Small doses of droperidol do not present relevant torsadogenic actions: a double-blind, ondansetron-controlled study

Abstract

AIM

Drugs used for postoperative nausea and vomiting prophylaxis are believed to provoke torsadogenic changes in cardiac repolarization. The aim of this study was to assess the effect of small doses of droperidol on the parameters of cardiac repolarization, including the QT_c interval and transmural dispersion of repolarization.

METHODS

A total of 75 patients were randomly allocated to receive 0.625 or 1.25 mg droperidol or 8 mg ondansetron. The QT_c interval was calculated using Bazett's formula and the Framingham correction. The transmural dispersion of repolarization was determined as T_peak–T_end time.

RESULTS

Transient QT prolongation, corrected with both formulae, followed 1.25 mg of droperidol 10 min after administration. No change in the QT_c value was observed in the other groups. When corrected with Bazett's formula, QT_c was prolonged above 480 ms in two patients receiving 1.25 mg droperidol (at the 10^th and 20^th minute of the study) and in one receiving ondansetron. No patients developed a QT_cB prolongation over 500 ms. No increase above 480 ms was observed relative to the Framingham correction method. There were no significant differences in the T_peak–T_end time either between or within the groups.

CONCLUSION

In men without cardiovascular disorders small doses (1.25 mg) of droperidol prophylaxis induced transient QT_c prolongation without changes in transmural dispersion of repolarization. The apparently low risk of the drug applies only in low risk male patients with a low pro-QT_c score.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Small doses of droperidol are highly effective in the prevention of postoperative nausea and vomiting.

• As droperidol provokes corrected QT interval prolongation and was reported to provoke serious cardiac arrhythmias, the FDA issued a ‘black box’ warning on droperidol.

• Sparse data are known about the influence of droperidol on the transmural dispersion of repolarization, although only a concurrent assessment of any changes in this parameter and in the QT_c could accurately determine its torsadogenic action.

WHAT THIS STUDY ADDS

• Droperidol 1.25 mg induces transient QT_c prolongation, but the lack of simultaneous changes in the transmural dispersion of repolarization makes the risk of its torsadogenic action low.

• Ondansetron does not present any torsadogenic action in male patients without cardiovascular diseases.

• The apparently low risk of the drugs applies only on low risk male patients with low pro-QT_c score.

Introduction

Droperidol has been widely used for the prevention and treatment of postoperative nausea and vomiting (PONV) due to its high effectiveness and low cost [1]. In 2001, the FDA issued a ‘black box’ warning on droperidol because of concerns related to serious cardiac arrhythmias following its potential QT interval prolongation. The warning was based on 273 cases, out of which 127 resulted in serious adverse outcomes. However, in only two of these cases was droperidol administered in the appropriately low doses recommended by PONV management guidelines [2]. This ‘black box’ warning provoked a substantial decrease in droperidol use as the first line treatment for PONV, despite the fact that more than 90% of the responding members of the Society for Ambulatory Anesthesia did not believe that such a warning was warranted [3]. This paradoxical problem remains a source of contention [4–6].

Although many papers have described the influence of droperidol on cardiac repolarization, all of them have focused exclusively on QT and corrected QT (QT_c) intervals. Most authors showed that droperidol provoked a dose-dependent QT_c prolongation. Although QT_c interval prolongation is a risk factor for ventricular arrhythmia development [7], it is not the sole determinant of a drug's potential to cause torsade de pointes polymorphic ventricular tachycardia (TdP) [8,9]. Another electrocardiographical marker of torsadogenic drug action is the increased transmural dispersion of repolarization (TDR), which indicates the time elapsed between the peak of the T wave and the end of the T wave (Tp–e) on the surface ECG (Figure 1). TDR represents differences in the repolarization of the myocardial ‘layers,’ such as the epicardium, M-cells and endocardium. It is believed that the induction of QT lengthening must be accompanied by a parallel increase in TDR to promote torsadogenesis [8].

Figure 1.

