Remifentanil Prevents the Hemodynamic Response to Orotracheal Intubation
Ratan Alexander, MB, FRCA
Robert Hill, MB, FRCA
Habib E. El-Moalem, PhD
Tong J. Gan, MB, FRCA
Department of Anesthesiology
Duke University Medical Center
Durham, North Carolina
KEY WORDS: Anesthetic techniques, induction; opioid analgesics, remifentanil; tracheal intubation
Study Objective: To investigate the efficacy of remifentanil in preventing the hemodynamic response to laryngoscopy and orotracheal intubation in a simulated rapid sequence induction process in healthy patients.
Design: Double-blind, randomized, placebo-controlled.
Setting: Major teaching institution.
Patients: Forty healthy patients having general anesthesia for elective surgery.
Interventions: Patients were randomized to receive either saline (group S; n = 20) or remifentanil (1 µg/kg; group R; n = 20) as a bolus 1 minute before laryngoscopy.
Measurements: Heart rate and mean arterial pressure (MAP) were measured before induction of anesthesia (time 1), before intubation (time 2), and then every minute after intubation for 5 minutes (time 3 to 7).
Main Results: There was a significant increase in heart rate in group S after intubation (time 3 to 7) compared with baseline (time 1; P < .01). MAP also increased significantly at time 3 to 4 compared with baseline (P < .01). Remifentanil resulted in significant decreases in heart rate and MAP at all time points (time 2 to 7) after administration of the drug (P < .001). There was a highly significant difference in heart rate and MAP between the two groups at each time point, after induction of anesthesia, and until the end of the study period (time 2 to 7; P < .001).
Conclusions: Remifentanil 1 µg/kg prevents the rise in heart rate and MAP associated with laryngoscopy and orotracheal intubation.
Laryngoscopy and orotracheal intubation are associated with hemodynamic responses and a rise in plasma concentrations of catecholamines.1-2 The resulting tachycardia and hypertension may be associated with an increase in morbidity and mortality in some patients.3-5
Remifentanil is a new, ultra–short-acting, selective µ-receptor agonist.6 It has an onset of action that is similar to alfentanil (60 to 90 seconds)7 but is rapidly metabolized by nonspecific tissue and plasma esterase.6 Remifentanil (1 µg/kg) has been shown to obtund the pressor response following intubation after rapid sequence induction.8-9 Anesthesia was induced with thiopental (3-5 mg/kg), and muscle relaxation was achieved with either rocuronium (0.75 mg/kg) or succinylcholine (1 mg/kg).
We therefore conducted a double-blind, randomized study to investigate whether the administration of remifentanil (1 µg/kg) would attenuate the hemodynamic response following a simulated rapid sequence induction technique.
MATERIALS AND METHODS
Institutional review board approval was obtained for the study, and after obtaining written, informed consent, 40 patients (ASA physical status 1 or 2) were studied. Exclusion criteria included a history of previous difficulty with intubation or a suspected difficult airway, esophageal reflux or hiatus hernia, cardiovascular disease, hepatic or renal failure, allergies to any of the study drugs, and administration of sedative or narcotic drugs in the previous 24 hours. The patients’ airways were assessed using a modified Mallampati test, as described by Samsoon and Young.10
The patients were randomized in a double-blind fashion using a computer-generated table to one of two groups: group S (saline) received normal saline (5 ml), and group R (remifentanil) received remifentanil (1 µg/kg) diluted to 5 ml with normal saline. They were premedicated with midazolam (2 mg IV) 10 minutes prior to induction of anesthesia. Standard monitoring including electrocardiography (ECG), heart rate, noninvasive mean arterial pressure (MAP), and peripheral arterial hemoglobin oxygen saturation were commenced and baseline variables recorded (time 1).
