Anesth Analg 2002;95:389-392
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Heart Rate Response to Intravenous Atropine During Propofol Anesthesia
Takashi Horiguchi, MD, and
Toshiaki Nishikawa, MD
Department of Anesthesia, Akita University School of Medicine, Akita, 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
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Abstract
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We studied the dose-response relationships for atropine-induced heart rate (HR) changes in 61 patients during propofol anesthesia. The control group (n = 15) received no propofol. Group P-5 (n = 22) received IV propofol 1.25 mg/kg over 1 min followed by propofol at 5 mg · kg-1 · h-1. After tracheal intubation, anesthesia was maintained with propofol 5 mg · kg-1 · h-1 and 67% nitrous oxide in oxygen. Group P-10 (n = 24) received IV propofol 2.5 mg/kg over 1 min followed by propofol at 10 mg · kg-1 · h-1. The P-10 protocol was otherwise identical. All patients received incremental doses of IV atropine 5 µg/kg over 5 s at 2-min intervals until HR increased >20 bpm from baseline values. Heart rate response to atropine 10 µg/kg was attenuated in Groups P-5 (12 ± 7 bpm) and P-10 (9 ± 6 bpm) compared with the control group (28 ± 13 bpm, P<0.05). When atropine 20 µg/kg was administered, HR increased >20 bpm in all patients of the control group, but in only 43% and 13% of patients in Groups P-5 and P-10, respectively (P<0.05). These results indicate the decreased HR responsiveness to IV atropine in patients receiving propofol, which cannot be effectively overcome by a large dose of atropine, is possibly attributable to propofol-induced suppression of the sympathetic nervous system.
IMPLICATIONS: Heart rate response to IV atropine is attenuated during propofol anesthesia, and the decreased responsiveness to atropine cannot be effectively overcome by a large dose of atropine.
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Introduction
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Propofol increases the risk of bradycardia compared with other anesthetics. According to Tramer et al.’s (1) systematic search for the incidence of bradycardia based on previous reports, the number-needed-to-harm for one bradycardic episode was approximately seven during propofol anesthesia. The odds ratio of the incidence of bradycardia was 2.5 during propofol anesthesia as compared with during anesthesia using other drugs (1). Indeed, several clinical reports have implicated propofol as causing intraoperative bradyarrhythmias (2,3). More important, profound bradycardia and asystole with the use of propofol in healthy adult patients, despite prophylactic administration of anticholinergics, have been reported (4,5), whereas a relatively large dose of atropine was needed to treat bradycardia (5), or inadequate responses of propofol-induced bradycardia to atropine were reported (4,6).
No clinical investigation has systematically studied the dose-related hemodynamic interaction between propofol and atropine in humans. In the present study, we examined this proposition by evaluating the interaction between propofol and IV atropine, according to dose, and tested whether a larger dose of atropine can overcome the suppression of heart rate (HR) response induced by propofol.
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Methods
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Sixty-one adult patients, aged between 21 and 60 yr undergoing a variety of general surgical procedures classified as ASA physical status I or II, were studied. The study was approved by our local ethics committee 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 (H2-blocker) 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 an automated blood pressure (BP) cuff at the contralateral arm were applied. Heat rate was determined as an average of 4-s intervals recorded on the ECG monitor, and mean BP (mBP) was calculated electronically.
The patients were randomly assigned to one of three groups according to the dosage of propofol. The control group (n = 15) received no anesthetic medication. After breathing oxygen, Group P-5 (n = 22) received IV propofol 1.25 mg/kg over 1 min followed by continuous infusion of propofol 5 mg · kg-1 · h-1. Tracheal intubation was facilitated with IV vecuronium 0.2 mg/kg, and anesthesia was maintained with propofol 5 mg · kg-1 · h-1 and 67% nitrous oxide in oxygen. Mechanical ventilation was performed to maintain ETCO2 at approximately 35 mm Hg. Group P-10 (n = 24) received propofol 2.5 mg/kg over 1 min followed by propofol 10 mg · kg-1 · h-1. The following protocol is identical to that in Group P-5.
