Abstract
OBJECTIVE
To evaluate the safety of the combination of methadone and an atypical antipsychotic in PICU patients.
METHODS
This was a retrospective observational cohort pilot study in a single-center PICU in an academic children's hospital. Children 1 month to 18 years of age were included if they received methadone, were then initiated on an atypical antipsychotic (i.e., quetiapine or risperidone), and had EKG monitoring before and after medication initiation.
RESULTS
Prolongation of the corrected QT (QTc) interval occurred in 5 of the 34 included patients when an atypical antipsychotic was added to methadone. Of the 5 patients who had a prolonged QTc interval, 4 (80%) were older than 12 years and had a median weight of 91.3 kg. There were statistical differences between age and weight when comparing patients who experienced QTc prolongation, but no differences in sex, ethnicity, electrolyte deficiencies, number of additional QTc-prolonging medications, and number of additional drug-drug interactions were identified. When comparing atypical antipsychotics, 9.5% of patients receiving risperidone had a prolonged QTc interval, versus 23% of patients receiving quetiapine (p = 0.04). The net change in QTc interval after initiation of methadone was 0.19 milliseconds (IQR: −3, 15), which increased after atypical antipsychotic initiation to 4 milliseconds (IQR: −16, 15).
CONCLUSIONS
Our pilot trial suggests there is no clinically significant difference in incidence of QTc prolongation with addition of atypical antipsychotics to methadone.
Keywords: antipsychotic agents; child; critically ill; intensive care units, pediatric; long QT syndrome; methadone
Introduction
Admission to the PICU frequently requires administration of multiple sedatives and analgesics to achieve patient comfort during a time of critical illness. Use of these medications as well as disrupted sleep-wake cycle because of nursing care, monitoring, and frequent stimulation lead to risk for PICU delirium. Failure to recognize and treat delirium in mechanically ventilated pediatric patients has resulted in increased morbidity and mortality during the hospital admission.1 Prevention is targeted by use of an appropriate assessment tool, minimizing of environmental factors, and limiting use of medications that may lead to delirium, including anti-cholinergic agents and benzodiazepines.2–4 Treatment of delirium includes managing the underlying disease, recognizing iatrogenic factors, instituting environmental modifications, and, finally, pharmacologic treatment with antipsychotics. There are limited data regarding the choice of antipsychotic for treatment of pediatric delirium, but currently an atypical antipsychotic, for example, risperidone or quetiapine, is preferred over haloperidol.5,6
Methadone, an opioid with a longer half-life than morphine, is often used to prevent iatrogenic abstinence syndrome when patients are weaning off long-term continuous opioid infusions.7 Both atypical antipsychotics and methadone are associated with the risk of interval prolongation of QT corrected for heart rate (QTc); this risk can be increased if agents associated with QTc prolongation are used concomitantly.8–10 Corrected QT prolongation increases the risk of syncope and fatal arrhythmias. Because there are limited studies evaluating QTc prolongation in pediatrics while the patient is on methadone and an atypical antipsychotic, clinicians at our institution cautiously use both agents concomitantly.
Heath et al8 evaluated methadone effects on QTc prolongation in 64 critically ill children and found no significant increase in QTc interval with methadone. Their study concluded that there is still the need for a prospective and larger study to confirm that methadone has little impact on the QTc interval. Corrected QT prolongation has been reported5 in up to 6% of patients receiving quetiapine and even less often with administration of risperidone in delirium treatment studies involving pediatric patients. Additional evidence of QTc prolongation with methadone and antipsychotic agent monotherapy in children is largely based on case reports, with a lack of larger trials; we aim to contribute data that may help optimize withdrawal and delirium medication selection while avoiding the risks of QTc prolongation in a critically ill pediatric population. The purpose of this pilot study was to evaluate the safety of the combination of methadone and an antipsychotic agent in PICU patients.
Materials and Methods
Patient Population. In this retrospective study, patients were included if they had been admitted to the medical PICU between January 2015 and July 2018, received methadone, were then initiated on an antipsychotic agent (i.e., quetiapine or risperidone), and had an EKG completed during methadone monotherapy and after antipsychotic agent initiation. Patients were excluded if they had received an antipsychotic agent prior to initiation of methadone, had no EKG data available, displayed a prolonged QTc interval at baseline, or had chronic methadone or antipsychotic agent use. The primary outcome was incidence of QTc prolongation after initiation of an antipsychotic to methadone. Corrected QT prolongation was defined as an interval greater than 450 milliseconds or an increase in QTc interval of 20 milliseconds from baseline.10,11 Additionally, a subcategory of patients were evaluated who experienced severe QTc prolongation or a QTc interval of greater than 500 milliseconds, which indicates increased risk for a pro-arrhythmic state such as torsades de pointes.12 Secondary outcomes included comparing the incidence of QTc prolongation risk with either quetiapine or risperidone and comparing the net change in EKG post-methadone and post-antipsychotic initiation.