QT interval measurement using the tangent method (the end of the T wave is the intercept between the isoelectric line with the tangent drawn through the maximum down slope of the T wave). X represents T_peak − T_end time (modified from http://en.ecgpedia.org/wiki)

At present, sparse data are known about the influence of droperidol on the TDR, although only a concurrent assessment of any changes in this parameter and in the QT_c interval following drug administration could accurately determine its torsadogenic action. Therefore, the aim of this study was to verify whether the small doses of intravenous droperidol (0.625 mg and 1.25 mg) routinely used in PONV management provoked a parallel prolongation of the QT and QT_c intervals and an increase of the TDR, thereby promoting ventricular arrhythmias. To blind the study properly, a control group of patients receiving ondansetron was included in the analysis. Ondansetron is widely used for PONV prophylaxis and treatment in adults and children and has also been reported to prolong the QT_c interval [10].

Methods

After obtaining approval from the Bioethical Committee of the Medical University of Gdańsk and written informed consent from the study participants, 75 males were recruited to take part in the study (Trial Registry Number NCT01819857). All patients were already due to undergo elective orthopaedic surgery and were between 18 and 60 years of age, with an American Society of Anesthesiologists (ASA) grade I or II and a pre-operative QT and QT_c (corrected with Bazett's formula) less than 440 ms. Patients with abnormal conductions and arrhythmias (including sinus bradycardia/tachycardia and sinus arrhythmia), those treated with drugs known to prolong QT duration, those suffering from coronary heart disease or heart failure and those with congenital or acquired heart defects and myocarditis in anamnesis were excluded. Patients were also excluded if they had any history of hypersensitivity to droperidol or ondansetron or pre-operative electrolytic imbalances (serum magnesium <0.7 mmol l⁻¹, serum calcium <2.2 mmol l⁻¹, serum potassium <3.5 mmol l⁻¹) or if they had been treated with anti-arrhythmics, psychotropic drugs, macrolides or fluoroquinolones.

A randomization scheme was generated using the generator of Wichmann & Hill, as modified by McLeod (available at http://www.randomization.com). Patients were randomly allocated to receive either 0.625 mg or 1.25 mg droperidol (Xomolix® 2.5 mg ml⁻¹ ProStrakan, Galashiels, UK), group D 0.625 or D 1.25, respectively or 8 mg ondansetron (Zofran®, Glaxo Wellcome, Brentford, UK) intravenously, group O. Both medicines were diluted to 10 ml using a 0.9% NaCl solution.

The risk of PONV was assessed using Apfel scores [11] the day before anaesthesia. The risk of TdP was calculated as the pro-QT_c score proposed by Haguaa et al. [12]. All patients were premedicated with midazolam (7.5 mg orally 1 h before anaesthesia). After the patients' arrival in the operating theatre, routine monitoring, consisting of ECG, pulse oximetry and non-invasive blood pressure measurement, was begun. Then, 12-lead ECG electrodes were placed, and continuous acquisition commenced. Patients were positioned in the supine position throughout the study. A slow intravenous infusion of 0.9% NaCl was given. Immediately after the monitoring began, droperidol (0.625 mg or 1.25 mg) or ondansetron (8 mg) was administered from a previously prepared syringe, as marked with the randomization number. Both the patients and the staff members who administered the droperidol or ondansetron and performed the measurements were blinded to the substance administered. The staff member who prepared the solution and knew its composition was permanently and directly available by phone but did not participate during any stage of the study. The staff member who read the ECG charts was blinded to the administered drug. No surgical procedures, including patient positioning or urinary catheterization, were performed during the study period (until the moment of the last ECG chart registration). The electrocardiographic curve was recorded using a continuous 12-lead registration with a Siemens Megakart device. The obtained ECG charts were scanned, magnified and analyzed with AutoCad 2009 (Autodesk, San Rafael, USA) using appropriate scaling.

The effects of the tested drugs on repolarization were analyzed according to the E14 instructions developed by the International Conference on the Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [13].

