Milrinone reduces the risk of low cardiac output syndrome for some pediatric patients after congenital heart surgery. Data from adults undergoing cardiac surgery suggest an association between milrinone and an increased risk of postoperative arrhythmias. We tested the hypothesis that milrinone is an independent risk factor for tachyarrhythmias after congenital heart surgery. Subjects undergoing congenital heart surgery at our institution were consecutively enrolled for 38 months, through September 2010. The data were prospectively collected, including a review of full-disclosure telemetry and the medical records. Within 38 months, 603 enrolled subjects underwent 724 operative procedures. The median age was 5.5 months (range 0.0 to 426), the median weight was 6.0 kg (range 0.7 to 108), and the cohort was 45% female. The overall arrhythmia incidence was 50%, most commonly monomorphic ventricular tachycardia (n = 85, 12%), junctional ectopic tachycardia (n = 69, 10%), accelerated junctional rhythm (n = 58, 8%), and atrial tachyarrhythmias (including atrial fibrillation, atrial flutter, and ectopic or chaotic atrial tachycardia, n = 58, 8%). Multivariate logistic regression analysis demonstrated that independent of age <1 month, the use of cardiopulmonary bypass, the duration of cardiopulmonary bypass, Risk Adjusted classification for Congenital Heart Surgery, version 1, score >3, and the use of epinephrine or dopamine, milrinone use on admission to the cardiac intensive care unit remained independently associated with an increase in the odds of postoperative tachyarrhythmia resulting in an intervention (odds ratio 2.8, 95% confidence interval 1.3 to 6.0, p = 0.007). In conclusion, milrinone use is an independent risk factor for clinically significant tachyarrhythmias in the early postoperative period after congenital heart surgery.
Off-label use of the phosphodiesterase inhibitor milrinone is common after congenital heart surgery in children. The prophylactic use of milrinone in some children has been shown to reduce the risk of low cardiac output syndrome after congenital heart surgery. Although few reported data in pediatric congenital heart surgery studies are available to suggest an association between milrinone use and postoperative arrhythmias, data have emerged supporting such an association in adults undergoing elective cardiac surgery. We hypothesized that milrinone was also an independent risk factor for clinically significant tachyarrhythmias after congenital heart surgery.
Methods
The subjects included in the present analysis were enrolled in the ongoing prospective, observational Postoperative Arrhythmia in Congenital Heart Surgery (PACS) study. All patients undergoing congenital heart surgery at Monroe Carell, Jr. Children’s Hospital at Vanderbilt and subsequently admitted to the pediatric cardiac intensive care unit (CICU) from July 2007 through September 2010 were prospectively approached for enrollment. The Vanderbilt University Institutional Review Board for Research on Human Subjects approved the present study. Each patient’s parents or legal guardians provided written informed consent, and patient assent was obtained as age appropriate.
The perioperative data collection included patient demographic characteristics, anatomic diagnoses, noncardiac medical history, preoperative medications, any history of arrhythmias, and any family history of arrhythmias. Any history of preoperative arrhythmia was ascertained both through chart review and enrollment history. The operative details noted included the primary procedure and any associated secondary procedures, in addition to the aortic cross-clamp and cardiopulmonary bypass times. Operative procedures were also categorized according to the Risk Adjusted Classification for Congenital Heart Surgery, version 1 (RACHS-1), method. Patients received general endotracheal anesthesia, traditionally consisting of induction with a combination of fentanyl or etomidate and pancuronium, and maintenance with fentanyl, isoflurane, and pancuronium. Vasopressors and inotropes were used, with separation from the cardiopulmonary bypass at the surgeon’s and anesthesiologist’s discretion. Milrinone therapy was also specifically initiated at the discretion of the anesthesiologist and surgeon. Administration often consisted of a loading dose of 50 μg/kg during the termination of cardiopulmonary bypass, followed by a continuous infusion at a rate of 0.25 to 1.0 μg/kg/min. Milrinone was also often used for patients who did not undergo cardiopulmonary bypass. Again, this practice was instituted at the discretion of the anesthesiologist and surgeon.
The early postoperative data recorded included admission pH, serum lactate, hematocrit, serum electrolytes, and continuous infusions administered on admission to the CICU. Patients underwent continuous monitoring with a full-disclosure telemetry system (Phillips Medical Systems, Bothell, Washington) for the duration of their hospitalization. The study personnel reviewed the telemetry recordings daily at a central station, and all arrhythmias were confirmed and coded by a board-certified pediatric cardiologist. Each postoperative arrhythmia was coded with respect to the location of onset, type, and any associated therapy. Serum electrolytes were assessed and replaced either parenterally or enterally at the discretion of the provider, traditionally with goals of maintaining potassium 3.5 to 5.0 mEq/L, ionized calcium 4.5 to 5.5 mg/dl, and serum magnesium 1.8 to 2.2 mEq/L. Sedation, analgesia, and neuromuscular blockade were all managed at the discretion of the anesthesia and CICU teams.
