© 2003 by European Society of Cardiology
Diazepam or midazolam for external DC cardioversion (The DORM Study)
The Department of Cardiology, Eastbourne General Hospital Eastbourne, UK
Manuscript submitted 10 October 2002. Accepted after revision 14 June 2003.
Correspondence: Andrew R. J. Mitchell, Department of Cardiac Rhythm Management, John Radcliffe Hospital, Oxford, OX3 9DU, U.K. Tel.: +44-1865-220981; Fax: +44-1865-221432. E-mail: mitcharj{at}doctors.org.uk
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Abstract |
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AIMS: To compare the clinical efficacy and tolerability of two intravenous sedatives for physician-led DC cardioversion of atrial arrhythmias.
METHODS AND RESULTS: One hundred and forty-one patients attending for elective DC cardioversion of atrial arrhythmias were randomized to intravenous midazolam or diazepam. Sedation was administered using titration protocols. Procedure times, operator satisfaction scores and adverse events were documented. The patients' immediate, 24- and 48-h recall and awareness of after-effects were obtained from questionnaires. Seventy-one patients received midazolam (mean 12.5 mg) and 70 patients received diazepam (mean 28.1 mg). There were 16 minor adverse events with midazolam (20% hypotension, 3% oxygen desaturation) and nine with diazepam (7% hypotension, 6% required additional analgesia), P=0.14. There were no major adverse events. Sedation time was 5.0±3.4 min for midazolam and 6.5±3.4 min for diazepam (P=0.0016). Patients awoke 77±46 min post-sedation with midazolam and 39±24 min with diazepam (P<0.0001). There was no recall of the procedure at 48 h and no difference in awareness of after-effects between the two groups at 24 or 48 h, P=ns.
CONCLUSION: Physician-led cardioversion of atrial arrhythmias using intravenous sedation is effective and well tolerated. Sedation with diazepam was associated with fewer minor adverse events and a quicker recovery time than midazolam.
Key Words: Atrial fibrillation, cardioversion, sedation, diazepam, midazolam
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Introduction |
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When cardiologists around the world started using Lown's techniques for cardioverting atrial arrhythmias in the 1960s and 1970s, numerous studies were published showing that intravenous diazepam as sole sedative agent was safe, easy to use and well tolerated by patients[1–
6]. In the late 1970s and 1980s, newer, rapidly acting, anaesthetics (especially propofol) led to an increased use of general anaesthesia for cardioversion[7–10]. Over the last decade there has been a slow move back to intravenous benzodiazepines for elective cardioversion, largely driven, in the U.K., by rising waiting lists and cost concerns.
It has recently been shown that physician-led cardioversion using the benzodiazepine diazepam is safe and has a positive impact on patient acceptability of the procedure[11]. Its use has also led to an increase in the number of procedures being performed. A similar study published in the same journal revealed positive data on the use of midazolam for day-case cardioversion procedures[12]. One possible disadvantage of using diazepam rather than midazolam is that it has a long half-life (20–40 h) compared with the mean half-life of 2 h for midazolam. In addition, since the doses of diazepam used during cardioversion can be quite high, there is the potential for significant accumulation of the metabolites of diazepam. This could lead to after-effects including drowsiness for some time after the procedure, affecting the patient's quality of life and affecting their ability to drive[13].
The aim of this study was to compare the clinical effectiveness, cost effectiveness and after-effects of midazolam and diazepam in a single-blinded randomized design, during physician-led day-case cardioversion of atrial arrhythmias.
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Methods |
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The local research ethical committee approved the study. All patients who attended Eastbourne General Hospital for elective day-case cardioversion of atrial tachyarrhythmias between February 2001 and November 2001 were screened for inclusion in the study. Patients were excluded if they did not give consent or if they had already been cardioverted under sedation. Patients were randomized in a single-blinded manner to either diazepam (as Diazemuls®, Apharma, U.K.) or midazolam (as Hypnovel®, Roche, U.K.) for intravenous sedation during the procedure. Patients were not told which type of sedation they received but operators were unblinded.
A minimum of two members of staff trained in advanced cardiac life support and endotracheal intubation performed cardioversion. An anaesthetist was always available for emergencies and was known to be no more than 5 min from where cardioversion took place. The attending doctor (the operator) administered the sedative according to a titration protocol designed by the investigators and senior pharmacy staff. Diazepam was given as a 5–10 mg intravenous bolus followed by aliquots of 5–10 mg each minute to a maximum of 70 mg. Midazolam (2 mg/ml) was given as an undiluted intravenous bolus of 5 mg with further aliquots of 1–2 mg each minute up to a maximum dose of 30 mg. Continuous ECG, oxygen saturation and blood pressure monitoring were performed in keeping with recommendations from the Royal College of Anaesthetists[14]. Adequate sedation was determined by loss of response to verbal stimulus or tactile stimulus. Sedation time was recorded as the time from first injection to the time of adequate sedation. DC cardioversion was performed according to the standard hospital protocol.