The analysis included an assessment of the ECG parameters and of the values of arterial blood pressure before antiemetic administration, as well as 5, 10, 15 and 20 min following drug administration. The QT and RR intervals were measured on lead II of the ECG curve. Correction of the QT interval was calculated using Bazett's correction (QT_cB = QT RR^−1/2) and the Framingham formula (QT_cF = QT + [1 − RR] × 0.154). Analysis of the categorical data was also performed, comparing the number of patients with maximal QT_c prolongations (throughout the study) over 450, 480 and 500 ms in both study groups. The TDR was determined as the time between the peak and the end of the T wave and was measured on the V5 lead of the ECG. Both in QT interval measurement and in Tp−e time determination, the end of T wave was detected with the tangent method (Figure 1). The mean value of three successive cardiac cycles was included for statistical analysis. The results of the obtained ECG parameters were expressed in milliseconds. The measurement was performed without knowledge of the treatment the patient had received. The results were decoded after all electrocardiographic calculations had been carried out.

Statistical analysis

A minimal sample size of 23 persons per group was calculated assuming an α level = 0.05 and a β level = 0.90 for the detection of a mean difference of 15 ms of QT_c interval between groups based on population data presented by Benhorin and colleagues: a mean (SD) QT_c value of 414 (17) ms [14]. To allow for dropouts, 25 individuals were analyzed per group.

Data are expressed as the mean values (95% CI) or n (proportion). Statistical analysis was performed using STATISTICA 10.0 PL software (Polish version) (StatSoft, Tulsa, OK, USA). A normal data distribution was verified using the Shapiro–Wilk's test, and the homogeneity of variance was verified using Levene's test. Comparisons were performed using two-sided anova tests for repeated measurements with the subsequent analysis of significant differences using a post hoc method (Tukey HSD test) if appropriate or chi-squared test (with the Yates correction if necessary). P < 0.05 was adopted as indicative of a significant difference.

Results

Demographic data are presented in Table 1. There were no significant differences in the mean age, body mass or height among the three groups. Similarly, no differences in the ASA pre-operative status, Apfel scores as well as in serum magnesium, calcium and potassium concentrations were detected. No one individual had pro-QT_c score greater than 0.

Table 1.

Patient details

Parameter	Group
	D 0.625	D 1.25	O
	n = 25	n = 25	n = 25
Age (years)	35 (30–40)	36 (31–42)	34 (29–39)
Body mass (kg)	84 (79–90)	87 (81–93)	87 (80–94)
Height (cm)	179 (176–181)	181 (179–184)	180 (178–183)
ASA status; I:II	24:1	23:2	23:2
Apfel score; 1:2	12:13	16:9	14:11
Arterial hypertension; yes:no	1:24	2:23	2:23
Pro-QTc score = 0	25	25	25
Serum magnesium (mmol l−1)	0.82 (0.78–0.86)	0.81 (0.76–0.86)	0.85 (0.80–0.90)
Serum calcium (mmol l−1)	2.26 (2.20–2.32)	2.28 (2.20–2.36)	2.33 (2.26–2.40)
Serum potassium (mmol l−1)	4.1 (3.9–4.3)	4.0 (3.8–4.2)	4.1 (3.9–4.3)

ASA, American Society of Anesthesiologists.

Figure 2 presents the changes in the uncorrected QT time in the study groups. Sedative administration caused no prolonged ventricular repolarization in either group. Figures 3 and 4 present changes in the QT interval, corrected according to Bazett's formula and the Framingham correction, respectively. A significant prolongation of the QT_cB and QT_cF intervals, followed by a subsequent decrease, was observed in the D 1.25 group at the 10^th and 15^th minute, respectively. No significant changes in QT_cB or QT_cF were detected in the other groups. We did not observe any significant intergroup differences, irrespective of the method of correction applied.

Figure 2.

Mean and 95% confidence intervals of uncorrected QT intervals during different time points. +5, +10, +15, and +20 refer to the time in minutes from the study's beginning. , group D 0.625; , group D 1.25; , group O

Figure 3.

