Incessant atrial and junctional tachyarrhythmias occur frequently after congenital cardiac surgery and can be a cause of increased morbidity and mortality.1,2 These rhythm disturbances that may be well tolerated in a normal heart often cause significant hemodynamic instability in patients with congenital heart defects and particularly during the vulnerable postcardiopulmonary bypass period. Typical antiarrhythmic therapy may be inadequate and it often carries a significant risk of side effects. Amiodarone, one of the most common antiarrhythmic drugs used in this setting, has an 87% risk of adverse events, including mortality, hypotension, and atrioventricular (AV) block.3
Dexmedetomidine, an α-2 adrenoreceptor agonist, has been successfully used in our cardiac intensive care unit (CICU) for the sedation and analgesia of infants and children after cardiac surgery. Its potential role, however, in the setting of atrial and junctional tachyarrhythmias has not been studied. The only available evidence is limited animal data, showing that dexmedetomidine can potentially prevent certain types of ventricular tachycardia.4–6 Hayashi et al. demonstrated that an infusion of dexmedetomidine at 0.5 μg · kg−1 · min−1 increased the arrhythmogenic threshold of halothane-anesthetized dogs by threefold.4
The purpose of this study was to investigate the theoretical therapeutic role of dexmedetomidine during perioperative atrial and junctional tachyarrhythmias.
Approval for this retrospective, nonrandomized, noncontrolled, observational study was obtained from the IRB of University of Pittsburgh Medical Center. A written, parental informed consent for innovative use of a drug for the purpose of sedation and stabilization of heart rate (HR) was obtained from all patients. Informed consent to review the charts was waived. This study included patients admitted to the CICU at Children’s Hospital of Pittsburgh from February 2006 to June 2007 who received dexmedetomidine for both sedation/analgesia and atrial or junctional tachyarrhythmias.
All patients were monitored using full-disclosure telemetry that stores information up to 48 h and allows detailed analysis of HR, respiratory rate, arterial blood pressure, central venous pressure, and oxygen saturation. With every tachyarrhythmia detected, a 12-lead electrocardiogram (ECG) was obtained and if pacing wires were available an atrial electrogram. All telemetry tracings, ECGs and electrograms were reviewed every 12–24 h by one of the investigators and confirmed by an attending electrophysiologist at a later time.
Junctional Ectopic Tachycardia
Junctional ectopic tachycardia (JET) was defined according to the following criteria: 1) A HR ≥170 bpm with a QRS morphology similar to the baseline normal sinus rhythm (NSR) or atrial rhythm QRS complex, 2) AV dissociation with ventricular rate higher than or equal to the atrial rate, 3) ventriculo-atrial (VA) association with retrograde 1:1 or Wenckebach conduction, 4) A pattern of “warm-up” phenomenon at initiation, though not necessary. In cases of 1:1 VA conduction, short VA interval and no obvious “p” waves or where tachycardia onset was abrupt, attempts were made to exclude a reentrant type mechanism. Abrupt termination with either the use of adenosine or rapid atrial pacing was consistent with the diagnosis of reentry type supraventricular tachycardia (Re-SVT) and not JET.
Junctional Accelerated Rhythm
The same criteria used to define JET were also used for junctional accelerated rhythm (JAR), with the exemption that the HR ranged between 100–169 bpm. In the postoperative period, JAR and JET probably share the same underlying mechanism, and JAR could progress to JET after certain surgical repairs. These high risk surgical repairs include tetralogy of Fallot, complete AV septal defect (CAVSD), transposition of the great arteries (TGA), truncus arteriosus, Norwood stage I procedure and infants with ventricular septal defect.
Atrial Ectopic Tachycardia
Atrial ectopic tachycardia (AET) was defined by different “p” wave morphology than the sinus “p” wave, HR between 150–250 bpm, substantial HR variability through its course and typically a “warm-up” phenomenon.
Atrial flutter (AF) was defined by abrupt onset tachyarrhythmia with no distinct “p” waves but rather typical flutter waves, HR between 250–350 bpm, variable AV block or 1:1 AV conduction with QRS complex morphology similar to baseline.
