Although supplemental fentanyl has been widely used to blunt the hemodynamic responses to laryngoscopic intubation, its residual vagotonic effect may increase the risk of reflex bradycardia. We compared the incidence and severity of significant reflex bradycardia after a bolus injection of equivalent doses of fentanyl and remifentanil (control drug).
In this prospective, randomized, double-blind study, 220 adult patients undergoing major abdominal surgery were randomly assigned to receive fentanyl (1.5 µg/kg) or remifentanil (1.5 µg/kg). No anticholinergic prophylaxis was administered. Symptomatic reflex bradycardia was defined as a sudden decrease in heart rate to < 50 beats per minute (bpm) or to 50-59 bpm associated with a systolic arterial pressure < 70 mmHg in connection with surgical maneuvers. If bradycardia or hypotension developed, atropine or ephedrine was administered following a predefined treatment protocol.
In total, 188 subjects (remifentanil, 95; fentanyl, 93) were included. The proportion of subjects with symptomatic reflex bradycardia in the fentanyl group was similar to that in the remifentanil group (30.1% vs. 28.4%, respectively). Atropine and/or ephedrine were needed similarly in both groups. The differences between the group of 55 patients who presented with symptomatic reflex bradycardia were not statistically significant with respect to the lowest heart rate, anesthetic depth-related data (bispectral index and end-tidal sevoflurane concentration), or the proportion of causative surgical maneuvers.
Fentanyl (1.5 µg/kg) administered intravenously during anesthetic induction is unlikely to increase the incidence and severity of significant reflex bradycardia in patients undergoing major abdominal surgery.
Bradycardia and bradyarrhythmia in connection with certain surgical maneuvers, such as abdominal wall retraction or manipulation of the bowel or mesentery, are commonly encountered during major abdominal surgery. In most cases, these are short lived and rapidly respond to relief of surgical traction or anticholinergic administration [
Supplemental intravenous (IV) fentanyl has been widely used to blunt the hemodynamic response to laryngoscopy and tracheal intubation [
Therefore, in the present prospective, randomized, double-blind study, we evaluated whether IV fentanyl administered during induction of anesthesia increased the incidence or severity of clinically significant reflex bradycardia during major abdominal surgery. These effects were compared to an equivalent IV dose of a control drug, remifentanil, which was selected because of its ultra-short duration of action.
This study protocol was approved by our Institutional Review Board, and written informed consent was obtained from all subjects before study enrollment. In total, 220 surgical patients, aged 18-75 years, classified as American Society of Anesthesiologists physical status I or II and who were scheduled to undergo major abdominal surgery under general anesthesia, were enrolled. Exclusion criteria were patients with known cardiovascular disease, those taking drugs with known cardiovascular activity, and those with electrocardiogram (ECG) abnormalities including sinus bradycardia or tachycardia. An independent investigator evaluated all inclusion/exclusion criteria and randomized the subjects into two groups of 110 subjects each using a computer-generated random number table. These patients received either 1.5 µg/kg remifentanil (group R) or 1.5 µg/kg fentanyl (group F).
Because the optimal timing of a bolus injection of fentanyl and remifentanil to blunt cardiovascular intubation responses differs [
No premedication was administered to any patient. Heart rate (HR), arterial oxygen saturation, ECG, and bispectral index (BIS) were monitored continuously. Anesthesia was induced with 1.0 mg/kg propofol followed by an additional 10 mg every 5 s until loss of verbal contact. After loss of consciousness, the lungs were manually ventilated with 2% sevoflurane and 100% oxygen, and then 0.1 mg/kg vecuronium and the first syringe (either 1.5 µg/kg fentanyl or NS of an equal volume) were injected intravenously. Three minutes after administering the contents of the first syringe, the second syringe (1.5 µg/kg remifentanil or NS of an equal volume) was injected. Each syringe was injected over a 5-s period. Tracheal intubation was performed 2 min after injection of the second syringe. An arterial catheter for continuous monitoring of arterial blood pressure was inserted immediately after induction of anesthesia. The patient's lungs were then mechanically ventilated to maintain a partial pressure of end-tidal carbon dioxide of 30-40 mmHg.
