Anesth Analg 2003;96:132-135
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Propofol-Nitrous Oxide Anesthesia Enhances the Heart Rate Response to Intravenous Isoproterenol Infusion
Takashi Horiguchi, MD, and
Toshiaki Nishikawa, MD
Department of Anesthesia and Intensive Care, Akita University School of Medicine, Japan
Address correspondence and reprint requests to Takashi Horiguchi, MD, Department of Anesthesia, Akita University School of Medicine, Hondo 1–1-1, Akita-City, Akita 010–8543, Japan. Address e-mail to thorigu{at}doc.med.akita-u.ac.jp
 |
Abstract
|
|---|
Heart rate (HR) response to IV atropine is attenuated during propofol-nitrous oxide (N2O) anesthesia. We studied the effects of propofol-N2O anesthesia on isoproterenol-induced HR changes. The control group (n = 15) received no propofol and no N2O. Patients in the propofol-N2O group (n = 21) received IV propofol 2.5 mg/kg over 1 min followed by a continuous infusion of propofol 10 mg · kg-1 · h-1. After tracheal intubation, anesthesia was maintained with propofol 5 mg · kg-1 · h-1 and 67% N2O in oxygen. All patients in both groups received IV isoproterenol at incremental infusion rates (2.5, 5, 7.5, 10, 12.5, 15, and 17.5 ng · kg-1 · min-1 for 2 min at each dose) until HR increased more than 20 bpm from baseline values. At the end of each infusion period, hemodynamic data were collected. The HR response to isoproterenol 7.5 ng · kg-1 · min-1 was increased more in the propofol group than in the control group (20 ± 5 versus 14 ± 4 bpm; P < 0.05). During the isoproterenol infusion at 10 ng · kg-1 · min-1, HR increased by more than 20 bpm in all patients in the propofol group but in only 31% of patients in the control group (P < 0.0001). These results suggest that continuous isoproterenol infusion might be useful when a large dose of atropine is ineffective in restoring normal HR during propofol-N2O anesthesia.
IMPLICATIONS: We demonstrated that the heart rate response to IV isoproterenol infusion is enhanced during propofol-nitrous oxide anesthesia. This suggests that continuous isoproterenol infusion may be useful when a large dose of atropine is ineffective for restoration of normal heart rate in patients receiving propofol-nitrous oxide anesthesia.
|
Introduction
|
|---|
Bradycardia is one of the adverse events associated with propofol anesthesia. When compared with other anesthetics, propofol significantly increased the risk of bradycardia by a factor of 2.5 (1). Several clinical reports have also implicated propofol as causing intraoperative bradyarrhythmias (2,3). Furthermore, the heart rate (HR) response to IV atropine is attenuated during propofol anesthesia (4,5).
Based on these considerations, a potent ß-adrenergic agonist such as isoproterenol may be required in certain patients receiving propofol when a large dose of atropine, as much as 20–30 µg/kg, is ineffective for the treatment of bradycardia (5). However, no clinical investigation has systematically studied the infusion rate-related hemodynamic interaction between propofol and isoproterenol in humans. We hypothesized that the HR response to IV isoproterenol would be altered during propofol-nitrous oxide (N2O) anesthesia compared with the awake state. In the current study, we compared the HR response to IV isoproterenol infusion between awake and propofol-N2O anesthetized patients and evaluated the hemodynamic interaction between propofol and isoproterenol.
|
Methods
|
|---|
Thirty-seven adult patients, ASA physical status I or II, aged 20–48 yr old, and undergoing a variety of general surgical procedures were studied. Our local ethics committee approved the study, and written informed consent was obtained from each patient. Patients with a history of cardiovascular disorders, diabetes, disorders known to affect autonomic functions, and those taking medications known to affect cardiovascular functions were excluded. All patients received 20 mg of famotidine orally as preanesthetic medication 90 min before arrival in the operating room.
On arrival in the operating room, a 20-gauge IV cannula was inserted, and lactated Ringer’s solution was administered at a rate of 10 mL · kg-1 · h-1 throughout the study. Standard lead II electrocardiography (ECG) and automated blood pressure (BP) cuff on the contralateral arm were applied. HR was determined as an average of 4-s intervals recorded on the ECG monitor, and mean BP was electronically measured.