Reentry Type Supraventricular Tachycardia
Abrupt onset, regular tachycardia with QRS complex morphology similar to baseline and HR between 200–350 bpm. “P” waves are not usually seen. Atrial electrogram may show retrograde “p” waves with a short VA interval. The tachycardia is often precipitated by a premature atrial beat.
- Patients with significant hemodynamic instability did not receive dexmedetomidine and were thus excluded from the study.
- Patients who did not need sedation, analgesia and/or anxiolysis at the same time arrhythmia occurred did not receive dexmedetomidine and were thus excluded from the study.
Dexmedetomidine was used as a first-line drug. It was started as a continuous infusion between 0.5–2 μg · kg−1 · h−1 and if an immediate effect was considered necessary by the attending physician, an initial loading dose of 0.5–1 μg/kg was given. Patients with Re-SVT and AF received dexmedetomidine over 1–5 min and all other patients over 5–10 min. Patients with JET, JAR, AET, and AF received a second loading dose if no HR response was seen after 10–15 min.
Dexmedetomidine was used as a rescue drug if previous treatment with amiodarone or amiodarone with hypothermia (34.5°–35.5°C) was ineffective in controlling the arrhythmia or there was a breakthrough arrhythmia episode. The same dexmedetomidine dosing guidelines used for primary treatment were used in this setting.
Given the retrospective nature of the study and lack of strict standardization, we could not determine when and why intensivists used dexmedetomidine as a primary treatment or as a rescue. However, towards the later stages of the study, and with more experience, there was a tendency for dexmedetomidine to be used as the primary drug. In all cases, however, use of dexmedetomidine was limited only to patients who also needed sedation and/or analgesia.
Evaluation of Treatment Response
The efficacy of dexmedetomidine was assessed by the following outcomes:
- Any of the following, associated with the ability for efficient overdrive atrial or AV sequential pacing:
- HR reduction to ≤170 bpm within 2 h and not associated with any rebound tachycardia i.e., JET rate ≥171 bpm within 6 h or,
- HR reduction by ≥20% within 2 h and to ≤170 bpm within 4 h and not associated with any rebound JET within 6 h or,
- Conversion to NSR within 2 h.
- Prevention of progression to JET or conversion to NSR within 2 h.
- Reduction of AET rate by ≥20% or conversion to NSR within 2 h and not associated with any rebound tachyarrhythmia within 6 h.
- Reduction of ventricular rate to ≤150 bpm by increasing AV block or conversion to NSR within 2 h and not associated with any rebound tachyarrhythmia within 6 h.
- Conversion to NSR within 3 min.
Patients who failed to respond based on the above criteria, were consequently treated with the appropriate, conventional approach.
Other data collected include standard demographics, requirement for inotropic support, and level of sedation and analgesia. Sedation and analgesia were assessed using a 0–3 ICU sedation scale (0; none, 1; mild, 2; moderate, 3; severe sedation) and two 0–10 pain score scales, the (Face, Legs, Activity, Cry, and Consolablity), and the (Cries, Requires O2 for saturation <95%, Increased vital signs, Expression, Sleepless) scale.7,8 Our standard CICU protocol includes maintaining a serum potassium level >3.5 mmol/L, magnesium >2 mg/dL, and ionized calcium >1.1 mmol/L. Additionally, in all patients with JET we try to maintain a temperature between 36°–37°C. The postoperative period was defined as up to 30 days after surgery.
All data are expressed as mean ± sd. Continuous data were compared with a Student’s t-test. A P value ≤0.05 was considered significant.
Patient demographics are shown in Table 1. There were 14 patients, 11 male and 3 female. The mean age and weight were 2 ± 3 mo and 4 ± 1.5 kg, respectively. Thirteen patients’ lungs were mechanically ventilated at the time dexmedetomidine was administered. Five of these 13 patients were extubated during the study period. Most of the arrhythmias (79%) occurred during the postoperative period.
Dosing and Adverse Effects
Dexmedetomidine was administered as a primary treatment in nine and as a rescue in five patients. Ten patients (71%) received an average initial loading dose of 1.1 ± 0.5 μg/kg. A continuous infusion, 0.9 ± 0.3 μg · kg−1 · h−1 was administered in 12 patients, four of whom did not receive a loading dose. The two patients who did not receive a continuous infusion were a patient with Re-SVT who converted to NSR after a bolus of dexmedetomidine and a patient with AF who did not respond. Table 2 shows the dexmedetomidine dosage and rate of administration in all patients.
