Cardiac arrhythmias, especially supraventricular cardiac tachyarrhythmias, are well recognized complications observed often after noncardiac thoracic operations (1–4). The direct cause of tachyarrhythmias after thoracic surgery remains unclear. However, some reports have indicated that a relatively sympathotonic status caused by injury to the cardiac parasympathetic nerves caused by surgical manipulations can increase the incidence of postoperative cardiac arrhythmias (4–7). If the potential cause of the arrhythmias is the sympathotonic status associated with injury to the cardiac parasympathetic nerves, postoperative sympathetic blockade by thoracic epidural anesthesia may reduce the occurrence of tachyarrhythmias after thoracic operations. Accordingly, in this study we examined whether postoperative continuous thoracic epidural infusion of a local anesthetic (bupivacaine) would more effectively attenuate the cardiac tachyarrhythmias after pulmonary resection compared with postoperative continuous epidural morphine infusion.
After obtaining approval of our Committee on Clinical Investigation and informed consent of participants, we selected 50 patients with primary or metastatic lung cancer who underwent elective pulmonary resection at Tochigi Cancer Center Hospital. Excluded from the study were patients who received preoperative chemotherapy and those who required pneumonectomy. Patients with a history of preoperative chronic supraventricular cardiac tachyarrhythmias were not enrolled. Before the operation, patients had an epidural catheter inserted by an attending anesthesiologist. With the subject in the horizontal lateral position, the T5-6, T6-7, or T7-8 interspace was identified with the paramedian approach by the loss of resistance technique with a 17-gauge needle. After an epidural catheter had been inserted, placement of the epidural catheter was assessed by the administration of a 3-mL dose of 2% mepivacaine. Bilateral sensory anesthesia level above T4 was demonstrated by pinprick 5 min after a test dose of 2% mepivacaine. A standardized general anesthetic technique was used during surgery, consisting of propofol (1.0 to 2.0 mg/kg) or thiopental (3.0 to 5.0 mg/kg) IV for the induction and isoflurane or sevoflurane in oxygen for the maintenance of anesthesia. No patient received an epidural injection of local anesthetics during the operation. Muscle relaxation was achieved with pancuronium or vecuronium. During thoracotomy, one-lung ventilation was used to facilitate surgical exposure.
Fifty patients were randomized to the Epidural Bupivacaine Infusion group (Group B) or the Epidural Morphine Infusion group (Group M) for postoperative pain management. At the end of the surgical procedure, patients in Group B were given 6 to 10 mL of 0.25% bupivacaine epidurally as an initial dose, followed by continuous epidural infusion at 3 to 5 mL/h of 0.25% bupivacaine for 3 days for pain relief during the postoperative period. Patients in Group M were given an epidural initial dose of morphine 2–3 mg, followed by a continuous epidural infusion of morphine 0.1 mg/mL at a rate of 2 mL/h for 3 days. Inadequate analgesia in either group was treated with incremental doses of 0.25% bupivacaine or morphine to ensure adequate analgesia. If necessary, indomethacin sodium suppositories (25 to 50 mg) were available on patient demand for supplemental analgesia in both groups. Postoperative tachyarrhythmias were treated with deslanoside, verapamil, or propranolol. Patients with heart rates exceeding 100 bpm and not in sinus rhythm (atrial fibrillation, atrial flutter, or other supraventricular tachyarrhythmias) were given a 0.4- to 0.6-mg loading infusion of deslanoside over 5 min, followed by a 0.2 to 0.3 mg/d maintenance IV bolus. Patients with heart rates exceeding 120 bpm were given a 5-mg infusion of verapamil over 5 min or a 2-mg infusion of propranolol over 5 min.
The quality of analgesia during the study period was assessed with an 11-point numeric rating scale: 0 = no pain and 10 = most severe pain. After receiving instruction in the use of the numeric rating scale, each patient assessed the pain intensity 3 to 5 h after the operation and on the morning of the first, second, and third days after the operation. Patients were evaluated daily by the anesthesiologist and the nursing staff for side effects or complications (for example, nausea and vomiting, hypotension, or mental status changes). Daily epidural bupivacaine and morphine consumption and the amount of indomethacin administration were recorded. All the heartbeats in the postanesthetic care unit were continuously monitored with an electrocardiogram (ECG) monitor (Component Monitoring System; Hewlett-Packard, Boeblingen, Germany) and recorded via a central monitoring system (Clinical Event Review/HP M1251A; Hewlett-Packard) until the morning of the third postoperative day. The central monitoring system stored 24 h of ECG data in random access memory and produced trends of heart rate and arrhythmia (Fig. 1). Postoperative heart rates were measured 1 to 2 h after the operation and between 4:00 am and 6:00 am of the first, second, and third days after the operation. The heart rates were defined as the minimum rates during each monitoring period. Significant tachyarrhythmias after thoracotomy were defined as a heart rate of >100 bpm other than sinus tachycardia (atrial fibrillation, atrial flutter, or other supraventricular tachyarrhythmias) occurring for >60 min during postoperative days. On the morning of the first to the third days after the operation, tachyarrhythmias were diagnosed by the observer by using the ECG stored in memory, the heart rate trend, and the arrhythmia trend with a central monitoring system.