The patients were randomly assigned to one of two groups. Patients in the control group (n = 15) received no anesthetic medication. After preoxygenation, patients in the propofol group (n = 22) received IV propofol 2.5 mg/kg over 1 min followed by a continuous infusion of propofol 10 mg · kg-1 · h-1. Intubation of the trachea was facilitated with IV vecuronium 0.2 mg/kg, and anesthesia was maintained with propofol 5 mg · kg-1 · h-1 and 67% N2O in oxygen. Mechanical ventilation was adjusted to maintain the ETCO2 at approximately 35 mm Hg.
We obtained stable hemodynamics 10 min after lying quietly on the operating table in the control group and 10 min after tracheal intubation in the propofol group. All patients in both groups received IV isoproterenol (Nikkenkagaku Co, Ltd, Tokyo, Japan) at incremental infusion rates (2.5, 5, 7.5, 10, 12.5, 15, and 17.5 ng · kg-1 · min-1 for 2 min at each dose) with a controlled infusion pump (TE-312, Terumo Co, Ltd, Tokyo, Japan) until the HR increased by more than 20 bpm more than the baseline values before surgical stimulation. Isoproterenol chloride solution was diluted with normal saline to a concentration of 4 µg/mL. HR and BP were measured at 1-min intervals until the end of each infusion period, whereas the ECG was monitored continuously. Values of HR and BP at the end of each infusion period were recorded and subjected to data analyses because the HR response reached a plateau in every patient at 1–2 min after each increase in the isoproterenol infusion rate. If systolic BP decreased to less than 80 mm Hg and HR less than 50 bpm, rescue treatment was given. That patient was then excluded from subsequent data analyses. Changes in HR were plotted against the isoproterenol infusion rates of 2.5, 5.0, and 7.5 ng · kg-1 · min-1 because a HR of more than 20 bpm was noted at an isoproterenol infusion rate of 7.5 ng · kg-1 · min-1 in 16 of 20 patients in the propofol group. The cumulative percentage of patients in whom the HR increased more than 20 bpm was also plotted against the isoproterenol infusion rate.
Data are expressed as mean ± SD. Statistical analysis was performed by two-way analysis of variance to compare changes in hemodynamic variables between groups. When a significant difference was identified, this was followed by an unpaired Student’s t-test with Bonferroni’s correction. Intergroup differences in demographic data were also compared by an unpaired Student’s t-test or 
2 analysis. Changes in hemodynamic variables over time within each group were analyzed by repeated-measures analysis of variance followed by paired Student’s t-test. Testing for significance in the incidence of positive HR responses after isoproterenol infusion between the two groups was accomplished by 2 analysis. P < 0.05 was considered the minimum level of significance.
|
Results
|
|---|
There were no significant differences between the groups with respect to age, weight, and height (Table 1). One patient in the propofol group required pharmacological treatment for hypotension (systolic BP <80 mm Hg). This patient was excluded from the study. No patient developed a HR <50 bpm. HR values remained unchanged after the induction of anesthesia in the propofol group (Table 2). There were also no differences between groups in basal HR (before isoproterenol infusion). Because systolic BP decreased significantly in the propofol group after the induction of anesthesia, baseline mean BPs (before isoproterenol infusion) in patients who received propofol were significantly lower than in those not receiving propofol (Table 2).
The changes in HR were greater in patients in the propofol group in whom the isoproterenol infusion at 7.5 ng · kg-1 · min-1 caused a HR increase of 20 ± 5 bpm, as compared with an increase of 14 ± 4 bpm in the control group (P < 0.05; Fig. 1). When isoproterenol was infused at a rate of 10 ng · kg-1 · min-1, HR increased by more than 20 bpm in all patients of the propofol group but in only 31% of patients in the control group (P < 0.0001 versus the control group; Fig. 2).