After a stable hemodynamic state was obtained, all patients received incremental doses of atropine 5 µg/kg over 5 s at 2-min intervals until HRs increased >20 bpm from baseline values before surgical stimulation. Atropine was diluted in a concentration of 50 µg/mL. HR and BP were measured at 1-min intervals until 2 min after the last dose of atropine, while ECG was monitored continuously. Values of HR and BP 2 min after each dose of atropine were recorded and subjected to data analyses, because HR responses in every patient reached plateaus 1–2 min after atropine injection. The total dose of atropine was limited to 30 µg/kg. If a patient’s systolic BP decreased to <80 mm Hg and HR <50 bpm, rescue treatment was given. The patient was then excluded from subsequent analysis. Changes in HR were plotted against the cumulative dose of atropine 5 and 10 µg/kg. The cumulative percentage of patients in whom the HR increased >20 bpm was also plotted against the cumulative dose of atropine.
Data were expressed as mean ± SD. Patient characteristics were compared by using analysis of variance and unpaired Student’s t-test. Student’s t-test with Bonferroni’s correction was used for comparisons among groups, with P < 0.05 being significant. Testing for significance in the incidence of positive HR responses after atropine between the two groups was accomplished by 
2 analysis.
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Results
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There were no significant differences among the three groups with respect to age, weight, and height (Table 1). One patient in Group P-5 and 3 patients in Group P-10 required pharmacologic management for hypotension because of systolic BP of <80 mm Hg. These patients were excluded from analysis. None of the patients had a HR of <50 bpm. HR values remained unchanged after the induction of anesthesia in both Groups P-5 and P-10 (Table 2). There were also no differences among the three groups in basal HR (before atropine injection). Because mBP decreased significantly in Groups P-5 and P-10 after the induction of anesthesia, baseline mBPs (before atropine injection) in patients who received propofol were significantly less than in those not receiving propofol (Table 2).
In patients receiving propofol, HR did not change with the atropine dose of 5 µg/kg (2 ± 5 bpm in Group P-5, 3 ± 4 bpm in Group P-10), but increased by 12 ± 7 and 9 ± 6 bpm in Groups P-5 and P-10, respectively, after the cumulative dose of atropine 10 µg/kg was administered. These changes in HR were significantly less than those in patients not receiving propofol in whom atropine 10 µg/kg caused a HR increase of 28 ± 13 bpm (P < 0.05; Fig. 1). When the cumulative atropine dose reached 20 µg/kg, HR increased by >20 bpm in all patients of the control group, but in only 43% and 13% of patients in Groups P-5 and P-10, respectively (P < 0.0001 versus the control group; Fig. 2). In Group P-10, when the cumulative dose of atropine reached 25 µg/kg, an additional patient demonstrated a HR increase of >20 bpm. In the remaining 16 patients, no significant additional increase in HR was observed even when the cumulative dose of atropine reached 30 µg/kg. In these patients, mean maximal HR increases were 12 bpm during the study.
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Figure 1. Heart rate responses to the cumulative IV atropine dose of 5 and 10 µg/kg in patients receiving no propofol (n = 15), 5 mg · kg-1 · h-1 (n = 22), and 10 mg · kg-1 · h-1 (n = 24). Mean ± SD; *P < 0.05 compared with the control group.
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Figure 2. The cumulative percentage of patients whose heart rate increased >20 bpm from baseline values after the cumulative IV administration of atropine in patients receiving no propofol (control), propofol 5 or 10 mg · kg-1 · h-1.
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mBPs in Groups P-5 and P-10 and in the control group remained unchanged after the administration of atropine 5 and 10 µg/kg (Table 2). No patient receiving propofol developed any arrhythmia after atropine injection. There were no other adverse effects related to large doses of atropine or to propofol-atropine interaction.
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Discussion
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Our new finding is that HR responses to IV atropine are attenuated in patients receiving propofol compared with awake patients. No detrimental effects related to propofol, no increased incidence of arrhythmia attributed to atropine, and no serious propofol-atropine interaction were observed. The hyporesponsiveness to atropine induced by propofol could not be reversed effectively by as much as 30 µg/kg atropine in all patients.
