Electrocardiogram Before Tricyclic Antidepressant Use: Minimal Impact in Pediatric Functional Gastrointestinal Disorders

Abstract

Objectives: 

The aim of this study was to determine the effect of electrocardiogram (ECG) findings on the initiation of tricyclic antidepressants (TCAs) for functional gastrointestinal disorders (FGIDs) and to evaluate cardiac outcomes related to low dose TCA use.

Methods: 

We performed a retrospective chart review of all pediatric outpatients at a tertiary pediatric hospital with an ECG ordered by a pediatric gastroenterologist when considering initiation of a TCA between January 2011 and February 2018. We collected demographics, previous cardiovascular testing results, TCA dosing, and pertinent outcomes, including cardiology referrals, emergency department, and hospital admissions, and death during the study period. All ECGs were reviewed for corrected QT (QTc) interval, heart rate, and other abnormalities.

Results: 

Of 233 patients with screening ECGs, most (84.1%) were prescribed a TCA. Functional abdominal pain or dyspepsia account for 82.0% of diagnoses. Initial TCA dosing of amitriptyline varied widely, 10–50 mg/day, and the dose was not associated with QTc intervals. TCAs were not started in only 1.7% (4/233) due to ECG results. A significant ECG abnormality prompting cardiology referral was found in eight (3.4%) with a prolonged QTc interval in one (0.4%). In 10.7% (25/233) of patients, screening ECG was obtained despite available ECG in the chart. No deaths and no emergency department or hospital visits for arrhythmia or drug overdose occurred.

Conclusion: 

Screening ECGs infrequently influence TCA initiation and may lead to increased resource utilization. The overall frequency of cardiology referral due to ECG results is low. Serious adverse cardiac events are unlikely with low dose TCA administration.

What Is Known/What Is New

What Is Known

• Tricyclic antidepressants (TCAs) are often prescribed at a low dose to treat functional gastrointestinal disorders (FGIDs).
• Current practice utilizes electrocardiogram screening before the administration of TCAs for FGIDs.

What Is New

• Screening electrocardiograms infrequently influence TCA prescription for FGIDs.
• Serious adverse cardiac events appear unlikely with low dose TCA administration utilized for FGIDs.

Functional gastrointestinal disorders (FGIDs) are classified by gastrointestinal symptoms related to disordered gut–brain interaction ⁽¹⁾. FGIDs are common in pediatrics and have a significant impact on the quality of life of affected children ⁽²⁾. Treatment regimens are often empirical, with no specific treatment regimen uniformly effective.

Pediatric gastroenterologists treat FGID associated refractory abdominal pain with tricyclic antidepressants (TCAs), predominantly amitriptyline. TCAs function by affecting pain pathways and/or treating comorbid psychological conditions ⁽³⁾. In a pediatric trial, the therapeutic benefit of low dose amitriptyline was not significantly better than placebo, highlighting the benefit of placebos in the management of FGIDs ⁽⁴⁾.

Consideration of the risk profile of TCAs is critical if their benefit is not greater than placebo. TCAs prolong cardiac repolarization corrected QT (QTc) interval, which can lead to ventricular tachycardia and cardiac death, especially in those with ischemic or structural heart disease ⁽⁵⁾. The QTc interval changes are considered dose-dependent ⁽⁶⁾. Previous TCA safety studies have been for depression treatment doses, which are much higher than dosing for FGIDs.

The existing literature on the safety of TCAs for FGIDs is limited without firm guidelines on use leading to wide practice variability. Generally, pediatric gastroenterologists will obtain a baseline electrocardiogram (ECG) to establish the patient's QTc interval ⁽⁷⁾. The practice of obtaining follow-up ECGs for QTc interval monitoring is more variable, with some questioning its utility ⁽⁸⁾. We aimed to determine the effect of ECG findings on the management of the most common TCA, amitriptyline, for FGIDs, and resource utilization of repeat ECGs and evaluate cardiac outcomes related to low dose amitriptyline use.