Anesthesia was maintained with sevoflurane in combination with 67% air in oxygen. Depth of anesthesia was controlled by altering the inhaled sevoflurane concentration, based on the hemodynamic response to surgery and BIS value (target value, 40-60) at the discretion of the attending anesthesiologist. Neuromuscular block was monitored intraoperatively using a peripheral nerve stimulator at the ulnar nerve of the wrist. Muscle relaxation was supplemented with vecuronium to maintain a train-of-four count < 2 during the study period.
The study period was predefined as the first 2 h after the start of anesthetic induction, because the vagotonic effect of fentanyl almost disappears after that time [
Syringes containing atropine and ephedrine were always available in all cases. Atropine (0.5 mg) or ephedrine (4 mg) was administered if spontaneous return to the normal HR range was not observed after 10 s, depending on severity. This treatment protocol is described in
The primary outcome was the difference in the proportion of patients with symptomatic reflex bradycardia between groups R and F. In an unpublished preliminary study, in which the protocol was identical to the present study except for no use of opioids during anesthetic induction, we observed that symptomatic reflex bradycardia occurred in six of the 30 patients who underwent major abdominal surgery. Thus, the incidence of symptomatic reflex bradycardia was estimated to be 20% in group R. Because critical reflex bradycardia that does not respond to prompt cardiovascular drug therapy is rare in a clinical situation, we considered at least a 100% increase of this incidence in group F to be clinically significant. Based on these figures, and using α = 0.05 and β = 0.2 for the clinical study design incorporating two groups of equal size, we calculated that a sample size of 91 patients per group would be required. Therefore, we enrolled 110 patients per group to compensate for possible dropouts.
Categorical variables were compared using Pearson χ2-tests with a continuity correction or Fisher's exact test as applicable. Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Values for normally distributed variables are presented as mean ± standard deviation and compared using an unpaired two-tailed t-test. BIS values and end-tidal sevoflurane concentrations at the time of symptomatic reflex bradycardia, and at the onset time of symptomatic reflex bradycardia are reported as medians (interquartile range) and compared using an unpaired two-tailed t-test. SPSS ver. 13.0 (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. P values < 0.05 were considered statistically significant.
Of the 220 subjects, 32 did not complete the study. Fifteen patients in group R and 16 in group F required cardiovascular drugs because of cardiac instability, which developed irrespective of surgical vagal stimulation during the study period. One subject in group F was additionally excluded because of an incomplete study period, during which surgery was aborted after discovering advanced carcinoma. Finally, 95 subjects in group R and 93 subjects in group F were included in the analysis (
Both groups were similar in terms of demographic characteristics, baseline HR, and type of surgery (
In 55 patients presenting with symptomatic reflex bradycardia, the differences between the groups were not significant with respect to the lowest HR, anesthetic depth-related data (BIS value and end-tidal sevoflurane concentration), or the proportion of causative surgical maneuvers (
The main finding of our study was that 1.5 µg/kg fentanyl by bolus injection during anesthetic induction did not increase the incidence or severity of clinically significant reflex bradycardia during major abdominal surgery compared to that of an equivalent IV dose of remifentanil.
Although the incidence of reflex bradycardia has not yet been separately evaluated, the overall incidence of intraoperative bradycardia varies from 20 to 42% in the absence of anticholinergic prophylaxis [
In this study, eligible surgical procedures were limited to major abdominal surgery consisting of gastrectomy, colectomy, pacreatectomy, and major hepatobiliary surgery, which are surgical procedures with known potential for high vagal stimulation [
The mechanism of the oculocardiac reflex observed during strabismus surgery has been well established in many clinical studies and neuroanatomical investigations. However, detailed evidence for the pathway involved in reflex bradycardia during abdominal surgery is still lacking. Similar to the oculocardiac reflex observed during strabismus surgery, reflex bradycardia is commonly assumed to be caused by increased vagal tone. Mechanical manipulations of the viscera, mesentery, or abdominal wall stimulate the hepatic plexus, celiac plexus, splanchnic nerve, or vagus nerve. In turn, these afferent stimuli cause increased vagal activity in the heart, thereby leading to bradycardia and/or hypotension as an efferent response [
