analyses of hemodynamic parameters and comparison with baseline was done using paired t-test. One-way analysis of variance (ANOVA) was used for comparison among and between the groups. The Bonferroni's correction was applied when a significant difference was found between groups after applying ANOVA. Results were considered statistically significant at P ≤ 0.05 (confidence interval of 95%).

RESULTS

A total of 132 patients were enrolled in the study. Six patients were excluded as laryngoscopy and intubation took longer than 15 s. Two more patients were excluded from the diltiazem group, as one patient developed hypotension and the other developed bradycardia, both of which were managed appropriately with drugs. Patient demographic characteristics, induction doses of thiopentone and fentanyl, and duration of laryngoscopy were similar between the groups [Table 1].

Table 1

Demographic characteristics, anesthetic doses, and duration of laryngoscopy among the study groups

Heart rate

A significant increase in HR was noted till 3 min (P < 0.001–0.002) after laryngoscopy in the control and diltiazem groups. In contrast, esmolol (P < 0.01) and combination (P < 0.003) groups were associated with a significant fall in HR after administration of the test dose, and no significant rise was noted after laryngoscopy. In the esmolol group, HR was significantly less than control from 1 min (P < 0.01) after giving the test dose till 5 min (P < 0.001) after laryngoscopy. In the combination group, a significant decrease in HR was noted after laryngoscopy till 5 min (P < 0.002) later, as compared to the control. In both esmolol and combination groups, HR was significantly (P < 0.002) less than diltiazem group from 1 min before till 2 min after laryngoscopy. There was no difference in HR between esmolol and combination groups and between diltiazem and control groups [Table 2 and Figure 1].

Table 2

Changes in heart rate as compared to the baseline

Figure 1

Heart rate variability among esmolol, diltiazem, combination, and control groups

Blood pressure (systolic, diastolic, and mean arterial pressure)

There was a significant decrease in SBP in all the groups after induction, as compared to the baseline. The control group was associated with a significant rise in SBP after laryngoscopy which lasted till 2 min (P < 0.001). In contrast, a significant decrease in SBP occurred after 1 min (P < 0.01), 2 min (P < 0.001), and 3 min (P < 0.001) of LTI in the combination, esmolol, and diltiazem groups, respectively, and this lasted till 10 min in all the groups. As compared with the control, all the other groups were associated with a fall in SBP after the test dose, and this lasted for 5 min after laryngoscopy in the esmolol and combination groups and for 1 min in the diltiazem group. There was no difference between esmolol and combination groups [Table 3 and Figure 2].

Table 3

Changes in systolic blood pressure as compared to the baseline

Figure 2

Systolic blood pressure variability among esmolol, diltiazem, combination, and control groups

A fall in DBP and MAP was noted in all the groups after induction, as compared to the baseline. All groups except combination were associated with a significant rise in DBP and MAP after laryngoscopy. This lasted for 2 min in the control and diltiazem groups and for 1 min in the esmolol group. Subsequently, the DBP and MAP fell between 3 and 4 min after laryngoscopy in all the groups except for the control, as compared to the baseline. In the combination group, DBP and MAP were significantly less than control from 1 min after giving the test dose till 5 min (P < 0.001) after laryngoscopy. On comparing diltiazem with esmolol, a significant decrease in MAP (P < 0.002) was noted in the former after the test dose, but no significant difference was found after laryngoscopy [Tables 4, 5 and Figures 3, 4].

Table 4

Changes in diastolic blood pressure as compared to the baseline

Table 5

Changes in mean arterial pressure as compared to the baseline

Figure 3

Diastolic blood pressure variability among esmolol, diltiazem, combination and control groups

Figure 4

Mean arterial pressure variability among esmolol, diltiazem, combination, and control groups

DISCUSSION

The hemodynamic consequences of laryngoscopy and endotracheal intubation are well established. Both beta-blockers and calcium channel blockers have consistently been shown to obtund hemodynamic responses to laryngoscopy and intubation.[78910] The former is more effective for obtunding tachycardia[8910] and the latter for suppressing the pressor effects of intubation.[7] A combination of both may, therefore, be able to provide a more efficacious suppression of hemodynamic sequelae as compared to either drug alone.