METHODS

Study Population

We conducted a single-center, retrospective chart review of all patients age <18 years with an ECG ordered during an outpatient pediatric gastroenterology visit at a tertiary referral center from January 2011 to February 2018. Subjects were identified using the Duke Enterprise Data Unified Content Explorer. For all subjects, demographic data (including age, sex, race, ethnicity), weight, family history, gastrointestinal diagnosis, previous and current cardiovascular testing results, and TCA dosing were collected. Other medications were not collected. All patients in whom TCA was considered, even if never started, were included. Per current institutional practice, an ECG is routinely performed before starting a TCA. The intent to start a TCA was confirmed via direct chart review of the practicing clinician documentation. TCA dosing was at the discretion of the prescribing clinician. Patients were excluded if already on TCA therapy for other indications. All ECGs, including from any prior visits, the gastroenterology visit, and any subsequent visits, were reviewed to find abnormalities, heart rate, QRS, and QTc intervals. From the time of the initial gastroenterology visit, all subsequent pediatric cardiology visits, cardiac diagnoses, and test results (echocardiogram, ECG, cardiac magnetic resonance imaging [MRI], and exercise testing) were collected via chart review.

Data Collection and Definitions

The patient data were de-identified and stored in a Research Electronic Data Capture (REDCap) database by three authors. The REDCap electronic data capture tool, hosted at Duke University, is a secure, web-based software platform designed to support data capture for research studies. ECG measurements were obtained from finalized interpretations by a board-certified cardiologist. ECG abnormalities were classified as trivial if they were variants of normal or did not result in a cardiology referral. These include sinus arrhythmia, sinus bradycardia, borderline QTc interval prolongation, incomplete bundle branch block, and non-specific ST segment changes. ECG abnormalities were significant if they resulted in cardiology referral. The diagnosis of borderline or prolonged QTc interval was per finalized ECG interpretation with prolonged QTc defined as >460 ms. Contributory family history was defined as a family member with a history of arrhythmia, arrhythmia syndrome, or sudden cardiac death. Adverse outcomes included death during the review period, admission to emergency department, hospital, or intensive care unit, or outpatient clinic visit for an indication of arrhythmia or drug overdose recorded in the local medical record. The review period for adverse events queried in Duke Enterprise Data Unified Content Explorer extended 1 year beyond the initial gastroenterology visit (January 2011 to February 2019). Primary outcomes included TCA initiation and change in QTc interval from baseline for patients with a follow-up ECG obtained during the study review period.

Statistical Analysis

Standard summary statistics were used to describe patient characteristics. Summary statistics were expressed as median (interquartile range [IQR]) for continuous variables and count with percent of the total for categorical variables. The average value of the QTc was calculated and using subsequent ECGs when available, an average change in QTc interval while on TCA was calculated. Summary statistic comparisons were made by t-test, chi-squared test, or Fisher exact test, as appropriate. Scatterplots compared weight-based dosing to initial QTc interval, as well as a change in QTc when available. Proportions of variance were calculated from scatterplots to quantify the association between amitriptyline dose, initial QTc interval, and QTc interval change. To determine whether baseline QTc influenced TCA initiation, bivariate and multivariate analyses were performed using logistic regression while controlling for age, gastrointestinal diagnosis, baseline ECG abnormality, and contributory family history. Data were analyzed using Stata 14.0 (College Station, TX). Statistical significance was defined as a P-value <0.05.

This institutional review board at Duke University Medical Center approved this study. The need for patient consent was waived for retrospective review. The authors had full access to the data and took full responsibility for its integrity. All authors have agreed to the manuscript as written.

RESULTS

Patient Characteristics and Amitriptyline Dosing

A total of 233 children had an ECG obtained in anticipation of starting on a TCA. Patients were predominantly white and female, with an average age of 13.4 ± 3.1 years (Table 1). The majority (196/233, 84.1%) were prescribed a TCA, with the most common diagnosis being pain associated with irritable bowel syndrome (55.4%). Initial amitriptyline dosing varied widely between 10 and 50 mg/day. The average starting dose of the TCA was 18.2 ± 7.9 mg/day (0.36 ± 0.32 mg/kg per day (Fig. 1) with 10.7% (21/196) having a starting dose >0.5 mg/kg per day.