Adverse effects that could potentially be attributed to dexmedetomidine were seen in four patients (28%). Three patients developed mild hypotension that responded easily to intravascular volume and calcium administration and one patient developed transient complete atrioventricular block (CAVB) with a junctional rhythm of 115 bpm that lasted 2 h. This latter patient had a prior episode of CAVB, immediately after his CAVSD repair while not receiving dexmedetomidine. Subsequently, a second episode of CAVB occurred 3 h after starting dexmedetomidine. However, despite continuing dexmedetomidine for more than 40 h, there were no further events. Although we believe that the CAVB was unrelated to dexmedetomidine, this possibility could not be excluded.
Nine patients (64%) were transiently paced with atrial (seven) or AV sequential (two) pacing to optimize AV synchrony and hemodynamics. Five of these were patients with JET. None of the 14 patients had any significant bradycardia, and none required any escalation in inotropic support. Table 3, shows the inotropic drug requirements before and after dexmedetomidine. There were no episodes of vomiting or significant ileus and there were no mortalities.
Junctional Ectopic Tachycardia
Six patients developed JET during the early postoperative phase. Overall, the primary outcome was met in all six patients. The average JET rate before starting dexmedetomidine was 197 ± 22 bpm. This decreased to 165 ± 17 bpm (P = 0.01) within 67 ± 75 min of administering dexmedetomidine, median 32, range 10–210 min. The average HR while receiving maintenance dexmedetomidine infusion decreased to 154 ± 9 bpm (P = 0.02). One patient remained in JAR and all others had a conversion to NSR within 39 ± 31 h, median 24 h, range 13 to 88 h. Five of these patients received dexmedetomidine as a first-line treatment and one as a rescue.
The patient who received rescue dexmedetomidine had failed to respond to amiodarone and hypothermia, with HR remaining over 200 bpm for >2 h. Forty-five minutes after dexmedetomidine load (2 μg/kg), the HR decreased from 232 to 182 bpm (21% change) and 210 min from its initiation it decreased to just below 170 bpm and was able to be AV sequentially paced. Patient did not receive any further amiodarone and remained hemodynamically stable through the dexmedetomidine infusion.
One patient, status post-CAVSD repair, responded well to dexmedetomidine for 33 h with HR remaining <160 bpm for most of the time. Nevertheless, because he continued to remain in JAR, in addition to dexmedetomidine, amiodarone was started to prevent possible progression to JET. Over the following 20 h, this patient had three breakthrough episodes of JET despite 27 mg/kg amiodarone and hypothermia. It is noteworthy that all three breakthrough episodes acutely resolved from additional dexmedetomidine boluses.
One of the patients with JET had a Norwood stage I repair for hypoplastic left heart syndrome (HLHS). Table 4, shows patients’ baseline and postdexmedetomidine hemodynamic variables.
Three patients required hypothermia, 35.5 ± 0.5°C, but none of them appeared to have responded. In all three patients, hypothermia was initiated before dexmedetomidine was started and two patients required temporary paralysis. None had any documented shivering, though patients this age are less likely to shiver as they rely on nonshivering thermogenesis. The average temperatures of these three patients while receiving dexmedetomidine were 34.9°C, 36°C, and 35.6°C. All patients’ lungs were mechanically ventilated at the time JET occurred. The average baseline sedation level was 2.3 ± 0.3 (moderate sedation), and 1 h after dexmedetomidine administration was 2.4 ± 0.2 (moderate sedation). Overall, there was no significant fluctuation in arterial blood pressure. Table 5 shows the individual baseline and postdexmedetomidine systolic blood pressure values. Figure 1 displays the individual HR response after the initiation of dexmedetomidine therapy. Figure 2 shows the ECG tracings of a patient before and after dexmedetomidine administration.