The present study was designed to capture all arrhythmias, including those clearly resulting from discrete events such as myocardial ischemia or hypoxia. If a subject underwent >1 operative procedure during an admission, an arrhythmia after the second procedure was classified as an arrhythmia only if the arrhythmia was distinctly different in morphology and character relative to previous arrhythmias. Furthermore, numerous subjects experienced >1 class of arrhythmia after a single operative procedure. These events were also classified as 2 separate arrhythmias if the arrhythmia was distinctly different in morphology and character relative to the previous rhythm disturbances. Arrhythmias originating in the operating room were captured only if sustained on admission to the CICU. An arrhythmia was considered clinically significant for the purposes of this investigation if it directly led to a provider intervention, including pharmacotherapy, vagal maneuvers, surface cooling, temporary or permanent pacing, pace termination of a re-entrant tachycardia, direct current cardioversion or defibrillation, or cardiopulmonary resuscitation. Monomorphic ventricular tachycardia was defined as a uniform, wide-complex rhythm consistent with a ventricular origin, >2 beats in duration (nonsustained) or 30 seconds in duration (sustained). Ventricular tachycardia and junctional ectopic tachycardia were each differentiated from accelerated ventricular and junctional rhythm, respectively, by an increase in rate of >10% above the baseline rate, noted before the onset of tachycardia.
Normally distributed continuous data are reported as the mean ± SD or median (range) in the case of non-normally distributed variables. Categorical variables are reported as frequencies with percentages. The demographic and clinical data were compared using the Mann-Whitney U test for continuous variables and the chi-square or Fisher’s exact test, as appropriate, for categorical variables. The odds of tachyarrhythmia were assessed through both univariate and multivariate logistic regression analyses. Variables with a univariate significance threshold (determined a priori) of p <0.1 were considered for inclusion within the multivariate logistic regression model after assessing for multicollinearity. Patient weight and admission lactate, although significant on univariate analysis, were each excluded from additional multivariate analysis due to multicollinearity with patient age ( R 2 = 0.85, p <0.001) and cardiopulmonary bypass time ( R 2 = 0.24, p <0.001), respectively. The RACHS-1 category also demonstrated weak multicollinearity with cardiopulmonary bypass time ( r 2 = 0.12, p <0.001), but remained within the multivariate analysis as a recognized index of surgical complexity. The number of covariates included within the model was limited to 1 covariate for every 10 events. All multivariate models underwent assessment of fit with the Hosmer and Lemeshow goodness-of-fit test. Data from logistic regression analyses are reported as the estimated odds ratios (ORs) and 95% confidence intervals (CIs). Data were analyzed using the Statistical Package for Social Sciences, version 18 (SPSS, Chicago, Illinois). We had full access to, and take full responsibility for, the integrity of the data, and all have read and agreed to the manuscript as written.
Results
From July 2007 through September 2010, 603 subjects were enrolled in the study and underwent 724 operative procedures. The baseline demographic data are summarized in Table 1 . Nearly ¼ of all operative procedures were undertaken in children <30 days old, and >1/3 had at least one documented arrhythmia preoperatively. As demonstrated in the operative characteristics ( Table 2 ), there was a broad distribution of operative procedures represented in this cohort. Of the 724 operative procedures, 116 (16%) were performed without cardiopulmonary bypass.
| Characteristic | Value |
|---|---|
| Age (months) | 5.5 (0.0–426) |
| Age <1 month | 175 (24%) |
| Weight (kg) | 6.0 (0.7–108) |
| Females | 327 (45%) |
| Primary lesion ⁎ | |
| Hypoplastic left heart syndrome | 90 (12%) |
| Atrioventricular canal defect | 84 (12%) |
| Tetralogy of Fallot | 69 (9.5%) |
| Ventricular septal defect | 65 (9.0%) |
| Coarctation of the aorta | 48 (6.6%) |
| Secundum atrial septal defect | 43 (5.9%) |
| Double outlet right ventricle | 40 (5.5%) |
| Preoperative arrhythmia (% yes) | 268 (37%) |
| Characteristic | Value |
|---|---|
| Primary procedure ⁎ | |
| Ventricular septal defect closure | 64 (9%) |
| Tetralogy of Fallot | 53 (7%) |
| Bidirectional Glenn | 51 (7%) |
| Coarctectomy | 47 (7%) |
| Fontan | 43 (6%) |
| Stage 1 (Norwood) palliation | 43 (6%) |
| Systemic to pulmonary artery shunt | 41 (6%) |
| Atrioventricular canal repair | 40 (6%) |
| Secundum atrial septal defect closure | 29 (4%) |
| Arterial switch | 26 (4%) |
| Primum atrial septal defect closure | 25 (4%) |
| Truncus arteriosus repair | 8 (1%) |
| Total anomalous pulmonary venous return repair | 7 (1%) |
| Risk adjusted classification for congenital heart surgery, version 1, classification | |
| 1 | 66 (9%) |
| 2 | 287 (39%) |
| 3 | 242 (33%) |
| 4 | 33 (5%) |
| 6 | 48 (7%) |
| Unable to classify | 48 (7%) |
| Cardiopulmonary bypass time (min) | 102 (0–731) |
| Cross-clamp time (min) | 36 (0–217) |
The incidence of ≥1 documented arrhythmia occurring after an operative procedure was 50% (n = 365). Of these, 65% (n = 237) were deemed clinically significant to warrant at least one type of therapeutic intervention. The specific arrhythmias noted in the early postoperative period are detailed in Table 3 . Although monomorphic ventricular tachycardia was the most commonly reported arrhythmia, junctional and atrial tachycardias more frequently prompted therapeutic intervention. Of all the recorded tachyarrhythmias (n = 392), 208 (53%) prompted ≥1 intervention. These included surface cooling in 28% (n = 111), atrial overdrive pacing in 21% (n = 82), amiodarone administration in 18% (consisting of either a loading dose or continuous infusion, n = 70), pace termination in 7% (n = 27), adenosine administration in 6% (n = 25), and synchronized cardioversion in 3% (n = 10).