After 3 minutes of preoxygenation, anesthesia was induced with propofol (2 mg/kg) at an infusion rate of 40 mg in 10 sec. Succinylcholine (1 mg/kg) was administered immediately followed by the study drug, given as a rapid bolus. At 60 sec, the measurements were repeated (time=2) and orotracheal intubation was performed within 30 seconds by one of three experienced anesthesiologists. Further measurements of MAP and heart rate were taken every minute postendotracheal intubation for 5 minutes (time 3-7). The anesthesiologists intubating the patient were unaware of which study drug had been administered. Anesthesia was maintained with Isoflurane 1%, nitrous oxide 66% in oxygen 33% and the patient was ventilated to normocapnia. No further stimulation was applied to the patient during the study period. Ephedrine 0.5 mg/kg was to have been administered if MAP <60 mm Hg.
The number of subjects enrolled were based on a power calculation of finding a 30% difference between the two groups in MAP with a baseline MAP of 90 mm Hg at alpha of 0.05 and beta of 0.2. Wilcoxon two-sample rank sum test was used to compare demographic data and MAP and heart rate at each time point. A Bonferroni correction was applied for the multiple comparisons. Repeated measures ANOVA and Wilcoxon singed rank test were used to compare time points 2 to 7 with time 1. The statistical tests had a 98% power to detect the observed difference at the 0.05 significance level.
Forty patients (2 groups of 20) completed the study. Patient demographic data was similar for both groups (Table 1). There was no difference in heart rate and MAP between group S and group R before induction of anesthesia (time=1). Changes in heart rate and MAP from time 1 to 7 are shown in Figures 1 and 2, respectively. Systolic arterial pressure and diastolic arterial pressure reflected similar changes as MAP and so are not reported.
The heart rate significantly increased following induction of anesthesia (time 2) in group S (P < .05) and increased further following intubation (time 3 to 7) compared with baseline readings (time 1; P < .01). There was a significant fall in heart rate in group R for the duration of the study (time 2 to 7) after induction of anesthesia compared with baseline readings (P < .001). There was a highly significant difference in heart rate between the two groups at each time point after induction of anesthesia (time 2 to 7; P < .001).
The MAP increased significantly after intubation in group S (time 3 to 4; P < .01). It significantly decreased however in group R after induction of anesthesia (time 2 to 7) compared with baseline for the study period (P < .001). The MAP was significantly higher in group S compared with group R for the duration of the study period following induction of anesthesia (time 2 to 7; P < .001).
Ephedrine was administered to three patients in group R for hypotension (MAP < 45 mm Hg). The hemodynamic results from these three patients were excluded from the calculation of the mean MAP and heart rate from the time of administration of the ephedrine.
We have shown that a bolus dose of remifentanil (1 µg/kg) administered after induction of anesthesia prevents the rise in heart rate and MAP associated with laryngoscopy and tracheal intubation. After administration of remifentanil, there was a significant fall in heart rate and MAP. This was partly due to the bradycardia associated with remifentanil and partly due to the vasodilation associated with administration of propofol and isoflurane. Patients in the placebo group exhibited an increase in heart rate, commonly seen after administration of propofol, as a reflex initiated by the decrease in systemic vascular resistance (SVR). The MAP rose significantly for the first 2 minutes after intubation compared with the baseline reading. A further reduction in SVR due to the vasodilator effect of isoflurane is the probable reason for the return of the MAP to similar values compared with baseline after time 4.
The use of remifentanil to prevent the rise in blood pressure and heart rate following laryngoscopy and intubation has been reported.8,9,11 McAtamney et al administered remifentanil in several doses as part of a rapid sequence technique using thiopental and rocuronium 0.75 mg/kg for induction of anesthesia.8 They showed that remifentanil (1 µg/kg) attenuated but did not prevent a rise in blood pressure and heart rate following intubation. In another study, the same group demonstrated similar findings with remifentanil (1 µg/kg) administered with thiopental (5 to 7 mg/kg) and tracheal intubation followed by succinylcholine (1 mg/kg).9 In these two studies, no premedication was administered.