Heart rate did not change after the induction of propofol anesthesia as described previously (7), and there were no significant differences in baseline HR (before atropine injection) among the three groups. Although there were no differences in baseline HRs among the three groups (Table 2), a lesser increase in HR to the cumulative dose of atropine in the propofol anesthesia groups seemed to be dose-dependent of propofol (Fig. 2).
Mechanisms of bradycardia with propofol are not fully understood. The dose-response relationships demonstrated in this study clearly indicate that the chronotropic effect of atropine is significantly reduced during propofol-nitrous oxide anesthesia compared with no anesthetic medication. These differences are likely to be the manifestation of anesthetic-induced alterations in the balance between sympathetic and parasympathetic influences on the heart (8). According to previous clinical investigations, propofol either resets or inhibits the baroreflex control of HR, thus reducing the tachycardic response to hypotension (9,10), and does not have a direct effect on the sinoatrial node (11). Hence, the differences in the HR responses to atropine between awake and propofol-anesthetized humans may be attributable to propofol-induced suppression of autonomic nervous activity, especially of the sympathetic nervous system (9,10). This assumption is supported further by the fact that the hyporesponsiveness to atropine induced by propofol could not be reversed effectively by as much as 30 µg/kg atropine in all patients, because an adequate parasympathetic block of the sinoatrial node could be obtained with atropine 40 µg/kg (12). An investigation of each component of the autonomic nervous system using HR variability favors our assumption (13). It is also supported that propofol has no direct effect on sinoatrial node activity or intraatrial conduction (11).
There was no arrhythmia attributable to propofol and atropine interaction in the present study. No increased occurrence of arrhythmia even after a large dose of atropine in patients given propofol would exclude the possibility of serious interaction between propofol and atropine.
In conclusion, the HR response to IV atropine is attenuated during propofol anesthesia. The decreased responsiveness to atropine in patients receiving propofol cannot be effectively overcome by a large dose of atropine. These results suggest that propofol can induce pronounced depression of the sympathetic nervous system, and a potent ß-adrenergic agonist may be required to restore the normal HR or to increase the HR up to a desired level in certain patients receiving propofol.
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Acknowledgments
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Supported solely by institutional or departmental sources.
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Footnotes
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Presented in part at the annual meeting of the American Society of Anesthesiologists, Orlando, FL, October 19, 1998.
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References
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- Baraka A. Severe bradycardia following propofol-suxamethonium sequence. Br J Anaesth 1988; 61: 482–3.[Abstract/Free Full Text]
- James MFM, Reyneke CJ, Whiffler K. Heart block following propofol: a case report. Br J Anaesth 1989; 62: 213–5.[Abstract/Free Full Text]
- Thomson SJ, Yate PM. Bradycardia after propofol infusion [letter]. Anaesthesia 1987; 42: 430.[ISI][Medline]
- Marsch SC, Schaefer HG. Pronounced bradycardia after application of POR-8 (Ornipressin) under total intravenous anesthesia with propofol. Acta Anaesthesiol Scand 1990; 34: 514.[ISI][Medline]
- Cross G, Gaylard D, Lim M. Atropine-induced heart rate changes: a comparison between midazolam-fentanyl-propofol-N2O and midazolam-fentanyl-thiopentone-enflurane-N2O anaesthesia. Can J Anaesth 1990; 37: 416–9.
- 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]
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- Ebert TJ, Muzi M, Berens R, et al. Sympathetic responses to induction of anesthesia in humans with propofol or etomidate. Anesthesiology 1992; 76: 725–33.[ISI][Medline]
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- Sharpe MD, Dobkowski WB, Murkin JM, et al. Propofol has no direct effect on sinoatrial node function or on normal atrioventricular and accessory pathway conduction in Wolff-Parkinson-White syndrome during alfentanil/midazolam anesthesia. Anesthesiology 1995; 82: 888–95.[ISI][Medline]
- Chamberlain DA, Turner P, Sneddon JM. Effects of atropine on heart rate in healthy man. Lancet 1967; 1: 12–5.[ISI][Medline]
- 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]
Accepted for publication April 11, 2002.
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Abstract
Introduction