After the procedure the operator scored their evaluation of the effectiveness of the sedation on a visual analogue scale between 0 (not satisfactory) and 10 (extremely satisfactory). In addition, the type and dose of drugs used and any adverse events were documented. Minor adverse events included the need for additional analgesics (such as diamorphine, morphine, pethidine), the need for reversal of sedation with flumazenil, hypotension (BP drop of >20 mmHg and <100 mmHg systolic) and oxygen desaturation (SaO2<90%) in spite of oxygen 4 litres per minute by mask. Major adverse events were defined as the need for ventilation or the requirement of assistance from an anaesthetist, cardiac arrest, major morbidity or mortality.
Following cardioversion, the patient was recovered in the dedicated cardiac recovery unit staffed by trained nurses from the coronary care unit. The time to waking was recorded as the time from cardioversion to spontaneous eye opening or speech. On waking, patients were immediately asked to complete a questionnaire relating to their recall of the procedure. The patient completed a similar questionnaire 24 h (delayed recall) and 48 h (late recall) following the procedure and returned them in a pre-paid envelope. These questionnaires included open questions on patients' awareness of any symptoms and after-effects following the procedure and whether they would have the procedure again. Any mortality was recorded up to one month following cardioversion by examination of hospital records and telephone contact with the primary care doctor.
Statistics
Data are presented as mean±standard deviation. Comparisons of non-parametric data were by Mann–Whitney U tests. Parametric data were compared with unpaired Student's t tests. Adverse event rates were compared using the Fisher exact test. A P value of less than 0.05 was considered statistically significant. Cost data were obtained from the September 2001 edition of the British National Formulary. Currency conversion was based on 1 U.K. Pound to 1.55 Euros.
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Results |
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Between February and November 2001, 224 consecutive patients attended the cardiology day-case unit for DC cardioversion. Eight patients were already in sinus rhythm on arrival in the department. Seventy-five further patients were excluded from the study as they did not give consent or they were attending for repeat cardioversion. One hundred and forty-one patients (age 72.4±9.0, 66% male) were randomized. Seventy-one received midazolam (mean dose 12.5±5.0 mg, cardioversion success rate 89%) and 70 received diazepam (mean dose 28.1±12.0 mg, cardioversion success rate 87%). There was no difference in cardioversion success rates, age or gender between the two groups. The dose of each drug was inversely correlated with age (midazolam, P=0.0005; diazepam, P=0.005).
Adverse events
There were 16 minor adverse events (23% of patients) in the midazolam group (20% hypotension, 3% oxygen desaturation) and nine adverse events (13% of patients) in the diazepam group (7% hypotension, 6% required additional analgesia), P=0.14. There were no major adverse events. Hypotension was treated by intravenous fluids (two patients receiving midazolam), the administration of flumazenil (four patients receiving diazepam, 11 patients requiring midazolam) or the patients were allowed to recover spontaneously (one patient receiving diazepam and two patients receiving midazolam).
The mean dose of diazepam was higher in those patients with adverse events (38.1±20.8 mg) than those without (26.6±9.5 mg), P=0.006. The mean dose of midazolam was similar in those with adverse events (12.9±5.4 mg) to those without (12±4.9 mg), P=0.69. The occurrence of adverse events was not associated with age or gender in either group. At one month there was no mortality.
Procedure scores
The mean operator satisfaction scores (0–10) for the effect of sedation were similar; 8.2±2.0 for midazolam and 7.9±2.1 for diazepam, P=0.35. Sedation time was 5.0±3.4 min for midazolam and 6.5±3.4 min for diazepam (P=0.0016). Awakening time was 77±46 min with midazolam and 39±24 min with diazepam (P<0.0001). Patients receiving flumazenil were excluded from this analysis. Only one patient (0.7%) had recall of the procedure at 24 h (diazepam 60 mg). No patient recalled the procedure at 48 h.
After-effects
There was no difference in the number of patients with after-effects between the two groups at 24 (P=0.81) or 48 h (P=0.26). Thirty-four percent of patients who received diazepam reported after-effects at 24 h. These were predominantly unsteadiness in 48%, tiredness in 48% and lightheadedness in 8% (non-exclusive). The mean score for unpleasantness (0, none to 10, worst) for these after-effects was 2.7±2.2. Thirty-two percent of patients who received midazolam reported after-effects at 24 h. These were particularly tiredness in 57%, lightheadedness in 26% and drowsiness in 13%. The mean score for unpleasantness was 3.0±2.9. There was no difference in the scores for unpleasantness of after-effects between the two groups at 24 h (P=0.73). The occurrence of after-effects was not associated with age or gender for either group.