Previous research has demonstrated that elevations in plasma catecholamine levels and MAP are significantly greater following intubation after induction of anesthesia with thiopental compared with propofol.12-14
Song et al14 compared two doses of remifentanil (0.5 and 1 µg/kg) with fentanyl (1 µg/kg). They found that although there was a significant reduction in MAP after induction of anesthesia and intubation compared with baseline (P < .05), the heart rate rose after intubation although not significantly in the 1 µg/kg remifentanil group. This may be accounted for by the timing of the administration of study drug in this assessment. During induction of anesthesia, patients were administered propofol (2 mg/kg) and succinylcholine (1 mg/kg) 1 minute after the study drug. The patients were intubated approximately 3 minutes after administration of the study drug. Given the rapid metabolism remifentanil, the plasma concentration of the drug at the time of intubation may have been less than the peak concentration. In the present study, patients were intubated within 90 seconds of the administration of remifentanil.
Succinylcholine is commonly used to facilitate endotracheal intubation for rapid sequence induction. In the present study, we simulated a rapid sequence intubation technique. Cricoid pressure was not administered, as none of the study patients were at risk of reflux of gastric contents. We felt that this maneuver would not have influenced the results and could have unnecessarily added to patient morbidity. We chose to administer the study drug following succinylcholine for the following reasons. Should IV access have been lost after administration of remifentanil but before the neuromuscular agent, this may have proved to be deleterious to the patient with “a full stomach”. We wanted to allow our patients to be fully awake before induction of anesthesia.
The ideal anesthetic drug for obtunding the pressor response should have a rapid onset of action, be safe and easily administered, and have a relatively short duration of action. The use of opioids to attenuate the pressor response has been previously described. Alfentanil (30 µg/kg) has been shown to obtund the rise in blood pressure and heart rate.15-16 With an onset of action of 1 minute, alfentanil can be administered with the induction agent as part of a rapid sequence. The rapid metabolism of remifentanil, however, makes this an ideal agent compared with alfentanil for surgery of short duration or when the effects of opioids may be undesirable for a prolonged period of time (e.g., cesarean section). However, three patients in the remifentanil group in this study required treatment for severe hypotension. Therefore, caution should be used when using this technique in patients who could be compromised by marked hypotension such as those with a fixed cardiac output sate.
We conclude that remifentanil (1 µg/kg) administered after propofol and succinylcholine anesthetic induction successfully prevents a rise in heart rate and MAP following laryngoscopy and tracheal intubation.
1. Russell WJ, Morris RG, Frewin DB, et al: Changes in plasma catecholamine concentrations during endotracheal intubation. Br J Anaesth 53:837-839, 1981.
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3. Fox EJ, Sklar GS, Hill CH, et al: Complications related to the pressor response to endotracheal intubation. Anesthesiology 47:524-525, 1977.
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9. O’Hare R, McAtamney, Mirakhur RK, et al: Bolus dose remifentanil for control of haemodynamic response to tracheal intubation during rapid sequence induction of anaesthesia. Br J Anaesth 82:283-285, 1999.
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12. Vohra A, Thomas AN, Harper NJ, et al: Noninvasive measurement of cardiac output during induction of anesthesia and tracheal intubation: thiopental and propofol compared. Br J Anaesth 67:64-68, 1991.
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15. Miller DR, Martineau RJ, O’Brian H, et al: Effects of alfentanil on the hemodynamic and catecholamine response to tracheal intubation. Anesth Analg 76:1040-1046, 1993.
16. Martineau RJ, Tousignant CP, Miller DR, et al: Alfentanil controls the hemodynamic response during rapid-sequence induction of anesthesia. Can J Anaesth 37:755-761, 1990.
Table 1. Demographic characteristics of patients in each group.
Data are mean ± SD.
Figure 1. Changes in heart rate from baseline (time 1) in saline group (u) and remifentanil group (n) after administration of study drug (time 2) and every minute after intubation for 5 minutes (time 3 to 7). Values are mean ± SD. n = 20 for each group.
*P < .001; group S versus group R.
†P < .05.
††P < .01; time 2 to 8 compared with baseline.
Figure 2. Changes in MAP from baseline (time 1) in saline group (u) and remifentanil group (n) after administration of study drug (time 2) and every minute after intubation for 5 minutes (time 3 to 7). Values are mean ± SD. n =20 for each group.
*P < .001; group S versus group R.
†P Ł .05.
††P < .01; time 2 to 8 compared with baseline.
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