Reentry Type Supraventricular Tachycardia
There were four patients with Re-SVT and all had resolution of their arrhythmia. In three patients, dexmedetomidine was a primary therapy and in one a rescue from amiodarone. Three patients received dexmedetomidine as a rapid bolus at a rate of 0.5–1.0 μg · kg−1 · min−1 and converted to NSR. The fourth patient was started on a maintenance infusion without a bolus and converted to junctional rhythm.
One patient presented with arrhythmia-induced cardiogenic shock. Initially he was treated with repeated doses of adenosine and amiodarone. A subsequent Re-SVT episode was treated with dexmedetomidine 1 μg/kg bolus and converted to NSR within seconds. Another patient with HLHS, status post (s/p) repair of obstructed pulmonary veins had numerous paroxysmal episodes of Re-SVT for approximately 18 h and received several doses of adenosine. Forty-five minutes after dexmedetomidine was started, he had no further episodes of Re-SVT. The other two patients, one s/p repair of TGA and one with HLHS (Table 4) awaiting surgery both responded to dexmedetomidine bolus 1 μg/kg and converted to NSR within seconds. Figure 3 shows a rhythm tracing of Re-SVT and immediate conversion to NSR. Three patients’ lungs were mechanically ventilated when Re-SVT occurred. The fourth patient developed significant agitation and it was decided that he needed sedation to avoid losing his IV access.
Atrial Ectopic Tachycardia
One mechanically ventilated patient s/p TGA repair developed hemodynamically significant (5%–10% decrease in arterial blood pressure), prolonged paroxysmal episodes of AET (HR 220–270 bpm) during the immediate postoperative period. This patient initially was treated with IV amiodarone (34 mg/kg over 32 h) and hypothermia. This regimen was continued for 32 h and resulted in no significant change in the duration or frequency of these episodes. Dexmedetomidine was then given as a loading dose 0.5 μg/kg and infusion was started at 0.5 μg · kg−1 · h−1. Thirty-five minutes after the administration, the AET rate decreased from 180–200 bpm to 120 bpm (at least 33% reduction) in an ectopic low atrial rhythm and within 85 min converted to NSR. At that time amiodarone was discontinued. No further episodes of AET were noted throughout the study period. The mean HR after dexmedetomidine was 124 ± 8 bpm. Figure 4 shows the ECG tracing before and after dexmedetomidine administration.
One patient with a history of repaired truncus arteriosus 3 mo prior, chronic respiratory insufficiency with tracheostomy and chronic, recurrent AF receiving amiodarone was readmitted for breakthrough AF. The patient was hemodynamically stable but significantly agitated, with limited IV access. He received 2 μg/kg of dexmedetomidine, both for sedation/analgesia before possible cardioversion as an attempt to treat the arrhythmia, but without any response. Twenty minutes later, the patient was electrically cardioverted to NSR.
Junctional Accelerated Rhythm
There were two patients, 4 and 3-mo-old, who developed JAR after complete repair of double outlet right ventricle/pulmonic stenosis and CAVSD, respectively. Both patients’ lungs were mechanically ventilated. For the first patient, dexmedetomidine was started at 1.2 μg · kg−1 · h−1 and the JAR rate decreased from 166 to an average of 132 ± 9 bpm. In the latter patient, it was started at 1 μg · kg−1 · h−1 and the JAR rate decreased from 150 to 130 ± 12 bpm. In both patients temporary overdrive atrial pacing was used.
Perioperative atrial and junctional tachyarrhythmias can be difficult to manage. The currently available antiarrhythmic drugs are at times ineffective and poorly tolerated during the postcardiopulmonary bypass period when myocardial function is impaired.
In this preliminary study, we investigated the potential role of dexmedetomidine during perioperative atrial and junctional tachyarrhythmias. The primary outcome, i.e., resolution of the arrhythmia or improved HR and rhythm leading to improved hemodynamics, was met in 13 of the 14 patients (93%) without significant adverse events.