Esmolol and the combination of esmolol and diltiazem were associated with a significant fall in HR after administration of the test dose, and both were effective in controlling HR till 5 min and 3 min, respectively, after LTI. In a study on the efficacy of antidysrhythmic drugs, Singh et al. concluded that prophylactic treatment with esmolol (2 mg/kg) is most effective in blunting HR response to laryngoscopy and intubation.[12] Studies done by Kumar et al. and Gupta and Tank also showed that esmolol (2 mg/kg) given 90 s and 3 min before intubation, respectively, prevents a rise in HR.[1314]

Diltiazem alone was no different from control as both were associated with a significant rise in HR till 3 min after laryngoscopy. Similar to our study, Lee et al. and Singh et al. found that diltiazem (0.3 mg/kg) did not attenuate the increase in HR, when administered alone.[1516] This was in contrast to a study by Sarkar et al. which showed that attenuation in HR response after laryngoscopy was comparable between diltiazem and esmolol.[17] Perhaps, this is attributed to the fact that they had administered diltiazem (0.2 mg/kg) 1 min before laryngoscopy and intubation, unlike our study, in which we had administered diltiazem 2 min before LTI.

All groups were associated with a significant fall in the SBP, DBP, and MAP after induction as compared to the baseline. The control group was associated with a significant rise in SBP till 2 min after laryngoscopy. As compared to the control, esmolol and the combination groups were effective in preventing a rise in SBP till 5 min and the diltiazem group till 1 min after LTI. However, no difference was found between esmolol and combination groups. This is consistent with studies done by Singh et al. and Kumar et al., who showed that esmolol in a dose of 2 mg/kg, blunts the SBP response postintubation.[1213] Mikawa et al. showed that diltiazem in a dose of 0.2-0.3 mg/kg, successfully suppresses the pressor response to intubation, and its action is rapid and short.[18] Fujii et al similarly showed that esmolol and diltiazem attenuate the rise in SBP after laryngoscopy, as compared to control.[19]

All groups except combination were associated with a significant rise in DBP and MAP immediately after laryngoscopy, as compared to the baseline. In the combination group, the DBP and MAP remained less than control till 5 min after LTI. Atlee et al.[11] concluded that a combination of esmolol and nicardipine (one-half dose each) was effective in controlling rise in SBP, DBP, and MAP. We did not find any difference between diltiazem, esmolol, and control groups for preventing rise in DBP after LTI. Diltiazem and esmolol were better than control for preventing increase in MAP for 1 min and 5 min, respectively, after LTI; however, there was no significant difference between the two. To the best of our knowledge, till date, no studies have been done using a combination of esmolol and diltiazem to blunt pressor response to laryngoscopy and intubation. Kumar et al. showed that both diltiazem and esmolol were effective in controlling DBP after laryngoscopy and intubation; however, they did not record the effect on MAP.[13] In a study done by Parvez et al., it was concluded that esmolol is a better agent than diltiazem for attenuating pressor response to laryngoscopy and intubation (HR, DBP, and rate pressure product) in controlled hypertensives.[20]

Limitation of the study

Very few studies have used drugs in combination to blunt hemodynamic sequelae of LTI. Whether the combination doses of esmolol and diltiazem will be effective in attenuating the pressor response of laryngoscopy and intubation in hypertensive patients needs further evaluation.

CONCLUSION

Esmolol and the combination groups were both effective in blunting the rise in HR and SBP after LTI. However, only the combination group was found to be effective in preventing a rise in HR, SBP, DBP, and MAP. A combination of drugs offers the advantage of both the drugs while at the same time reduces their adverse effects due to decreased dosages. We, therefore, conclude that a combination of esmolol and diltiazem in appropriate doses can be used effectively and safely for attenuating hemodynamic responses during LTI.

Key notes

Layngoscopy and Intubation are known to be critical events during general anesthesia.

This leads to transient but significant rise in heart rate and blood pressure.

Various pharmacological methods as well as modification in anesthesia techniqueshave been studied to blunt the response.

Though Esmolol and Diltiazem have different mechanisms of action, when used in combination they were observed to be more effective in attenuating hemodynamic stress response than when used alone.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.