Thus, we hypothesized that residual excessive dominance of vagotonic activity caused by fentanyl administered during induction could increase the incidence and severity of reflex bradycardia during major abdominal surgery. Contrary to our hypothesis, a single dose (1.5 µg/kg) of IV fentanyl did not augment reflex bradycardia. This result was in contrast to the finding that the intraoperative use of opioids is associated with a higher incidence of oculocardiac reflex during pediatric strabismus surgery [
The usual recommended IV dose of fentanyl for attenuating hemodynamic responses to laryngoscopic intubation is 1.5-3.0 µg/kg [
No use of opioids during anesthetic induction was reasonable in the control group to clarify the influence of IV fentanyl administered during anesthetic induction on vagal-mediated reflex bradycardia during surgical procedures. However, no use of opioids during anesthetic induction did not blunt the hemodynamic responses of laryngoscopic intubation effectively in our preliminary study. Therefore, in this study, we chose remifentanil (1.5 µg/kg) as a control drug for comparison with fentanyl (1.5 µg/kg) because it has an ultra-short duration of action lasting an average of about 8 min [
When we designed this study, we wanted to deliver fentanyl or remifentanil during anesthetic induction in such a way that their peak site effects occurred at the same time; thus, most effectively attenuating the cardiovascular intubation response. The time required to reach peak effect-site concentration after a single bolus injection is 1-2 min for remifentanil and 5 min for fentanyl [
In this study, all episodes of symptomatic reflex bradycardia developed within 60 min after anesthetic induction (i.e., during the early part of the surgical period). The medians (interquartile range) of bradycardia onset times were 43.0 min (range, 32.0-51.0 min) in group R and 37.0 min (range 31.0-45.8 min) in group F. A possible explanation for this result is that repeated mechanical manipulations may lead to a reduced or fatigued reflex after the first manipulation. This phenomenon has also been reported for the oculocardiac reflex during strabismus surgery [
Some potential criticisms of our study exist. First, it may be suggested that routine use of anticholinergic premedication is sufficient for protecting the patient against excessive vagal tone mediated by surgical procedures. Although not consistently reliable, anticholinergic prophylaxis definitely decreases the incidence of reflex bradycardia [
The other major concern may be whether the depth of sevoflurane in both groups was comparable during surgical vagal stimulation. However, as the duration of surgical vagal stimulation was uncertain, and the strength of surgical stimuli is widely different in various surgical procedures, it was unethical to apply equally predetermined doses of sevoflurane during the study period. Previous studies [
Last, we excluded patients with known cardiovascular disease or those taking drugs with known cardiovascular activity from this study. Cardiac instability episodes occur frequently in these populations of patients during induction or maintenance of anesthesia, irrespective of surgical vagal stimulation. As a result, many patients would have been dropped out by our exclusion criteria (administration of cardiovascular drugs during the study period); thus, it may have been difficult to acquire a sufficient number of subjects. As vagally mediated reflex bradycardia can pose more risk to these populations [
In conclusion, compared to an equivalent IV dose of remifentanil, fentanyl (1.5 µg/kg) administered intravenously during anesthetic induction did not increase the incidence or severity of significant reflex bradycardia in patients undergoing major abdominal surgery. Therefore, this anesthetic technique is unlikely to increase the risk of reflex bradycardia, even during major abdominal surgery capable of invoking high vagal stimulation. However, as clinically significant reflex bradycardia occurs with a relatively high frequency (in up to 30% of patients undergoing major abdominal surgery), HR should be carefully monitored and appropriate treatments considered if significant bradycardia is observed.
Predefined treatment protocol for bradycardia and hypotension. Symptomatic reflex bradycardia was defined as a heart rate < 50 bpm or mild bradycardia (heart rate, 50-59 bpm) associated with a systolic arterial pressure < 70 mmHg, which corresponds to the shaded area.
Flow diagram for the study.
Demographic Characteristics of the Subjects and Type of Surgery
Data are mean ± standard deviation (SD) or number. ASA: American Society of Anesthesiologists.
Number (Proportion) of Patients with Reflex Bradycardia or Dysrhythmia Requiring Atropine and/or Ephedrine
Data are mean ± standard deviation (SD) or number (proportion). Bradycardia severity was graded as mild (50-59 bpm), moderate (40-49 bpm), or severe (< 40 bpm). Symptomatic reflex bradycardia was defined as a heart rate < 50 bpm or mildbradycardia associated with systolic arterial pressure < 70 mmHg.
Causative Surgical Maneuvers and Onset Time of Bradycardia, and Anesthesia Depth-related Data at the Moment of Bradycardia in 55 Patients Presenting with Symptomatic Reflex Bradycardia
Data are numbers (percent) or medians (interquartile range), BIS: bispectral index.