TABLE 1 - Summary of characteristics of patients receiving ECG screening in pediatric gastroenterology clinic reported as mean and standard deviation or counts and percent of the total

	Total N = 233	Amitriptyline N = 196	No amitriptyline N = 37	P-value
Demographics
Age (y), mean (SD)	13.4 (3.1)	13.6 (2.9)	12.0 (3.8)	0.004
Female, n (%)	151 (64.8)	126 (64.3)	25 (67.6)	0.789
Race, n (%)				0.574
Caucasian	166 (71.2)	138 (70.4)	27 (73.0)
African-American	27 (11.6)	22 (11.2)	4 (10.8)
Multi-racial	11 (4.7)	7 (3.6)	3 (8.1)
Other/not reported	29 (12.5)	29 (11.2)	3 (8.1)
Hispanic, n (%)	10 (4.3)	8 (4.1)	2 (5.4)	0.941
GI diagnosis, n (%)				0.268
Cyclic vomiting syndrome	15 (6.4)	11 (5.6)	4 (10.8)
Functional dyspepsia	17 (7.3)	14 (7.1)	3 (8.1)
Functional pain	45 (19.3)	43 (21.9)	2 (5.4)
Pain associated with IBS	129 (55.4)	103 (52.6)	26 (70.3)
Other	39 (11.6)	34 (17.4)	5 (13.5)
Family history of cardiac disease, n (%)				0.042
None	28 (12.0)	29 (14.8)	8 (21.6)
Non-contributory∗	37 (15.9)	19 (9.7)	9 (24.3)
Contributory∗	2 (0.9)	2 (1.0)	0 (0.0)
Unknown	166 (71.2)	146 (74.5)	20 (54.1)
ECG characteristics
Normal, n (%)	192 (82.4)	165 (84.2)	27 (73.0)	0.100
Abnormal, n (%)				0.246
Trivial/no cardiology referral	33 (14.2)	25 (12.8)	8 (21.6)
Significant/cardiology referral	8 (3.4)	6 (3.0)	2 (5.4)
QTc, mean (SD)	413.4 (22.2)	412.2 (21.4)	420.0 (25.2)	0.048
QTc Prolongation n (%)†	3 (1.3)	0 (0.0)	3 (8.1)	0.004
Heart rate, mean (SD)	73.7 (27.2)	73.0 (29.0)	77.1 (13.8)	0.408
Prior normal ECG, n (%)	18 (7.7)	16 (8.2)	2 (5.4)	0.898

P-values for the differences between groups of patients prescribed or not prescribed amitriptyline.ECG = electrocardiogram; IBS = irritable bowel syndrome; SD = standard deviation.

^∗Non-contributory cardiac family history includes adult non-structural heart disease (ie, first-degree relatives with hypertension, coronary artery disease, hyperlipidemia). Contributory cardiac history included one immediate family member with Wolf–Parkinson–White syndrome and one immediate family member with sudden cardiac death.

^†Two with borderline prolonged QTc (450, 453 ms) and one with prolonged QTc (473 ms).

FIGURE 1: Distribution of initial amitriptyline dosing. (A) Initial amitriptyline dosing in total mg per day. (B) Initial total daily amitriptyline dosing per kilogram. The outlier is one patient started on 20 mg TID as the initial dose. All other patients started on once-daily dosing.

Baseline Electrocardiogram Findings

Of the 233 ECGs obtained, a significant abnormality was found in eight (3.4%), with one patient (0.4%) having a significantly prolonged QTc at baseline (Table 1, Supplemental Digital Content, https://links.lww.com/MPG/C425). The average QTc at baseline was 413 ± 22 ms. In 10.7% (25/233) of patients, a prior baseline ECG was in the electronic medical record, and the screening ECG ordered by the pediatric gastroenterologist was a repeat. Figure 2 is a flowchart of ECG findings and subsequent initiation of amitriptyline. Amitriptyline was not started primarily due to ECG results in four (1.7%) of patients. In 35 patients with normal or trivial ECG results, amitriptyline was not started for unknown reasons. One patient had a prolonged QTc interval (473 ms), two had borderline QTc interval prolongation (450 and 453 ms), and one had an ectopic atrial rhythm that was cleared by cardiology. There was no association between the initial QTc interval on ECG and starting dose of amitriptyline (R² = 0.0004, P = 0.792) (Figure 1, Supplemental Digital Content, https://links.lww.com/MPG/C424). Additionally, in multivariable analysis adjusting for age, presence of an ECG abnormality, and contributory cardiac family history, there was no association between baseline QTc interval and prescription of amitriptyline (adjusted odds ratio 1.14, 95% confidence interval [CI] 0.97–1.36, P = 0.115).