View larger version (20K):
[in this window]
[in a new window]
|
Figure 1. Heart rate (HR) responses to IV isoproterenol infusion of 2.5, 5.0, and 7.5 ng · kg-1 · min-1 in patients receiving propofol of 0 (n = 15) and 5 mg · kg-1 · h-1 (n = 20). Mean ± SD. *P < 0.05 versus control (awake).
|
|
View larger version (19K):
[in this window]
[in a new window]
|
Figure 2. The cumulative percentage of patients whose heart rate (HR) increased more than 20 bpm from baseline values after the IV isoproterenol infusion in patients receiving no propofol (control) or 5 mg · kg-1 · h-1.
|
|
At an isoproterenol infusion rate of 2.5, 5.0, and 7.5 ng · kg-1 · min-1, systolic and diastolic BPs decreased significantly in the propofol group, but systolic, mean, and diastolic BPs remained unchanged in the control group. There were significant differences between the control and propofol-N2O groups in systolic, mean, and diastolic BPs at an isoproterenol infusion rate of 2.5 and 5.0 ng · kg-1 · min-1 (Table 2). No patient in both control and propofol groups developed any arrhythmia after isoproterenol infusion. There were no other adverse effects related to isoproterenol infusion or propofol-isoproterenol interaction.
|
Discussion
|
|---|
Our main finding is that propofol-N2O anesthesia enhances the HR response to IV isoproterenol infusion compared with awake, nonventilated individuals. No detrimental effects related to propofol, no increased incidence of arrhythmia because of isoproterenol, and no serious propofol-isoproterenol interactions were observed.
HR did not change after the induction of propofol anesthesia in the current study, as described previously (6,7). Because no significant difference was found in baseline HR (before isoproterenol infusion) between the control and propofol groups, the greater HR response to the isoproterenol infusion in the propofol group is most likely an effect of propofol per se.
The dose-response relationships between the infusion rate of isoproterenol and HR responses demonstrated in this study indicate that HR responses to isoproterenol were significantly enhanced during propofol-N2O anesthesia as compared with no anesthetic medication. Although the mechanisms of this finding remain unclear, it is likely to be the manifestation of alterations in the balance between sympathetic and parasympathetic influences on the heart (8). Deutschman et al. (7), using HR variability analysis, showed that propofol anesthesia reduced parasympathetic tone to a lesser degree than sympathetic tone. Furthermore, the HR response to IV isoproterenol infusion in awake subjects was increased after IV atropine 0.04 mg/kg, suggesting that there is an increase rather than a decrease in cardiac vagal tone during a continuous isoproterenol infusion (9). In other words, it seems that increased sympathetic tone during the isoproterenol infusion is accompanied by an increase in vagal tone in awake patients but not in propofol-anesthetized patients. Therefore, based on these previous studies, the enhanced difference in HR responses to IV isoproterenol infusion during propofol anesthesia may primarily be because of propofol-induced suppression of the parasympathetic nervous system.
An IV bolus of isoproterenol causes peripheral vasodilation, a decrease in mean BP, and a baroreceptor-mediated tachycardia caused by reflex withdrawal of cardiac vagal tone (10). In contrast, a continuous infusion of isoproterenol causes an increase in vagal tone in awake subjects (9), whereas a continuous infusion of propofol markedly impairs reflex tachycardia and sympathetic responses to hypotension (11). However, the decrease in BP caused by the isoproterenol infusion in our study might have partly altered the baroreceptor-mediated HR response in propofol-N2O anesthetized patients.
Propofol acted in a dose-dependent, competitive manner to antagonize ß-adrenoceptor binding in rat myocardial membranes, and the positive chronotropic action of isoproterenol was antagonized by propofol at a concentration of 200 µM but not at 100 µM and less (12). However, the negative chronotropic effect of propofol does not seem to play a role with clinical doses because plasma concentrations of propofol range from 3 to 90 µM in clinical settings (13).
There are several limitations in our study. First, we compared awake patients with anesthetized patients and spontaneously breathing patients with mechanically ventilated patients. Second, because we did not measure baroreceptor activity, we need to perform further investigation concerning the baroreceptor-mediated HR response to IV isoproterenol. Third, our current study did not examine the anesthetic effects of N2O alone or of propofol alone on the HR response to isoproterenol infusion. Last, we used vecuronium for tracheal intubation in the propofol group. Although drug interactions among vecuronium, propofol, and isoproterenol remain unclear in humans, it is reported that vecuronium did not exert any influence on the positive cardiac responses to isoproterenol in the cat (14) and guinea pig (15).
