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Interact CardioVasc Thorac Surg 2008;7:184-187. doi:10.1510/icvts.2007.160945 © 2008 European Association of Cardio-Thoracic Surgery
Propranolol: a new indication for an old drug in preventing postoperative junctional ectopic tachycardia after surgical repair of tetralogy of Fallot
a Division of Cardiothoracic Surgery, King Faisal Specialist Hospital and Research Center, MBC J 16, P.O.Box 40047, Jeddah 21499, Saudi Arabia Received 4 August 2007; received in revised form 6 November 2007; accepted 6 November 2007
*Corresponding author. Tel.: +966 2 6677777 5234; fax: +966 2 6639581.
Junctional ectopic tachycardia (JET) is a major cause of postoperative morbidity after complete repair of tetralogy of Fallot (TOF). Propranolol is a known medication used in patients with TOF to prevent and control hypercyanotic spells. Despite this, there is little information regarding the relation between preoperative use of propranolol and the incidence of postoperative JET. The aim of this study was to examine the effect of preoperative use of propranolol on the incidence of postoperative JET after full surgical repair of TOF. A retrospective analysis of 109 patients in whom 57 patients received preoperative propranolol (propranolol group) was compared with 52 patients who did not receive propranolol preoperatively (control group). The incidence of postoperative JET was significantly higher in the control group (38%) than the propranolol group (21%) P=0.042. The propranolol group had significantly less mechanical ventilation time, less ICU stay and less total hospital stay than the control group (P<0.05). Our findings suggest that the preoperative use of propranolol may decrease the incidence of JET after full surgical repair of TOF. A prospective randomized study may help to elucidate the exact relationship between the preoperative use of propranolol and the incidence of postoperative JET.
Key Words: Tetralogy of Fallot; Junctional ectopic tachycardia; Propranolol
Junctional ectopic tachycardia (JET) has been reported after surgical repair of tetralogy of Fallot (TOF) [1, 2]. The causes of JET are not clearly understood, but increased excitability of conducting bundle is probably due to various forms of irritation and minor trauma [3]. A variety of different therapeutic strategies has been reported to control JET including the use of propranolol [4–6]. Propranolol is a frequent medication used in patients with TOF to control hypercyanotic spells [7, 8]. The effectiveness of propranolol appears to be due to releasing the spasm of the right ventricular infundibulm [9]. Despite this, there is little information regarding the relation between preoperative use of propranolol and the incidence of postoperative JET. The aim of this study was to evaluate the effect of preoperative use of propranolol on the incidence of postoperative JET in patients after full surgical repair of TOF.
2.1. Study population A retrospective analysis was performed on all patients who had full surgical repair of TOF at our institution between January 2002 and March 2006. Patients who had pulmonary atresia and those who underwent initial palliative shunt were excluded from the study. Patients with incomplete data regarding the preoperative dose of propranolol were also excluded. Patients who had an associated atrial septal defect and/or patent ductus arteriosus were included in this study. Data collection was based on patient charts, operative reports, cardiac ICU records and postoperative 12-lead surface electrocardiogram (ECG). This study focused on the effect of preoperative use of propranolol on the incidence of postoperative JET. There were 109 patients who met our inclusion criteria. These patients were evaluated retrospectively. Two groups were identified: the propranolol group (n=57 patients) who received propranolol preoperatively, and the control group (n=52 patients) who did not receive propranolol preoperatively. In the propranolol group, the dose of propranolol was reported as mg/kg/day. Surgery was performed with similar techniques during the period of the study under standard cardiopulmonary bypass (CPB) techniques and cold antegrade blood cardioplegia.2.3. Electrocardiographic monitoring Standard 12-lead ECGs were registered in all patients preoperatively and at the time of ICU admission. Continuous ECG monitoring was performed during the entire ICU stay with Siemens monitors (Siemens Medical Systems, Danvers, USA). This monitoring system provides storage and retrospective printing of the monitored ECG. When JET was detected on the ECG monitor, this was also documented with a standard ECG. Diagnostic criteria for JET included the following: 1) narrow QRS tachycardia, 2) a ventricular rate more than 170 beats/min, 3) atrioventricular dissociation with or without hemodynamic compromise, and 4) a ventricular rate faster than the atrial rate [4].2.4. Management of postoperative JET Upon diagnosis of JET, a treatment protocol was initiated until JET converted to a stable rhythm. This protocol included minimization of inotropic support when possible, maintenance dose of digoxin, and moderate surface cooling to a core temperature of ±35 °C, sedation, muscle paralysis and amiodarone.2.5. Postoperative intensive care data Postoperative JET, hours of mechanical ventilation and days of total stay in the ICU were collected. Postoperative follow-up was defined as the period of time after hospital discharge until the first available ECG, which is usually two weeks.
Statistical analysis was performed with SPSS statistical program (SPSS 11 Inc., Chicago, Illinois). Data were presented as mean±S.D. or median with ranges or percentages as appropriate. The Fisher exact, the Mann–Whitney or independent sample t-test were used to draw comparisons between propranolol group and the control group. Statistical analysis was performed to find any correlation between the preoperative use of propranolol and the occurrence of postoperative JET using  2-test. Differences were considered to be statistically significant when P-value was <0.05.