FIGURE 2: Flow chart of patients with screening ECGs before consideration of amitriptyline initiation. The participant flow diagram illustrates ECG screening of 233 children with FGID, ECG results, and the subsequent decision to prescribe amitriptyline. ECG = electrocardiogram; FGID = functional gastrointestinal disorder.

Clinical Outcomes

There were no patient deaths during the review period (2011–2019)—furthermore, no emergency department or hospital visits for arrhythmia or drug overdose. Eight patients (3.4%) were referred to a cardiologist, and one was already followed for postural orthostatic tachycardia syndrome (Table 1, Supplemental Digital Content, https://links.lww.com/MPG/C425). Reasons for referral included: abnormal ECG results (7 of 8) and abnormal ECG with orthostatic symptoms (1/8). One underwent cardiac MRI to rule out an anomalous pulmonary vein after an echocardiogram was obtained for abnormally high voltages by ECG. The result was normal. One, previously mentioned, patient with prolonged QTc followed up outside of the local health system. In the remaining seven patients referred to a cardiologist, all were cleared to receive TCA medications. Overall, the prevalence of prolonged QTc was 0.43%, representing one patient.

Of those who had a repeat ECG while on a TCA (15/196, 7.7%), the average increase of the QTc was 10.1 ± 24.9 ms. The average daily dose increased by 11.8 ± 4.6 mg, and daily per-kilogram dosing increased by 0.12 ± 0.08 mg/kg. The average daily dose of TCA was not correlated with change in QTc (R² = 0.0013, P = 0.897) (Fig. 3). None of the patients with repeat ECG developed a prolonged QTc interval after starting on amitriptyline.

FIGURE 3: Scatterplot comparing the change in QTc interval from baseline to total daily amitriptyline dosing at follow-up ECG, N = 15. ECG = electrocardiogram.

DISCUSSION

The present study found that initial TCA dosing for abdominal pain varied widely. There was no correlation between initial QTc and starting dose for amitriptyline, yet abnormal screening ECG results may have affected the decision to initiate amitriptyline in four (1.7%) patients. Regarding resource utilization, screening ECG results lead to cardiology referrals relatively infrequently (3.4%); however, roughly 10% of patients had a screening ECG during the clinic visit, even though a prior ECG was available in the medical records. Although follow-up ECGs were rarely (8.2%) obtained, there were no patient deaths and no hospital admissions for arrhythmia or drug overdose during the review period.

TCAs are commonly used to treat functional gastrointestinal conditions or disorders of gut–brain interaction ^(9–11); however, there is no current FDA labeled indication for the use of TCAs for FGIDs. Dosing for TCAs for gastrointestinal indications tends to be lower than when the indication is for depression. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommends starting TCA doses of 0.25–0.5 mg/kg once nightly. The starting dose may be increased weekly by 10 mg per day to 1–1.5 mg/kg per day ⁽¹¹⁾. In a randomized controlled trial of amitriptyline for cyclic vomiting syndrome, dosing started at 0.5 mg/kg and increased to 1 mg/kg after 1 week ⁽¹²⁾. In a meta-analysis of amitriptyline dosing for irritable bowel syndrome in adults, the starting doses also tended to be low and between 10 and 12.5 mg/day ⁽¹⁰⁾. By comparison, the dosing for depression starts between 50 and 100 mg/day and increases to a total of 100–300 mg/day ⁽¹³⁾. Although there was variability in initial TCA doses noted in the present study, the doses were low. Relatively few patients, ∼10%, started on dosing >0.5 mg/kg per day, whereas ∼30% started on dosing <0.25 mg/kg per day.