Dexmedetomidine is an α 2 adrenoreceptor agonist with primarily sedative, analgesic and anxiolytic properties. In our previous pediatric study, we demonstrated that it can be used efficiently and without significant adverse effects after cardiac surgery.9 Its potential use, however, in the phase of arrhythmias has not been studied. The only published evidence is a metaanalysis by Wijeysundera et al. showing that the use of α 2 agonists in general had no effect on the incidence of supraventricular arrhythmias10 and three animal studies by Hayashi et al. and Kamibayashi et al. showing that dexmedetomidine can prevent epinephrine/halothane induced ventricular tachycardia.4–6 There are many unknown concerning which receptors are primarily responsible for dexmedetomidines’ possible antiarrhythmic property. Initially, Hayashi et al. suggested that this property is related to activation of the α 2 adrenoreceptors. However, later studies found evidence it is produced through its action on cerebral imidazoline receptors and an effect on the vagal nerve.5,6,11–13
In our two previous pediatric reports, we found that infants and children older than 1-yr-of-age required an average dose of 0.29 ± 0.17 μg · kg−1 · h−1 (0.1–0.75), whereas children <1-yr-of-age needed a noticeably higher dose, 0.66 ± 0.26 μg · kg−1 · h−1 (0.1–1.5) to achieve targeted sedation and analgesia.9,14 In the current study, the dexmedetomidine requirement to attain HR and rhythm control appeared to be higher. Ten patients received an average loading dose of 1.1 ± 0.5 μg/kg with a maintenance infusion of 0.9 ± 0.3 μg · kg−1 · h−1. We are not sure if this approximate 20% difference in the dose was related to the small sample size, to potentially more critically ill patients requiring more sedation/analgesia or if it really represented an increased requirement for HR control. In addition, the loading dose for Re-SVT was administered more rapidly than what is recommended for sedation by the manufacturer, 1 μg · kg−1 · min−1 vs 0.1 μg · kg−1 · min−1. Despite the higher dose and faster rate of administration the adverse effects were mild and easy to control. These findings are in agreement with other investigators. Shukry and Kennedy, reported administration of dexmedetomidine as an initial loading, 2–5 μg/kg, at a rate of 1 μg · kg−1 · min−1 as a total IV anesthetic in infants.15 Patients remained clinically and hemodynamically stable with arterial blood pressure and HR within 20%–30% from baseline. Rosen and Daume, reported a case of inadvertent dexmedetomidine infusion, 10 μg/kg at a rate of 1 μg · kg−1 · min−1.16 The patient remained hemodynamically stable with transiently elevated systemic blood pressure.
Effect on Arrhythmia Subtype
Junctional Ectopic Tachycardia
During the postoperative period, JET can be one of the most resistant and life-threatening arrhythmias. Current therapeutic algorithms include removal of exacerbating factors, such as pressors, core temperature cooling, use of amiodarone, and overdrive pacing.17,18 Amiodarone, with or without hypothermia, though effective in many cases, can be associated with significant side effects. Interestingly, there is only one pediatric, prospective, randomized, double-blind study examining the administration of amiodarone for incessant tachyarrhythmias.3 This study showed that amiodarone was effective in only 67% of the cases and was associated with an 87% incidence of significant side effects.
In the current study, dexmedetomidine was effective in all six patients. One patient, who had breakthrough episodes of JET after 33 h of well controlled rhythm, did respond acutely to repeat boluses of dexmedetomidine and it is possible that a higher dose of dexmedetomidine may have prevented it. The overall time needed to control JET rate was rather quick in most patients with a median time of 32 min.
A recent prospective study by Hammer et al.,19 investigated the electrophysiologic effects of dexmedetomidine in 12 children who underwent cardiac catheterization for possible ablation. Although this was a very small study, Hammer et al. found that dexmedetomidine depressed both sinus and AV nodal function. These findings on AV nodal depression seem to be in agreement with our results. The decrease in the HR that we witnessed in patients with JET was likely secondary to suppression of the AV node. Furthermore, despite this negative effect on the AV node, neither our study nor the study by Hammer et al. documented any episodes of CAVB. On the contrary, in this study dexmedetomidine was used in one patient who had an episode of CAVB immediately after surgery. This patient, other than a 2 h episode of hemodynamically stable CAVB, a few hours after starting dexmedetomidine, had no further CAVB events, despite continuing dexmedetomidine for >40 h. Nevertheless, the use of dexmedetomidine should be used with extreme caution in patients with or at risk for CAVB, since it may suppress the back-up junctional or ventricular escape rhythm, resulting in a hemodynamically unstable patient.