Exclusion criteria included the inability to control postoperative pain, severe postoperative cardiopulmonary complication (myocardial infarction, pulmonary thromboembolism, etc.), complication caused by analgesics (hypotension, systolic blood pressure <80 mm Hg; respiratory depression, respiratory rate <8 breaths/min; hypoxemia, Spo2 < 90%, etc.), or reoperation within 3 days.
Data were analyzed by using contingency tables, the Mann-Whitney U-test, unpaired t-test, or repeated-measures analysis of variance where appropriate. Post hoc testing was performed with the Tukey test. A P value <0.05 was considered significant.
Fifty patients were enrolled in the study. Two patients (Group B) were withdrawn from the study because of hypotension. After exclusion of these patients, 23 patients in Group B and 25 patients in Group M remained for analysis. The patients excluded from the protocol did not exhibit postoperative tachyarrhythmias during bupivacaine infusion. Patient demographics, preoperative morbid conditions, surgical staging, anesthetics, muscle relaxants, side of thoracotomy, type of surgery, duration of surgery, blood loss, intraoperative fluid replacement, and intraoperative arrhythmias were similar between the two groups (Table 1). The extent of pulmonary resection was slightly more in Group B than in Group M; however, there was no significant difference between the two groups. There was no arrhythmia lasting >5 s during the operation. There was no significant correlation between postoperative tachyarrhythmias and intraoperative arrhythmias (P = 0.655).
Postoperative analgesia was not statistically different between the two groups up to the third postoperative day as expressed by the numeric rating scale. In both groups, numeric rating scale scores were significantly lower on the first to the third postoperative day than on the day of the operation (Fig. 2). Most patients did not complain of pain at rest. Moreover, there was no significant difference in pain intensity between patients with and without arrhythmias (P = 0.260) (Fig. 3). An incremental dose of each epidural analgesic decreased as the numeric rating scale decreased. Conversely, total consumed doses of indomethacin suppositories were significantly more in Group B than in Group M (Table 2). This is probably because many patients in Group B complained of shoulder pain after the operation. The total doses of indomethacin received were 86 ± 62 mg (0–300 mg), expressed as mean ± sd (range), in those patients with postoperative arrhythmias (Arrhythmias[+] group) and 97 ± 100 mg (0–250 mg) in those without arrhythmias (Arrhythmias[−] group). There was no significant difference between the two groups (P = 0.787). There was no significant correlation between postoperative tachyarrhythmias and total administered dosage of indomethacin. Postoperative heart rates in Group B were slightly less than in Group M, but there was no significant difference between the two groups (P = 0.1058). In both groups, heart rates were significantly less on the first to third postoperative day than on the day of operation (P < 0.0001) (Fig. 4). The incidence of clinical complications caused by analgesics in the two groups was similar except for pruritus. The incidence of pruritus was more frequent in Group M compared with Group B. During the observation period after the operation, seven patients in Group M had at least one episode of postoperative tachyarrhythmias, whereas only one patient in Group B exhibited postoperative supraventricular tachyarrhythmias. The incidence of postoperative tachyarrhythmias in Group B was significantly less frequent in Group M (P = 0.0497, Fisher’s exact probability test). Atrial fibrillation was observed most often (seven of eight patients). Two patients had paroxysmal supraventricular tachycardia. One of them had combinations of the two types of tachyarrhythmias (Table 3). Table 4 shows the incidence and total duration of tachyarrhythmias up to the morning of the third postoperative day. The average number of arrhythmia episodes during observation periods was 8.3, and the average time of each episode was 39 min. No patient received deslanoside, verapamil, propranolol, or other antiarrhythmic drugs except the patients with tachyarrhythmias.
This study showed that the incidence of postoperative tachyarrhythmias in Group B was significantly less than in Group M, although the extent of pulmonary resection was more in Group B than in Group M. The principal finding of this study is that thoracic epidural anesthesia with bupivacaine reduces the incidence of supraventricular tachyarrhythmias after pulmonary surgery.