The cardiac side-effect of QT prolongation in TCAs is mediated by effects on the autonomic nervous system and rapid outward potassium currents, resulting in delayed repolarization ⁽¹⁴⁾. Although rare, this phenomenon is well documented and seen with TCA overdose and toxicity secondary to co-administration of other QT prolonging medications ^(15–17). A large adult population study in France found the incidence rate of a sudden cardiac event to be 0.0229 of 2703 patient-years while on amitriptyline ⁽¹⁸⁾. There are no FDA safety and monitoring recommendations on ECG screening for amitriptyline; however, guidelines in the psychiatric and gastroenterology literature support screening ECGs before initiating TCA therapy ^(11,19).

The QT prolongation risks of TCAs when taken as directed are less clear but appear to be exceedingly low for patients on low-dose amitriptyline. There are case reports of sudden cardiac death in pediatric patients on TCAs. Tinglestad et al ⁽²⁰⁾ reported three patients on TCAs who died of sudden cardiac causes with normal drug levels; however, all three had a concerning family history, and none were prescribed amitriptyline or on a TCA for a gastrointestinal (GI) indication ⁽¹⁷⁾. In an intensive prospective study of the cardiovascular effects of TCAs, investigators noted a mild increase in QT interval after initiation of doses ranging from 45 to 150 mg/day. This change was not statistically significant and stabilized after 13 months of therapy ⁽²¹⁾. Safety data for pharmacotherapy in pediatric patients for functional abdominal pain are scarce, but one systematic review found no reported serious adverse events ⁽²²⁾. Although small, two studies specifically evaluating ECG changes of pediatric patients on TCAs found no consistent pattern of change while on therapy ^(8,23). Although Chogle et al ⁽⁸⁾ found a statistically significant increase in QTc interval for patients receiving both amitriptyline and placebo, none of the patients developed QTc prolongation. Outside of the pediatric population, a more robust study of nearly 1500 sudden cardiac deaths in an adult population on TCAs found no increased risk of death for doses <100 mg/day ⁽⁶⁾. In our study, there were no cardiac adverse events found in the medical record over the study period. In addition, although not powered to detect a difference, there was no association between amitriptyline dose and change in QT interval on follow-up ECGs.

When considering the utility of screening and follow-up ECGs in pediatric patients with functional abdominal pain, the safety benefit of detecting a potentially life-threatening abnormality must be weighed with the cost of incidental findings from additional testing. A concise answer to the question of risk-benefit is beyond the scope of this study. In fact, the benefit of screening ECGs remains elusive for other pediatric populations when used for screening for extremely rare but catastrophic events ⁽²⁴⁾. Our study found higher rates of incidental ECG abnormalities (7/233, 3.0%) than QT prolongation rates (1/233, 0.4%) that would preclude amitriptyline initiation. Patra et al ⁽⁷⁾ found similar rates (0.4%) of truly prolonged QT intervals on screening ECG before amitriptyline initiation and concluded that screening ECG should always be performed. Although the cost associated with incidental findings may be challenging to avoid altogether, unnecessary costs may be safely reduced by limiting the number of ECGs obtained as a repeat before initiating therapy. Additionally, follow-up ECGs on therapy may be safely limited by developing a targeted approach of only repeating ECGs for patients on concomitant QT prolonging medications or increases to higher dosing ranges. Ultimately, in an age of medicolegal concerns and polypharmacy, it may be difficult to avoid a screening ECG in this clinical situation; however, slight the test's clinical impact may be.

There are several limitations to note for the present study. First, the study is a retrospective review; therefore, there is potential for unknown or unadjusted confounding. The study did not collect information on concomitant QT prolonging medications; however, there was no finding of increased risk for QT prolongation. Furthermore, the study is limited to encounters within the Duke University Medical System. As such, adverse events, hospitalizations, and referrals outside the hospital system were not collected.

Initial amitriptyline dosing for abdominal pain management varied widely at our tertiary referral center and was not associated with the QTc intervals on screening ECGs. Screening ECGs may lead to increased resource utilization, but the overall frequency of cardiology referral due to ECG results is low. Assessments regarding the utility of ECG screening to ensure safe TCA administration are complex, given the screening of rare but potentially life-threatening conditions. Although screening ECGs before initiation of a TCA were shown to have minimal clinical impact, they may be challenging to avoid within the constraints of current evidence. For patients on low-dose TCAs, repeat ECGs are only needed if on concomitant QT-prolonging medications.