| Variable | Overall | Treated |
|---|---|---|
| Arrhythmia incidence | 365 (50%) | 239 (66%) |
| Tachyarrhythmia incidence | 267 (37%) | 158 (59%) |
| Tachyarrhythmia | ||
| Monomorphic ventricular tachycardia | 85 (12%) | 23 (27%) |
| Junctional ectopic tachycardia | 69 (10%) | 61 (88%) |
| Accelerated junctional rhythm | 58 (8%) | 32 (55%) |
| Atrial tachyarrhythmia | 58 (8%) | 33 (57%) |
| Accelerated ventricular rhythm | 41 (6%) | 8 (20%) |
On admission to the CICU, milrinone, dopamine, and epinephrine were the most commonly administered continuous infusions, with milrinone administered in >70% of the operative procedures in this cohort. Milrinone was used in combination with other inotropes, including dopamine (n = 182, 25%) and epinephrine (n = 83, 12%) most commonly. The vasoconstrictor agents vasopressin (n = 16, 2%) and norepinephrine (n = 4, 0.5%) were also accounted for but were rarely used in our cohort.
Univariate analysis was performed using the incidence of postoperative tachyarrhythmia as a dichotomous end point ( Table 4 ). A total of 267 operative procedures resulted in ≥1 instance of a documented tachyarrhythmia, and 392 total events were classified as distinct tachyarrhythmias. Of all tachyarrhythmias recorded among the 724 operative cases, 8% (n = 30) were classified as first noted in the operating room, 81% (n = 318) in the CICU, and 11% (n = 44) after floor transfer. Most of these tachyarrhythmias occurred on postoperative day 0 (n = 278, 71%), with an additional 12% (n = 48) occurring by the conclusion of postoperative day 1.
| Variable | No (n = 457) | Yes (n = 267) | OR (95% CI) | p Value |
|---|---|---|---|---|
| Age (months) | 5.9 (0.0–275) | 4.6 (0–276) | 1.0 (0.99–1.001) | 0.33 |
| Age <1 month | 89 (19%) | 86 (32%) | 2.0 (1.4–2.8) | <0.001 |
| Weight (kg) | 6.3 (0.7–108) | 5.4 (1.6–97) | 1.0 (0.98–1.006) | 0.52 |
| Males | 236 (52%) | 161 (60%) | 1.4 (1.1–1.9) | 0.03 |
| History of preoperative arrhythmia | 166 (36%) | 102 (38%) | 1.1 (0.8–1.5) | 0.61 |
| Use of cardiopulmonary bypass | 359 (79%) | 259 (97%) | 10.0 (4.8–20.8) | <0.001 |
| Cardiopulmonary bypass time (min) | 88 (0–499) | 130 (0–731) | 1.011 (1.008–1.013) | <0.001 |
| Risk Adjusted classification for Congenital Heart Surgery, version 1, >3 | 35 (8%) | 44 (17%) | 2.5 (1.5–3.9) | <0.001 |
| At cardiac intensive care unit admission | ||||
| Initial pH | 7.35 ± 0.1 | 7.34 ± 0.1 | 0.27 (0.05–1.4) | 0.13 |
| Initial lactate (mmol/L) | 2.6 ± 2.5 | 4.1 ± 3.0 | 1.2 (1.1–1.3) | <0.001 |
| Dopamine | 122 (27%) | 99 (37%) | 1.6 (1.2–2.2) | 0.006 |
| Epinephrine | 36 (8%) | 55 (21%) | 3.0 (1.9–4.7) | <0.001 |
| Milrinone | 280 (62%) | 235 (88%) | 4.5 (3.0–6.9) | <0.001 |
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