Supraventricular tachyarrhythmias, of which atrial fibrillation was most common, are well described after pulmonary or esophageal surgery (1–7). We reported previously that tachyarrhythmias were identified in 22.3% of 121 consecutive operations after pulmonary surgery (7). They are associated with significantly increased mortality rates, especially in patients undergoing pneumonectomy (2,3). Despite much speculation, the direct cause of the arrhythmias after thoracic operations remains unclear. Some investigators suggest that postoperative arrhythmias after these operations may result from synergy of a relatively sympathotonic status produced by injury to the cardiac parasympathetic nerves and right atrial enlargement with pulmonary hypertension caused by a decrease in pulmonary vasculature or by fluid redistribution from the extracellular (so-called third space) to the intracellular space during postoperative periods (4,8). It is generally known that autonomic nervous system imbalance is one of the most common causes of supraventricular tachyarrhythmias, including atrial fibrillation (6,8–17). Otteni et al. (9) reported that radical neck lymph node dissection caused tachyarrhythmias, probably because of surgical trauma to the autonomic nervous system. Wyndham (10) suggested that atropine may increase atrial vulnerability, defined as the ability of one or more premature beats initiated in early diastole to induce atrial fibrillation, because of shortening of atrial refractory periods in humans. Kimura et al. (6) reported that pulmonary resection causes a relatively sympathotonic status because of injury to the cardiac parasympathetic or sympathetic nerves, inducing postoperative tachyarrhythmias. Balser et al. (18) reported that β-adrenergic blockade accelerated the conversion of postoperative supraventricular tachyarrhythmias after major noncardiac surgery, although β-blockade had no direct antiarrhythmic effects in atrial cells stimulated by catecholamines. Kamibayashi et al. (19) suggested that thoracic epidural anesthesia may attenuate myocardial sensitization, defined as the dysrhythmogenic dose of epinephrine under halothane anesthesia, and vagal activity may have an essential role in this action. Therefore, we speculated that postoperative thoracic sympathetic blockade by continuous thoracic epidural infusion of bupivacaine might attenuate the sympathotonic status and thereby decrease cardiac tachyarrhythmias after pulmonary resection. Our results support this hypothesis.
Although epidural anesthesia reduced cardiac arrhythmias after pulmonary resection, whether the decrease in sympathetic activity to the heart by thoracic epidural anesthesia is actually responsible for attenuation of the arrhythmias remains a question.
Kamibayashi et al. (19) indicated that attenuation of the sympathotonic status plays an essential role in the antidysrhythmic effect of epidural local anesthetics, because the beneficial effect disappeared by vagotomy.
On the other hand, local anesthetics that are sodium channel blockers and belong to class I of antidysrhythmic drugs may increase the dysrhythmogenic threshold (20). We did not measure plasma bupivacaine concentrations during the observation period. However, bupivacaine affects mainly the His-Purkinje system and ventricular tissue, and the effect on the R-R interval is considered to be minimal (21). Thus, we opined that circulating bupivacaine after epidural administration did not contribute to the antidysrhythmic benefit of epidural bupivacaine, although this conclusion is limited by the absence of measured plasma concentrations of bupivacaine.
In this study, we did not quantify the level of sympathetic nerve block by epidural bupivacaine. Postoperative heart rates in Group B were slightly less than in Group M, but there was no significant difference between the groups. Therefore, not all patients may attain block levels sufficient to produce the effects of thoracic sympathectomy (at or higher than T1). However, in many cases in Group B, heart rates were <70 bpm on the morning of the first, second, and third days after the operation. Hasenbos et al. (22) suggested that epidural bupivacaine had a specific autonomic system-saving effect in comparison to other local anesthetics. This effect may be the reason that heart rates in Group B were not significantly less than in Group M. However, most of the patients in Group B did not complain of wound pain, but rather of shoulder pain. The level of sympathetic segment blockade by epidural anesthesia exceeds the dermatomal borders of sensory blockade. Therefore, we assumed that the continuous infusion of epidural bupivacaine (3 to 5 mL/h) achieved an appropriate block level of cardiac sympathetic nerve (T1 to T4).
Pain alone may increase the incidence of tachyarrhythmias. However, most patients did not complain of pain at rest. Moreover, there was no significant difference in pain intensity between patients with and those without arrhythmias, and we concluded that pain did not significantly affect the incidence of tachyarrhythmias in this study.
In summary, the continuous infusion of thoracic epidural bupivacaine can reduce supraventricular tachyarrhythmias compared with continuous epidural morphine infusion in postoperative periods, presumably because the epidural anesthesia attenuates the sympathotonic status after pulmonary resection.
The authors thank Dr. Kohei Yokoi and Dr. Naomi Goto for advice about data acquisition and Dr. Takashi Nishino for reviewing the manuscript.
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