In conclusion, propofol anesthesia enhances the HR response to IV isoproterenol infusion, possibly because of propofol-induced depression of the parasympathetic nervous system. This finding suggests that continuous isoproterenol infusion may be useful when a large dose of atropine is ineffective in restoring normal HR in patients receiving propofol-N2O anesthesia. However, the potential risk of hypotension with the use of isoproterenol must be considered, particularly in patients with cardiac disease or patients receiving perioperative ß blockers.
|
Footnotes
|
|---|
Presented, in part, at the Annual Meeting of the American Society of Anesthesiologists, Dallas, TX, October 12, 1999.
|
References
|
|---|
- Tramer MR, Moore RA, McQuay HJ. Propofol and bradycardia: causation, frequency and severity. Br J Anaesth 1997; 78: 642–51.[Abstract/Free Full Text]
- Baraka A. Severe bradycardia following propofol-suxameth-onium sequence. Br J Anaesth 1988; 61: 482–3.[Abstract/Free Full Text]
- James MF, Reyneke CJ, Whiffler K. Heart block following propofol: a case report. Br J Anaesth 1989; 62: 213–5.[Abstract/Free Full Text]
- Cross G, Gaylard D, Lim M. Atropine-induced heart rate changes: a comparison between midazolam-fentanyl-propofol-N2O and midazolam-fentanyl-thopentone-enflurane-N2O anaesthesia. Can J Anaesth 1990; 37: 416–9.
- Horiguchi T, Nishikawa T. Heart rate response to intravenous atropine during propofol anesthesia. Anesth Analg 2002; 95: 389–92.[Abstract/Free Full Text]
- Coates DP, Monk CR, Prys-Roberts C, Turtle M. Hemodynamic effects of infusions of the emulsion formulation of propofol during nitrous oxide anesthesia in humans. Anesth Analg 1987; 66: 64–70.[Abstract/Free Full Text]
- Deutschman CS, Harris AP, Fleisher LA. Changes in heart rate variability under propofol anesthesia: a possible explanation for propofol-induced bradycardia. Anesth Analg 1994; 79: 373–7.[Abstract/Free Full Text]
- Yamaguchi H, Dohi S, Sato S, Naito H. Heart rate response to atropine in humans anaesthetized with five different techniques. Can J Anaesth 1988; 35: 451–6.[Abstract/Free Full Text]
- Arnold JMO, McDevitt DG. Vagal activity is increased during intravenous isoprenaline infusion in man. Br J Clin Pharmacol 1984; 18: 311–6.[ISI][Medline]
- Arnold JMO, McDevitt DG. Contribution of the vagus to the hemodynamic responses following intravenous boluses of isoprenaline. Br J Clin Pharmacol 1983; 15: 423–9.[ISI][Medline]
- Ebert TJ, Muzi M. Propofol and autonomic reflex function in humans. Anesth Analg 1994; 78: 369–75.[ISI][Medline]
- Zhou W, Fontenot HJ, Wang SN, Kennedy RH. Propofol-induced alteration in myocardial ß-adrenoceptor binding and responsiveness. Anesth Analg 1999; 89: 604–8.[Abstract/Free Full Text]
- Shafer A, Doze VA, Shafer SL, et al. Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 1988; 69: 348–56.[ISI][Medline]
- Marshall RJ, McGrath JC, Miller RD, et al. Comparison of the cardiovascular actions of Org NC 45 with those produced by other non-depolarizing neuromuscular blocking agents in experimental animals. Br J Anaesth 1980; 52: 21–32S.
- Marshall RJ, Ojewole JAO. Comparison of the autonomic effects of some currently-used neuromuscular blocking agents. Br J Pharmacol 1979; 66: 77–8P.
Accepted for publication September 10, 2002.
Top
Abstract
Introduction