Data Collection. Patient data collected included age, sex, weight, ethnicity, electrolyte deficiencies, dosing, number of additional QTc-prolonging medications, and number of additional drug-drug interactions. Other QTc-prolonging medications were determined by Credible Meds, a resource describing clinical factors and medications associated with prolonged QT, to have an independent risk of torsades even when taken as prescribed.9 Drug-drug interactions that could increase concentrations of methadone and/or antipsychotic agent were also recorded (Table 1).13 An EKG was initially obtained from the electronic medical record and then all readings were manually confirmed by a pediatric cardiology fellow. Corrected QT was calculated using the Bazett formula.14 All EKG data prior to initiation of either agent and after initiation of both methadone and an antipsychotic agent were collected. Labs obtained within 24 hours of the EKG readings were also collected, and electrolyte abnormalities were categorized based on the following rules: hypomagnesemia was defined as <1.5 mg/dL; hypermagnesemia was defined as >2.3 mg/dL; hypokalemia was defined as <3.3 mmol/L in infants; <3.5 mmol/L in ages 1 year and greater; hyperkalemia was defined as >5.5 mmol/L; hypocalcemia was defined as <8.8 mg/dL or an ionized calcium of <1 mmol/L; and hypercalcemia was defined as >10.4 mg/dL or an ionized calcium of >2.6 mmol/L.
Table 1.
QTc-Prolonging Medications
|
Drug-Drug Interactions
|
CYP, cytochrome P450; QTc, QT interval corrected for heart rate
Statistical Analysis. An approximate sample size of 154 was estimated to achieve 80% power for this study, with alpha set at 0.05. Sample size was calculated using an incidence of QTc prolongation with methadone of 21% and for quetiapine and risperidone of 22%.8,11 An expected incidence of QTc prolongation on both agents could be upward of 43%. Demographic data were collected using counts and percentages for categorical data and mean ± SD or median (IQR) for continuous data, depending upon distribution normality. Statistical tests were performed in Minitab (State College, PA), which consisted of chi-square for categorical data and Mann-Whitney U-test for continuous data.
Results
Baseline Characteristics. Of the 110 potentially eligible patients screened for the study, 76 patients were excluded (54 patients were initiated on atypical antipsychotic prior to methadone, 19 had incomplete EKG data, and 3 had a prolonged QTc interval at baseline), resulting in 34 patients included for analysis. Of these patients, 13 received methadone and quetiapine and 21 received methadone and risperidone. Patients were primarily Caucasian males, with a median age in the quetiapine group of 12 years (6.6 to 17.6 years) and in the risperidone group of 5 years (0.22 to 10.2 years). The quetiapine group received a median (IQR) quetiapine and methadone dose of 0.64 (0.51–1) mg/kg/day and 0.21 (0.19–0.39) mg/kg/day, respectively. The risperidone group received a median (IQR) risperidone and methadone dose of 0.01 (0.007–0.028) mg/kg/day and 0.29 (0.22–0.39) mg/kg/day, respectively. Patients in the quetiapine group were more likely to have concomitant hypokalemia or hypocalcemia, at a combined 66.7%, compared with 21.1% in the risperidone group.
QTc Prolongation. Corrected QT prolongation occurred in 5 of our 34 patients (14.7%; Table 2). Only one patient receiving risperidone had severe QTc prolongation with an interval > 500 milliseconds. When comparing antipsychotic agents, we found that 2 of the 21 patients (9.5%) receiving risperidone had a prolonged QTc compared with 3 of the 13 patients (23%) (p = 0.04) receiving quetiapine. Of the 5 total patients who had prolonged QTc, 4 (80%) were older than 12 years (range: 3–16 years) and weighed more than 68 kg (Table 3). Additionally, these patients received an antipsychotic agent for a median duration of 21.8 days (IQR: 7, 42.5). All 5 patients had at least one electrolyte deficiency; hypocalcemia had the highest prevalence (60%). No electrolyte elevations were noted. These patients received a methadone dose of 0.2 to 1 mg/kg/day.
Table 2.
