
==== Front
BMC Anesthesiol
BMC Anesthesiol
BMC Anesthesiology
1471-2253
BioMed Central London

2702
10.1186/s12871-024-02702-7
Research
Does IV fentanyl, frequently used in emergency departments, change QTC value? A prospective observational study
Öztürk Ayşe Yekta 12
http://orcid.org/0000-0003-4429-3100
Keleş Ayfer ayfer.keles@gmail.com

1
Demircan Ahmet 1
Kılıçaslan İsa 1
Bildik Fikret 1
http://orcid.org/0000-0002-7851-7881
Aslaner Mehmet Ali 1
http://orcid.org/0000-0002-8936-3988
Coşkun Yaş Secdegül secdecoskun@gmail.com

3
Çomruk Burhan 1
Şişik Burak 1
Türker Merve 1
Albayrak Aslıhan Küçük 1
1 https://ror.org/054xkpr46 grid.25769.3f 0000 0001 2169 7132 Department of Emergency Medicine, Faculty of Medicine, Gazi University, Ankara, Türkiye
2 grid.414879.7 0000 0004 0415 690X Department of Emergency Medicine, University of Health Sciences, Izmir Bozyaka Training and Research Hospital, Izmir, Türkiye
3 https://ror.org/02h67ht97 grid.459902.3 0000 0004 0386 5536 Department of Emergency Medicine, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Türkiye
4 9 2024
4 9 2024
2024
24 3071 6 2024
26 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Fentanyl is an opioid analgesic frequently used in the emergency department (ED) and is usually administered without knowing the QTC values of the patients or being monitored. However, the effect of fentanyl on QTC, prolongation or shortening, has not been elucidated. This study aimed to determine the effect of fentanyl on QTC.

Methods

This is a prospective observational study in the ED of a tertiary hospital on patients who received intravenous fentanyl for procedures other than intubation. ECG was performed before and at 1, 5, 15, 30, and 60 min after the initiation of fentanyl administration, and QTC value was calculated. Primary outcomes were QTC prolongation, defined as an increase in the QTC to ≥ 500 ms or any increase in QTC by ≥ 60 ms.

Results

The study included 109 patients. Of these, 60 patients were male, and the median age was 40. Compared with the baseline QTC value, statistically significant prolongation was detected at the 5th, 15th, 30th, and 60th minutes, with the maximum prolongation at 30 min, and the median was 13.08 ms. Most patients with QTC prolongation were female and over 40 years of age. Clinically, none of these patients developed malignant arrhythmias during the 60-minute monitored observation period.

Conclusion

Fentanyl prolonged the QTC value statistically significantly. Although no patient developed malignant arrhythmia clinically, our results suggest that this QTC-prolonging effect should be considered when using fentanyl in patients at risk of torsades.

Keywords

Emergency department
Fentanyl
Electrocardiography
QTC interval
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Pain has been one of the most common reasons for presenting to the emergency department (ED) in recent years. Opioid analgesics are commonly used drugs, and fentanyl, a synthetic opioid analgesic, is one of the first-line medications because it reaches a peak analgesic effect in a short time [1, 2].

Prolonging the QT interval in electrocardiography (ECG) potentially causes increased cardiac electrical instability and poses a risk for arrhythmias, but its clinical relevance is still controversial. Changes in the QT interval have been shown to have prognostic value in many medical conditions. Both congenital and acquired QT prolongation can result in potentially fatal tachyarrhythmias known as Torsades de Pointes (TdP) [3]. It can also cause consequences such as syncope and sudden death. Each 10 ms prolongation in QTC represents a 5–7% increased risk for TdP [4]. Acquired QT prolongation is associated with anesthetic drugs, antiarrhythmic drugs, electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia), myocardial ischemia, central nervous system pathology, hypothermia, hypothyroidism, and laryngoscopy. For this reason, QT prolongation is accepted as a risk factor for sudden cardiac death, regardless of age. It is accepted as an objective value in drug safety evaluation [5, 6].

In EDs, fentanyl is often used without knowing the basal QTC value of the patients or questioning their cardiac history or risk factors for fatal rhythms. In the literature, the effects of fentanyl on the QT interval during treatment and pretreatment use are controversial, and the impact of its use with other drugs during intubation procedures has been investigated. In our study, the main aim was to investigate the effect of fentanyl on QTC by excluding other factors that may affect QTC. At the same time, we tried to keep an eye out for any malignant arrhythmias that might happen during the follow-up.