The preoperative patients' characteristics are shown in (Table 1). Statistically significant differences existed between the two groups in relation to the preoperative oxygen saturation, the incidence of cyanotic spells, and preoperative pulmonary annulus size (P<0.05). Operative data are summarized in Table 2 and show no statistically significant differences between the two groups. Fig. 1 shows the incidence of JET in both groups. JET was documented in 32 patients out of 109 (29%). The incidence of postoperative JET was 21% in the propranolol group and 38% in the control group. The difference was statistically significant with a P-value of 0.04. Two patients in the propranolol group developed complete heart block with one dying on the 4th postoperative day from multiorgan failure. In the propranolol group, the patients who developed postoperative JET had a lower mean of preoperative doses of propranolol (0.99 mg/kg) compared with the patients who did not develop JET (1.59 mg/kg). However, the difference did not reach a statistical significance (P=0.08). The propranolol group required more dopamine (4.5±3 µg/kg/min) and dobutamine (4.7±3 µg/kg/min) vs. 3.6±2 and 3.3±2 for the control group. The differences between the two groups were statistically significant (P<0.05). However, there was no statistical difference for the requirement of epinephrine 0.028±0.01 µg/kg/min for the propranolol group and 0.03±0.02 for the control group. (P=0.24). Postoperative morbidity and mortality are shown in (Table 3).
Our results demonstrate that JET is a frequent early complication after full surgical repair of TOF (29%). We observed an increased risk of JET when propranolol was not used preoperatively. The incidence of our postoperative JET was 21% in the propranolol group and 38% in the control group. It is worthwhile to mention that in the propranolol group, the patients who developed postoperative JET had a lower mean of preoperative doses of propranolol (0.99 mg/kg) compared with the patients who did not develop JET (1.59 mg/kg). The difference did not reach a statistical significance with a P-value of 0.08 but we may assume that non-therapeutic preoperative doses of propranolol may be associated with higher incidences of postoperative JET. Propranolol is a nonselective beta-adrenergic receptor-blocking agent which is also used in the management of JET [10, 11]. The mechanism of the antiarrhythmic effect of propranolol has not been established. However, it may inhibit pacemaker potentials and decreases frequency of spontaneous depolarization [11]. Pharmacokinetic studies of propranolol may explain the preventive mechanism of preoperative use of propranolol on postoperative incidence of JET observed in our study. Preoperative propranolol pharmacokinetic studies reported biological half-life between 3.2 h and 5.2 h [12, 13]. However, the pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass. Carmona et al. [12] investigated the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting by CPB under moderate hypothermia (32°–34°). Their last dose of propranolol was administered to all patients the night before surgery. They reported a mean prolongation of the biological half-life of propranolol of more than 200% (from 4.5 h to 10.6 h). They also reported that the free fraction of propranolol was increased by 200% after CPB and fell progressively with time, reaching sustained troughs of 57% at 72–120 h. Likewise, Plachetka et al. [13] reported that the plasma levels of propranolol decreased by the onset of CPB by 50% but there were sustained increases in plasma levels up to 240 min after CPB. The effect of heparin administration on plasma protein binding is also of importance. Heparin results in lipoprotein lipase and hepatic lipase release, which in turn hydrolyze plasma triglycerides into non-esterified fatty acids which can lead to displacement of plasma protein bound drugs such as propranolol, raising their concentrations. Wood et al. [14] reported that administration of heparin pre-bypass resulted in a doubling of propranolol free fraction from 6.6% to 13.5% which was associated with an increase in free fatty acid. Lung isolation from the circulation during CPB can cause sequestration of several drugs including propranolol, which may return back after re-establishment of the pulmonary circulation [15]. From the pharmacokinetic data of propranolol we may assume that in the propranolol group, due to the effect of hypothermic cardiopulmonary bypass, patients receiving propranolol before surgery might still have therapeutic serum level of propranolol which was observed as a decreased incidence of postoperative JET. Another important observation in our study is that the propranolol group required higher doses of dopamine and dobutamine than the control group. This may be due to myocardial depression effect of propranolol. However, the propranolol group did not require higher epinephrine and norepinephrine. Moreover, the use of preoperative propranolol had an impact on the postoperative course of our patients with less duration of mechanical ventilation; intensive care unit stay and total hospital stay, which suggests that a cost reduction exists. In conclusion, our findings suggest that the preoperative use of propranolol may decrease the incidence of JET after full surgical repair of TOF. A prospective randomized study may help to elucidate the exact relationship between the preoperative use of propranolol and the incidence of postoperative JET. Because of the retrospective nature of the study, determination of the duration of propranolol treatment and sometimes the dose was not available for the excluded patients. Our hospital is a tertiary care center serving a large area of different geographic, ethnical and medical practice so the patients included in this study were treated with propranolol regimens tailored by the attending cardiologists according to clinical parameters and individual tolerance. This study included a relatively small number of patients as it was completed in March 2006 and we are performing a prospective study which will include all our patients with TOF requiring full primary repair to test our hypothesis.
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Abstract
1. Introduction