Patient Characteristics: QTc Prolongation Versus No QTc Prolongation
| Characteristic | QTc Prolongation (n = 5) | No QTc Prolongation (n = 29) | p value |
|---|---|---|---|
| Age, median (IQR), yr | 13 (7.5–14.5) | 7 (3–12) | 0.02 |
| Weight, median (IQR), kg | 91.3 (39.7–99.5) | 25.4 (14.7–37.4) | 0.01 |
| Sex, n (%), female | 2 (40) | 10 (34.5) | 0.81 |
| Race, n (%), Caucasian | 3 (60) | 21 (82.7) | 0.57 |
| QTc prolongation on methadone monotherapy, n (%) | 2 (40) | 6 (20.1) | 0.35 |
| Hypomagnesemia, n (%) | 0 (0) | 10 (34.4) | 0.39 |
| Hypocalcemia, n (%) | 3 (60) | 16 (55.2) | 0.84 |
| Hypokalemia, n (%) | 4 (80) | 23 (79.3) | 0.97 |
QTc, QT interval corrected for heart rate
Table 3.
Patients With QTc Prolongation With Methadone Plus Antipsychotic Agents
| Patient | Age, yr (Weight, kg) [Sex] | QTc, msec | Antipsychotic Agent | Methadone, mg/day | Electrolyte Deficiencies | Additional QTc-Prolonging Agents, n | Drug Interactions, n | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | Post | Agent | Dose, mg/day | Duration, days | Hypomagnesemia | Hypokalemia | Hypocalcemia | |||||
| 1 | 13 (103) [Female] | 393 | 441 | Quetiapine | 50 | 3 | 20 | No | Yes | Yes | 2 | 2 |
| 2 | 12 (68.2) [Male] | 425 | 452 | Quetiapine | 50 | 72 | 20 | No | No | No | 4 | 1 |
| 3 | 13 (96.1) [Male] | 417 | 456 | Quetiapine | 50 | 13 | 20 | No | Yes | Yes | 2 | 1 |
| 4 | 3 (16.5) [Male] | 404 | 481 | Risperidone | 0.1 | 13 | 10 | No | No | Yes | 1 | 2 |
| 5 | 16 (91.3) [Female] | 423 | 544 | Risperidone | 0.5 | 8 | 20 | No | Yes | Yes | 1 | 2 |
QTc, QT interval corrected for heart rate
Additionally, patients who experienced QTc prolongation had at least one cytochrome P450 drug interaction (range: 1–2) and received at least one (range: 1–4) QTc prolongation medication (Table 3). It was discovered that the percentage of patients receiving 2 or more additional QTc-prolonging drugs was less in the group that did not experience QTc prolongation (40% versus 51.8%; Figure 1). These findings were similar when evaluating the cytochrome P450 drug interactions (Figure 2).
Figure 1.
Additional QTc-prolonging agents.
Figure 2.
Cytochrome P450 drug interactions.
Because of the small sample size of our population, we also evaluated patients who experienced QTc prolongation on methadone or an antipsychotic agent and compared them with patients without QTc prolongation. The population no longer had significant differences between age and weight. There were no differences between the baseline characteristics, except that hypomagnesemia was more common in patients with no QTc prolongation, although this difference was not statistically significant (Table 2). Patients with QTc prolongation had fewer drug interactions and received fewer QTc prolongation medications; this was consistent with findings in patients who had a prolonged QTc after initiation of an antipsychotic agent (Figures 1 and 2). The net change in QTc interval after initiation of methadone was 0.19 milliseconds (IQR: −3, 15). The net change in QTc after initiation of methadone and atypical antipsychotic was 4 milliseconds (IQR: −16, 15). This difference was not significant (p = 0.92).
Discussion
To date this is the largest pilot study to evaluate the effects on the QTc interval with the combination of methadone and an antipsychotic agent in the PICU population. Our study found QTc prolongation in 15% of patients who received an antipsychotic agent in addition to methadone therapy. Furthermore, 80% of these patients were >12 years of age, weighed 68 kg or more, and were receiving methadone at a dose of 20 mg/day (Table 3). Although this study was unable to meet power, patients who meet these criteria may benefit from frequent EKG monitoring when using combined methadone and antipsychotic therapy.