Materials and methods

Study design

This prospective observational drug study was conducted on patients admitted to the adult emergency department of a tertiary university hospital for a 3-month between September 1, 2020, and December 1, 2020. Written informed consent was obtained from all patients. This clinical study was approved by the Republic of Turkey Ministry of Health Ankara City Hospital Clinical Research Ethics Committee (No: 888, Date: 02.07.2020).

Data collection

Patients aged 18 years and older, fentanyl administered for any reason other than intubation by their physician in the ED, were included in the study. Patients who were pregnant, who were also administered other drugs before, during, or following ECG recording in the ED, patients who were receiving drugs potentially affecting the QT interval at home (QT drug list, CredibleMeds), patients presenting with electrolyte imbalance (hypo/hyperkalemia, hypo/hypercalcemia, hypo/hypermagnesemia), atrial fibrillation, coronary artery disease, known congenital long QT syndrome, known congenital short QT syndrome, a pacemaker or Implantable Cardioverter Defibrillator (ICD), sick sinus syndrome, and atrioventricular block were excluded from the study.

The recommended dose of fentanyl to provide analgesia in clinical use is 0.5–1.5 mcg/kg [7]. As a standard, 1 mcg/kg fentanyl in 100 cc isotonic sodium chloride was administered to the patients as an IV infusion in 5 min. The patients’ QTC values were calculated by taking a 12-lead trace of ECG before fentanyl administration. After medication was started, the ECGs of the patients were taken at the 1st, 5th, 15th, 30th, and 60th minutes of the 60-minute observation period, and their QTC values were noted. The patients were monitored with a monitor for 60 min due to the risk of developing malignant arrhythmias (LIFEPAK® 15 monitor/defibrillator, Washington, USA). The same device calculated QTC values, and ECG printouts were taken, manually calculated, and verified by an emergency medicine specialist from leads II and V5–6. No other medication was administered to the patients during or before this time in the ED.

Outcome measures

The primary endpoint was to determine whether fentanyl affects the QT interval and if fentanyl affects the QT interval in any direction. According to the American Heart Association recommendations, it is considered prolonged for 450 ms for the male gender, over 460 ms for the female gender, and shorter than 320 ms for both genders [8]. A clinically significant threshold for the development of malignant arrhythmia was defined as a QTC value ≥ 500 ms for both sexes or an increase in QTC value ≥ 60 ms at any time (ΔQTC ≥ 60 ms) [9]. Although it differs according to heart rate since it is a frequently used and accepted formula, Bazett’s formula was used to correct the measured QT interval value according to heart rate [10, 11].

Our second goal was to figure out how fentanyl affects the chance of getting malignant arrhythmia if QTC is changed.

Analysis

Descriptive analyses are given as percentages using median (minimum-maximum) values for continuous variables. The conformity of the variables to the normal distribution was examined using visual (histograms and probability graphs) and analytical (Shapiro-Wilk Test) methods. In cases where the data did not fit the normal distribution, comparisons of more than two groups were analyzed using the Kruskal-Wallis Test. The groups with significant Kruskal-Wallis test results were evaluated in pairs with the Mann-Whitney U test by applying the Bonferroni correction. The Friedman test evaluated three or more repeated measures of dependent variables. The Wilcoxon test evaluated the repeated measurements with a significant Friedman test result. The statistical significance level was calculated as P < 0.005 in the double group evaluation of five independent groups with Bonferroni correction. In comparing pairwise measurements of triple repetitions, p < 0.017 with Bonferroni correction was accepted as the statistically significant limit. In this study, the statistical significance level was accepted as < 0.05. The Statistical Package for the Social Sciences (SPSS) for Windows 20.0 (IBM SPSS Inc., Chicago, IL) was used for the statistical analysis.

Results

In our study, 8557 patients presented to ED for three months, and fentanyl was administered to 457 patients. Of the 109 patients included in the study, 60 were male, and the median age was 40 (18–79) years (Fig. 1). The median weight of the patients treated with fentanyl was 80 kg, and the median dose of fentanyl administered was 80 mcg. Demographic characteristics are shown in Table 1.

Fig. 1 Flow chart for study design and patient selection

Table 1 Demographic characteristics of the patients

Variables	Total = 109	
Age, median (min-max)	40 (18–79)	
Male, n (%)	60 (55)	
Weight, median (min-max)	80 (35–125)	
Dose of fentanyl, median (min-max)	80 (35–125)	
Age group, n (%)		
 < 20 years	1 (0.9)	
 20–29 years	23 (21.1)	
 30–39 years	30 (27.5)	
 40–49 years	25 (22.9)	
 50–59 years	13 (11.9)	
 60–69 years	13 (11.9)	
 70–79 years	4 (3.7)	

Our study showed that the prolongation in the QTC value in patients treated with fentanyl was statistically significant (p < 0.001) (Table 2). Considering the pairwise comparisons that created this significant difference, the prolongation of the QTC value compared to the baseline was also found to be statistically significant at the 5th, 15th, 30th, and 60th minutes. The maximum prolongation was determined between the baseline value and 30 min, and the median was calculated as 13.08 ms (p < 0.001) (Table 3; Fig. 2).