Mean and 95% confidence intervals of the QT intervals corrected using Bazett's formula (QT_cB) across different time points. *P = 0.033 compared with initial values in the same group and P = 0.019 compared with subsequent measurements. , group D 0.625; , group D 1.25; , group O

Figure 4.

Mean and 95% confidence intervals of QT interval corrected using Framingham formula (QT_cF) across different time points. *P = 0.0009 compared with initial values in the same group and P = 0.036 compared with subsequent measurements. , group D 0.625; , group D 1.25; , group O

The number of patients with QT_cB prolongation over 450 and 480 ms and comparisons of the study groups are presented in Table 2. No patients developed a QT_cB prolongation over 500 ms. QT_cF increased above 450 ms in just one individual in the group D 0.625 at the 20^th minute of the study. No increase above 480 ms was observed relative to the latter QT_c correction method.

Table 2.

The number of patients with QT_cB prolongation over 450 and 480 ms and comparisons of study groups

	5th min	10th min	15th min	20th min	P value
QTcB >450 ms
Group D 0.625	1 (4%)	1 (4%)	0	2 (8%)	0.19
Group D 1.,25	3 (12%)	2 (8%)	2 (8%)	1 (4%)
Group O	0	0	0	1 (4%)
QTcB >480 ms
Group D 0.625	0	0	0	0	0.77
Group D 1.25	0	1 (4%)	0	1 (4%)
Group O	0	1 (4%)	0	0

T_peak–T_{end time} did not change significantly in the groups, as shown in Figure 5. Changes in the heart rate and mean arterial blood pressure (MAP) are shown in Figures 6 and 7, respectively. Mild but significant reductions in MAP were observed in the three study groups when the initial and subsequent values were compared. In patients receiving droperidol, these reductions were detected earlier compared with those receiving ondansetron. No intergroup differences in MAP were found. Mild heart rate decreases were observed in both groups receiving droperidol, without any significant change in the ondansetron group.

Figure 5.

Changes in the T_peak – T_{end time} during the study. , group D 0.625; , group D 1.25; , group O

Figure 6.

Mean and 95% confidence limits of the heart rate (HR) during the study. *P < 0.01 compared with the value at the 20^th min in the same group; †P < 0.05 compared with initial value in the same group; ‡P < 0.00005 compared with values at 15^th and 20^th minute of the study; §P < 0.005 compared with values at 15^th and 20^th min of the study. , group D 0.625; , group D 1.25; , group O

Figure 7.

Mean and 95% confidence limits of the mean arterial pressure (MAP) during the study. *P < 0.05 compared with initial value in the same group; †P = 0.02, ‡P = 0.0005, §P = 0.002 compared with initial value in the same group. , group D 0.625; , group D 1.25; , group O

Discussion

The major finding of this study was that small doses of droperidol, given intravenously, provoked slight and transient corrected QT interval prolongation without influencing the TDR. Ondansetron, when given as a control drug, does not alter any of the parameters of cardiac repolarization.

Independent of the correction method, the QT_c interval increased significantly at the 10^th minute after droperidol administration. This prolongation vanished 5 min later. We may suspect that such a time-related effect is due to droperidol's half-life of distribution, which is 10 min after its intravenous injection [15]. At this moment, the tissue concentration of this drug, including among cardiomyocytes, is the highest. Our analysis not only included changes in the actual values of QT and corrected QT_c intervals but also any increases in these parameters above the values considered to be critical for TdP development. It is believed that, even though values greater than 500 ms for QT_c represent a threshold of particular concern, some measure of attention should be paid even to shorter values (>450 ms) [13]. QT_cB prolongation above 450 ms was observed in a small number of individuals in the group D, 1.25, whereas the Framingham formula indicated only one patient. No one individual had a QT_c prolonged >500 ms. Our observations regarding the QT/QT_c changes after droperidol and ondansetron administration are only partially in accordance with those published by other authors. Lischke and co-workers observed significant QT_cB prolongation following intravenous droperidol, but they used high doses of the drug (0.1 to 0.25 mg kg⁻¹) [16]. Smaller doses were used by Charbit et al. in two published studies. In the first of these studies, the patients received 0.75 mg of droperidol or 4 mg of ondansetron (control group). In both groups, a significant lengthening of QT_cB was noted [17]. In our study, we observed no such effects of ondansetron, even after using a double dose. In the next study, patients received 1 mg of droperidol or 4 mg of ondansetron or droperidol, together with ondansetron or placebo. Significant QT_c prolongation followed the administration both of droperidol and ondansetron, and this effect was significantly longer in the droperidol group [18]. On the other hand, White and colleagues did not observe any significant QT_cB changes after the administration of 0.125 or 0.25 mg of droperidol compared with saline [19]. A slight prolongation of QT_cB was observed 3–6 min following droperidol administration, earlier than was found in our results. Unfortunately, droperidol was administered during general anaesthesia with desflurane, which is also known to prolong cardiac repolarization [10].