In a case report, Brahmbhatt and Whitgob6 documented low-dose risperidone (0.125 mg daily) with IV methadone (2.6 mg/kg/day) without adverse effects or an increase in QTc interval in a 5-month-old, trisomy 21 patient. Risperidone was titrated up to a dose of 0.3 mg daily in this infant without QTc prolongation. This report is one of the current published cases assessing QTc prolongation risk with the combination of an anti-psychotic agent and methadone. However, there have been no larger studies completed to evaluate the safety and efficacy of this combination. Heath et al8 evaluated methadone effects on QTc prolongation in critically ill children and found no significant increase in QTc interval with methadone. This finding did not reflect previous results of QTc prolongation seen with methadone use in an adult population. Heath et al concluded that there remains a need for a prospective and larger study to confirm that methadone has little impact on the QTc interval. A systematic review of antipsychotic use in the PICU from Capino et al5 found that 13% (3 patients) developed QTc prolongation, with quetiapine being the most common agent; our study aligns with these data.
The combination of medications known to increase the QTc interval has been shown11,13 to increase risk for fatal arrhythmias. Interestingly, in our study, the group that experienced QTc prolongation received fewer QTc-prolonging drugs. Patients were found to receive up to 5 additional QTc-prolonging medications without prolongation of QTc. This was also true for cytochrome P450 drug-drug interactions, because the group with more drug interactions, which one would expect would have a greater risk for QTc prolongation, did not experience QTc prolongation. While median duration for patients on both an antipsychotic and methadone was recorded, the exact time at which the prolongation occurred was not collected. Typically, prolongation was identified around week 1 of antipsychotic agent therapy. Therefore, median duration was likely not a driver for prolongation in our patients.
These data are not consistent with previously identified adult data, in which QTc prolongation risk is additive with agents. In healthy aging adults, it is hypothesized that QTc prolongation risk is affected by changes within the fibrosis of the myocardium, compounded by changes in medications that affect the risk of QTc prolongation. Specifically, opioid agonists, including methadone, can induce prolongation by blocking human ether-a-go-go-related gene K+ current in human cells, within the sodium-potassium pathway.15 This combination could be the result of QTc prolongation and arrhythmias in adults and supports the idea that younger healthy patients are at less risk compared with adults.
Researchers11,16 have attempted to identify the incidence of QTc prolongation with varying antipsychotic agents. It is estimated that quetiapine prolongs the QTc interval by 6 to 15 milliseconds and risperidone by 3.5 to 10 milliseconds. Our results could support this effect that risperidone and quetiapine have on the QTc interval. The low millisecond difference between risperidone versus quetiapine is likely not reliable because of small sample size and is likely does not reflect enough of an interval change to induce arrhythmia, making this finding not clinically significant.
Our study has several limitations. Most significantly, the study population was limited in number and did not meet power. It did not account for potential changes in the QTc interval outside of the snapshot in time of the EKG reading. Therefore, patients could have experienced more or less QTc prolongation incidence outside of this specified time frame. Although methadone dosing was similar among the 2 groups, other medication may have affected our results. Fluconazole and ondansetron were the most common additional QTc-prolonging agents and were dosed appropriately for age and weight. However, midazolam represented the most common drug-drug interaction, and dosing was variable, from intermittent to continuous infusion, as expected in an ICU population. Furthermore, being retrospective in nature, we were unable to account for potential pharmacogenomics differences in patients and for any variable metabolism of these agents. Additionally, the population that was evaluated may be considered low risk because patients from the cardiovascular ICU, which contains patients with preexisting cardiac conditions or congenital heart abnormalities, were not included.
Conclusions
In our small cohort study, there was no clinically significant difference in incidence of QTc prolongation with addition of antipsychotic agent to methadone. Furthermore, the number of drug-drug interactions and QTc-prolonging drugs did not increase risk of QTc. Therefore, our data suggest that it is safe to add antipsychotic agent therapy to methadone in the PICU population. However, our small sample size showed there may be situations in which patients could benefit from increased monitoring, for example, in older patients (>12 years) who are higher weight (>70 kg).
Results from this study have been incorporated into institutional education to increase awareness surrounding appropriate EKG monitoring by the PICU as QTc-prolonging agents are added to a patient's regimen. Future studies with this data set include analyzing patients who received an atypical antipsychotic prior to initiation of methadone. Additionally, larger prospective studies should be implemented to confirm the results.
Acknowledgments
Preliminary results were presented at the ACCP Resident Poster Presentation on October 26–29, 2019. The authors would like to acknowledge Shannon M. Lyon, DO, for her help in reading and interpreting EKG results.
ABBREVIATIONS
- EKG
electrocardiogram
- PICU
pediatric intensive care unit
- QTc
QT interval corrected for heart rate
Footnotes
Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Ethical Approval and Informed Consent. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and the study has granted “Exempt Approval” by the appropriate committees at our institution (Protocol 1808167517). Given the retrospective nature of the project, informed consent was not required.
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