Table 2 The change of QTC length with the treatment period of the patients

QTC interval (mm)	Median (min-max)	P*	
QTC baseline	412 (336–514)	< 0.001	
QTC 1. min	413 (333–490)	
QTC 5. min	416 (340–482)	
QTC 15. min	419 (351–526)	
QTC 30. min	423 (354–506)	
QTC 60. min	418 (348–518)	
*Friedman Test

Table 3 Relation of patients’ QTC measurement Times

QTC	Difference (ms)	P	
QTC 1. min- QTC baseline	4.3	0.062	
QTC 5. min- QTC baseline	6.98	0.001	
QTC 15. min- QTC baseline	10.62	< 0.001	
QTC 30. min- QTC baseline	13.08	< 0.001	
QTC 60. min- QTC baseline	10.09	0.001	
QTC 5. min- QTC 1. min	2.68	0.051	
QTC 15. min- QTC 1. min	6.32	0.0028	
QTC 30. min- QTC 1. min	8.78	< 0.001	
QTC 60. min- QTC 1. min	5.79	0.045	
QTC 15. min- QTC 5. min	3.64	0.143	
QTC 30. min- QTC 5. min	6.1	0.148	
QTC 60. min- QTC 5. min	3.11	0.646	
QTC 30. min- QTC 15. min	2.46	0.880	
QTC 60. min- QTC 15. min	-0.53	0.062	
QTC 60. min- QTC 30. min	-2.99	0.001	
Wilcoxon Test, Bonferroni correction p < 0.003. Statistically significant p values are shown in bold

Fig. 2 Box plots of QTc lengths over time (For each box plot, the central horizontal marks indicate the median, while the bottom and top edges of the box show the 25th and 75th percentiles, respectively. The whiskers indicate the range of data points not considered outliers. Outliers are plotted using a dot.)

The number of patients with QTC 500 ms and above was 6. Only one of these patients was male, and the others were female. The number of patients with ΔQTC ≥ 60 ms was 27. Of these patients, 10 were male (40–49 years old), while 17 were female (50–59 years old). These patients, considered clinically significant and at risk of developing malignant arrhythmia, were monitored for 60 min, and none of them developed malignant arrhythmias.

It was also observed that female patients had a longer QTC than male patients at the baseline and at all subsequent time intervals. The baseline QTC values showed that the mean QTC for females was 9.65 ms longer than for males. In addition, a statistically significant difference was found between the male and female genders in QTC values at the 15th, 30th, and 60th minutes.(Fig. 3).

Fig. 3 Average QTc values by sex at each time point (in minutes) after fentanyl administration

Discussion

Our study determined that fentanyl prolonged the QTC value by a small but statistically significant amount. This prolongation occurs most prominently at the 30th minute. Although we excluded conditions that may affect the QTC value, such as electrolyte imbalance, congenital long QT disease, coronary artery disease, and the use of other medications in the included patient group, a QTC greater than 500 ms or a QTC increase of 60 ms or more was observed in one-third of patients receiving fentanyl. Especially Females gender and patients over 40 years of age constitute most of the patient population exceeding the critical threshold value, but clinically no malignant arrhythmia was detected.

As the studies in the literature about fentanyl were investigated, some showed that it shortened the QTC [12–14], while others showed that it prolonged the QTC [15, 16]. In a study on human cardiac myocytes, it was reported that opioid agonists, including fentanyl, could block cardiac potassium currents. Accordingly, fentanyl could prolong the QT interval by prolonging the action potential [17]. A similar effect was found in a study on canine purkinje fibers, and it was found that fentanyl prolongs the action potential duration. In current clinical studies in humans, the effect of fentanyl on QTC is controversial. So far, antiarrhythmics, antibiotics, prokinetics, and antipsychotics have been shown to cause QT prolongation [18, 19]. Notably, there is no other study in which fentanyl was administered as a single drug. The study was the first to be conducted in ED. With this study, it was determined that IV fentanyl affects the QTC value and prolongs the QTC.