In our study, neither inter- nor intragroup changes in TDR were detected. This finding allowed us to conclude that the torsadogenic potential of the studied drug is low. There are sparse data on the impact of medicines used in anaesthesia on the TDR. Published reports have described such an impact for propofol and sevoflurane in children [20,21]. Among anti-emetics, promethazine has been tested and was found to prolong the QT_c interval without influencing the TDR [22]. The only currently existing study on droperidol and ondansetron was performed on children by Mehta and collaborators. These authors observed significant changes in QT_cB (determined as clinically irrelevant) without parallel changes in TDR. The authors concluded that neither drug provoked any risk of TdP, as they had no influence on TDR [23].

Our statements about the low torsadogenic potential of droperidol may be supported by other clinical observations published last year. That study included 20 122 persons receiving a total of 35 536 doses of 0.625 mg of droperidol intravenously. Eight hundred and fifty-eight of those individuals had ECG charts that could be analyzed and no one developed polymorphic ventricular tachycardia or death as a direct result of droperidol administration [24]. On the other hand, TdP has clearly been reported associated with droperidol in cases published in the literature. It may be due to fact that some people are more prone to the drug-induced QT_c lengthening and are at higher risk for TdP than others [25]. It is possible, that drug-induced TdP may be more probably observed in those with latent forms of congenital long QT syndrome (LQTS) medicated with QT-prolonging substances [26]. It is estimated, that LQTS mutation carriers are present in 1 of 1000 to 3000 individuals and are asymptomatic until the moment of QT-prolonging drug exposure [27].

In our study, we used ondansetron 8 mg as a control drug. This antiemetic is believed to be safe and is widely recommended and used for PONV prophylaxis and treatment in both children and adults [28–30]. Our observations may confirm that ondansetron can be safely used in a healthy population, although certain reservations remain regarding its safety in patients with cardiovascular disorders [31]. Additionally, in 2012, the FDA published a warning that 32 mg of ondansetron ‘may affect the electrical activity of the heart (QT interval prolongation), which could pre-dispose patients to develop an abnormal and potentially fatal heart rhythm known as torsades de pointes’ [32]. In our opinion, more extensive studies about the influence of high doses of ondansetron on the electrical function of the heart are needed.

There are some limitations of the present study. As mentioned, this study was performed on patients without any cardiac disorders. It may be possible that in patients with these diseases the influence of the drugs used for cardiac repolarization might be more significant. We decided to include only male patients in our study and exclude women for safety reasons, because they are more prone to torsadogenic drug activities [33].

In conclusion, small doses (1.25 mg) of droperidol, as used in PONV prophylaxis, induced transient QT_c prolongation in men without cardiovascular disorders. Neither inter- nor intragroup changes in TDR were detected. This finding allowed us to conclude that the torsadogenic potential of the studied drug is low in men. It must be emphasized that the apparently low risk of the drug applies only in low risk male patients with low pro-QT_c score. A further study is needed in women to assess the effects of droperidol and ondansetron on TDR.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.