At 48 h, 20% of patients who received diazepam reported after-effects (tiredness 64%, unsteadiness 21% and lightheadedness 14%). The mean score for unpleasantness was 2.0±2.7. Thirteen percent of patients who received midazolam reported after-effects at 48 h (tiredness 67%, unsteadiness 11%, drowsiness 11%). The mean score for unpleasantness was 3.1±3.0. There was no difference in scores for unpleasantness at 48 h (P=0.29).
Costs
The cost of a 5 ml ampoule of Hypnovel (midazolam 2 mg/ml) was 1.49 Euros. The cost of a 2 ml ampoule of Diazemuls (diazepam 5 mg/ml) was 1.18 Euros. Single use ampoules were used and excess drug was discarded between cases. The cost of sedation with diazepam, 3.56±1.43 Euros, was significantly higher than with midazolam, 2.28±0.82 Euros, P<0.0001.
Overall acceptability
Forty-eight hours after the procedure, patients were asked if they would have the procedure performed again under sedation (if required). Ninety-two percent of patients receiving diazepam and 98% of patients receiving midazolam answered yes, P=0.11.
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Discussion |
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This study shows that both midazolam and diazepam were safe and well tolerated as the sole agent for physician-led sedation during elective DC cardioversion. At the doses used they were also effective at generating anterograde amnesia with no long-term recollection of the cardioversion procedure. There were no major adverse events and no mortality up to one month following the procedure.
Important differences between the clinical effects of the studied drugs when used in this manner were identified. The sedation time was significantly reduced with midazolam compared with diazepam, however, the awakening time was considerably longer for midazolam (77 min) than diazepam (39 min) so that any time gained from induction of sedation was lost in the longer recovery. In comparative studies with diazepam in endoscopy procedures, midazolam proved more effective at inducing rapid sedation and induced a more pronounced amnesic effect[15–19].
It is recognized that even though midazolam has a short half-life, patients can take significantly longer to awaken than with other sedative agents[20,21]. The reason for this is likely to be related to differences in the clearing of active metabolites particularly alpha-hydroxymidazolam[22]. Midazolam is three to four times as potent per milligram as diazepam and can take several minutes to reach its peak clinical effect[23]. There is also a large inter-patient variability in the response to intravenous midazolam. Obese patients have an increased volume of distribution due to enhanced distribution in peripheral adipose tissues and interactions with other drugs that are metabolized through the cytochrome p450 system can influence the clinical response[22,26].
The incidence of hypotension observed with midazolam (20% of patients) may have been related to the high doses used to achieve sedation resulting in a more pronounced delayed clinical effect. It has been shown that the use of both diazepam and midazolam is associated with decreased systolic blood pressure but midazolam is particularly associated with reduction in both systemic vascular resistance and diastolic pressure[28]. All the episodes of hypotension in this study occurred within the first hour of recovery and may have been prevented by reversal of sedation with the benzodiazepine antagonist flumazenil. In the study from Raipancholia et al., patients routinely received flumazenil immediately after cardioversion to reverse sedation[12]. A blinded comparison of placebo and flumazenil after midazolam for cardioversion however indicated that, due to the rebound nature of the benzodiazepine antagonist, sedation scores were similar in both groups at 2 h[29]. In addition, it has been shown that psychomotor function in patients receiving high doses of midazolam does not completely improve after flumazenil[30]. The costs associated with flumazenil (24.16 Euros per 500 mcg vial of Annexate®, Roche, U.K.) increase expenditure considerably and its routine use after cardioversion is difficult to justify[31].
The incidence of reported after-effects was low for both drugs and there was no significant difference between the two types of benzodiazepine. This is in spite of a longer half-life for diazepam than midazolam. Using lower doses of sedatives may reduce these symptoms further but our practice of advising patients not to drive for 24 h after cardioversion has remained unchanged following this study.
Study limitations
The study was unblinded and operator scores may have been influenced by individual experience and preference with each form of sedation. Due to the different titration properties and appearances of the two drugs, blinding the drug to the operator was not possible. No adjustments were made in this study for body weight or concomitant drug use. We used the end-point of loss of response to verbal stimulus or tactile stimulus to indicate an adequate level of sedation. These end-points may also represent the early stages of general anaesthesia. Using alternative signs such as failure to focus eyes upon a moving object or exotrophic eyes may achieve adequate amnesia with lower doses of sedation[27]. The doses of midazolam used in this study were higher than those used in several previous studies[12,[23–25]. This may have been a result of the rapid titration protocol used. In elderly or smaller patients a smaller initial dose of midazolam may reduce adverse events.
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Conclusion |
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Physician-led cardioversion using intravenous diazepam and midazolam is highly effective and well tolerated, with only minor after-effects at 24 and 48 h. Even though anaesthetists have superior airway skills, these skills were not required in any of the patients who were sedated in this study[32]
. Sedation with diazepam is associated with a quicker recovery time than midazolam and allows a faster turnaround time for day-case cardioversion procedures. |
References |
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