In the study of Keller et al., prolonged QTC due to drugs was investigated, and fentanyl was shown to cause this prolongation [15]. Except for Keller et al.‘s study, all other clinical studies were performed during intubation in anesthesia clinics, and fentanyl was administered during premedication, induction, and paralysis. In addition, laryngoscopy and tracheal intubation are associated with hypertension and tachycardia by activating the sympathetic response, and it is known that they can affect QTC by causing catecholamine discharge [3, 16, 20, 21]. In our study, these procedures were excluded, and only procedures requiring analgesia were accepted.

Wilton and Hantler reported that fentanyl shortened the QTC interval in patients with long QT syndrome [22]. In the study of Chang et al., it was shown that fentanyl administration did not cause a change in the QTC interval within 5 min. During tracheal intubation, in which propofol was used for induction, a significant prolongation of QTC was found, and it was stated that 2 µg/kg fentanyl significantly alleviated this effect [12].

The effect of drugs such as propofol, midazolam, vecuronium, and thiopental used together with fentanyl during intubation on QTC is controversial in the literature [23, 24]. In studies conducted to determine the effect of fentanyl on the QTC value, the use of drugs whose effect on the QTC value is not known casts a shadow over the reliability of the results. Our study found that fentanyl affected the QTC value and prolonged the QTC at the highest 30th minute (median 13.08 ms). In our study, patients with drug use affecting the QTC value were excluded, and no other agent was administered to the patients before or during fentanyl administration. In addition, when compared with other studies in the literature, it was seen that our study had the most extensive sampling and the longest observation period of 60 min, with 109 patients treated with fentanyl.

The prolongation in the QTC value detected in the ECG is closely associated with the risk of developing ventricular arrhythmia and adverse cardiac events. The competent institutions related to drug development agree on evaluating QTC as the best predictor of the cardiac safety risk of a new drug. According to the FDA, “While the degree of QT prolongation is recognized as an imperfect biomarker for proarrhythmic risk, in general, there is a qualitative relationship between QT prolongation and the risk of TdP, especially for drugs that cause substantial prolongation of the QT interval.” [25]. Among 109 patients included in our study, 27 had ΔQTC≥60 ms, and 6 had QTC≥500 ms, but no malignant arrhythmia was clinically detected.

The age distribution of patients who exceeded the threshold indicates that the most common age ranges are 40–49 and 50–59. Many previous studies have determined that the QT interval responses are prolonged with age. The reasons are prolonged cardiac repolarization time, decreased RR variance, increased fibrosis due to myocyte aging, and impaired sympathetic and parasympathetic activity responses [26, 27]. It was determined that the QTC value lengthened with age, the difference measured between men and women increased with age, and this difference increased significantly over 50 years of age compared to those under 50 years old. The more pronounced increase in QTC duration with age means that drugs that cause QT prolongation can more easily reach potentially ‘dangerous’ QTC times in the elderly than in the young [28, 29]. However, since the number of patients in the different age groups did not show an equal distribution in our study, sufficient information was not obtained on this subject.

Our study has some limitations. The single-center nature of the study limits generalization. The patient numbers in subgroups separated by decades were not homogeneous. Studies with a larger population are needed to evaluate the effect of fentanyl on QTC values in different age groups. As ECG recordings could not be obtained from the patients after 60 min, this study presents observations made over a period of 60 min only. It is therefore not possible to comment on subsequent times. As this was an observational study, no placebo or control group was included. There is a need for randomized controlled studies.

Conclusion

By designing a study free of other QT-prolonging factors, we found that fentanyl had a statistically significant effect on QTC. When making a drug preference, physicians may consider these findings along with the patient’s comorbidities and other medications. Although none of the patients clinically developed a malignant arrhythmia, our results suggest that this QTC-prolonging effect should be taken into account when using fentanyl in patients at risk for TdP.

Acknowledgements

Not applicable.

Author contributions

Conceptualization: A.O., A.K.; Methodology: A.O., A.K., S.Y.; Data curation: B.C., B.S., M.T., A.A.; Formal analysis and investigation: M.A., I.K., F.K.; Writing - original draft preparation: A.O.; Writing - review and editing: A.K., M.A., S.Y.; Supervision: A.D.

Funding

The authors did not receive support from any organization for the submitted work.

Data availability

All data generated in this study are available from the corresponding author upon reasonable request.

Declarations

Ethical approval

This clinical study was approved by the Ankara City Hospital Clinical Research Ethics Committee (No: 888, Date: 02.07.2020).

Consent to participate

Patients provided written informed consent to participate in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Previous Presentation:

The study has been presented at the 5. EMAT Course Days Congress, February 24-27, 2022, Antalya, Turkey

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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