Because in many cases hypothermia is used as an adjunct to treat JET, another advantage dexmedetomidine offers is its ability to prevent shivering.20 Two patients in this study remained hypothermic without muscle relaxation and had no shivering or metabolic acidosis.
It is important to note, however, that given the lack of randomization and lack of a control group, we cannot conclude with certainty that these overall positive results are the effect of dexmedetomidine or the unpredictable, natural course of JET.
Reentry Type Supraventricular Tachycardia
As with JET, in the setting of postcardiopulmonary bypass or impaired ventricular function, Re-SVT is frequently not well tolerated. Adenosine remains the first-line option for acute termination though it may not be useful in difficult cases with multiple paroxysmal episodes. Furthermore, it may precipitate atrial fibrillation21 and it should be used with caution in patients with reactive airway disease, since it can cause severe bronchospasm.22
In this study, dexmedetomidine was effective in all four cases of Re-SVT with acute termination and no side effects. Though there are other medications that can be used in cases of Re-SVT, e.g., amiodarone, procainamide, and verapamil, dexmedetomidine offers the advantage of sedation and analgesia that most patients require in an ICU setting. Furthermore, both amiodarone and procainamide carry a significant adverse profile, including hypotension, negative inotropic effect and arrhythmias. Verapamil, on the other hand, has a relative contraindication in patients <1-yr-old and should be used with extreme caution because of potential refractory hypotension and cardiac arrest.
Junctional Accelerated Rhythm
Although there is not enough literature evidence about JAR and its progression to JET, we do know that certain types of congenital heart surgery are at a higher risk of developing JET.23,24 Furthermore, we know that JAR and JET seem to share the same pathomechanism and for many, JAR is actually considered a slower type of JET. Therefore in the context of high risk surgeries for JET, preemptively treating JAR to prevent possible progression to JET would make sense.
Two high-risk surgery patients in this study developed JAR and were treated with dexmedetomidine. Both responded well with decreasing HRs and never developed JET. Nonetheless, we do not know if this prevention of JET represents a dexmedetomidine effect or actual natural history of JAR.
Atrial Ectopic Tachycardia
One patient was treated with dexmedetomidine for amiodarone resistant AET. Soon after dexmedetomidine was started there was remarkable improvement and eventually conversion to NSR. It is clearly possible that dexmedetomidine’s effect may have been influenced by amiodarone, which has a very long half-life. On the other hand, the lack of any substantial benefit from amiodarone and the remarkable change minutes after dexmedetomidine was started, led us to believe that this was primarily related to dexmedetomidine’s effect.
Other than ibutilide, which is associated with a frequent incidence of ventricular fibrillation, no drug has been shown to be highly effective in conversion of AF. In this report, dexmedetomidine administration was unsuccessfully attempted in one case. This patient had a history of chronic, recurrent AF that is more resistant to chemical cardioversion than new onset AF.25 It is also possible that the time allowed for conversion (20 min) was too short. Many times, patients with chronic AF can not be chemically cardioverted or when they are, it may take hours or days to accomplish this.
- This study was based on an intention-to-treat approach and not a case-control format and biases towards positive results.
- There was no control group or randomization performed to compare dexmedetomidine with a more frequently used antiarrhythmic drug such as amiodarone.
- In some patients, it maybe difficult to distinguish the natural history of the arrhythmia, a delayed onset of amiodarone, or a possible synergistic effect between amiodarone and dexmedetomidine from an actual dexmedetomidine effect.
- Given that 9 of the 14 patients were transiently paced to improve AV synchrony, we may have under-estimated the incidence of underlying bradycardia.
- All patients were infants so the findings may not be applicable to older age groups.
- The number of patients included in this study was very small, and for some arrhythmias there were one or two patients only.
This preliminary, nonrandomized, noncontrolled, observational study shows that dexmedetomidine may have a potential therapeutic role in the acute phase of perioperative atrial and junctional tachyarrhythmias for HR control and/or conversion to NSR.
Nonetheless, larger prospective studies are needed to confirm these results. Dexmedetomidine remains primarily a sedative drug and thus its potential use during arrhythmias is not warranted in patients who do not require additional sedation, analgesia or anxiolysis.
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