Multicenter, Randomized, Controlled Trial of 150-J Biphasic Shocks Compared With 200- to 360-J Monophasic Shocks in the Resuscitation of Out-of-Hospital Cardiac Arrest Victims
Background—In the present study, we compared an automatic external defibrillator (AED) that delivers 150-J biphasic shocks with traditional high-energy (200- to 360-J) monophasic AEDs.
Methods and Results—AEDs were prospectively randomized according to defibrillation waveform on a daily basis in 4 emergency medical services systems. Defibrillation efficacy, survival to hospital admission and discharge, return of spontaneous circulation, and neurological status at discharge (cerebral performance category) were compared. Of 338 patients with out-of-hospital cardiac arrest, 115 had a cardiac etiology, presented with ventricular fibrillation, and were shocked with an AED. The time from the emergency call to the first shock was 8.9±3.0 (mean±SD) minutes.
Conclusions—The 150-J biphasic waveform defibrillated at higher rates, resulting in more patients who achieved a return of spontaneous circulation. Although survival rates to hospital admission and discharge did not differ, discharged patients who had been resuscitated with biphasic shocks were more likely to have good cerebral performance.
Sudden cardiac arrest associated with ventricular fibrillation (VF) remains a leading cause of unexpected death in the Western world.1 2 Rapid-response programs3 4 with automatic external defibrillators (AEDs) used as part of the “chain of survival”5 have achieved marked improvements in survival rates in selected localities. The European Resuscitation Council, the American Heart Association, and the International Liaison Committee on Resuscitation have advocated the widespread dissemination of AEDs.6 7 8
The success of widespread AED lifesaving programs depends on the development of therapeutic technology suitable for mass deployment with infrequent individual use. This will require great strides in defibrillator cost, size, and unattended reliability.
Traditional monophasic defibrillators deliver high and escalating energies, from 200 to 360 J. These waveforms and energy levels place fundamental limitations on device cost, weight, and volume reduction.9
Biphasic waveforms have replaced monophasic waveforms for implantable defibrillators because of proved advantages in energy requirements, size, and weight.10 11 12 The incorporation of low-energy impedance-compensating biphasic truncated exponential (ICBTE) waveforms into external defibrillators facilitates effective and automated application of the therapy to the general patient population. The safety and efficacy of these waveforms have been demonstrated under controlled laboratory and in-hospital conditions,13 14 15 and evidence that the use of lower energies and biphasic waveforms offers further benefit by reducing postshock myocardial dysfunction is mounting.16 17 18 19 20 21 22 23
Prospective, clinical studies to date have been conducted under highly controlled in-hospital conditions. Out-of-hospital cardiac arrest victims have more varied and longer arrest times. Data from out-of-hospital studies are needed to investigate the new role of low-energy biphasic waveforms in sudden cardiac arrest.24
Observational studies on patients with out-of-hospital cardiac arrest have previously demonstrated that a 150-J ICBTE AED terminated long-duration VF at high rates.25 26 27 We now present the results of the first prospective, randomized trial that compared a 150-J ICBTE AED with traditional, energy-escalating monophasic AEDs. The objective of this multicenter trial was to assess the effectiveness of the AEDs for victims of cardiac arrest in the out-of-hospital setting.
On approval by each local ethics committee, all patients who weighed ≥36 kg, who had a known or suspected cardiac arrest, and who were attended by the emergency medical services (EMS) system during the study period were included. All devices used in the study were CE (European Community)–marked and commercially available in Europe, so informed consent was not required under the circumstances of this study. Arrests witnessed by EMS personnel were excluded because the response time from collapse was not representative of out-of-hospital arrest. Patients with do-not-resuscitate instructions, patients whose arrest resulted from a noncardiac cause such as trauma or drowning, and patients who were not treated with AEDs were also excluded.
Patients were prospectively enrolled in 4 EMS systems (Table 1⇓). First responders, whether first or second tier, used either 150-J ICBTE AEDs or 200- to 360-J monophasic AEDs on victims of sudden collapse when defibrillator application was indicated. All consecutive incidents were included in the study in each area until the study was completed. Shocks were delivered with self-adhesive defibrillation pads recommended by the respective equipment manufacturers. Physicians also carried manual defibrillators as backup and to address other electrotherapy and monitoring needs (eg, synchronized cardioversion, external pacing).
If the responder suspected that the patient was in cardiac arrest, then the randomly preselected AED was immediately turned on. The patient was then positioned for cardiopulmonary resuscitation (CPR) and AED use. CPR was typically performed while the defibrillation pads were being attached to the patient. A sequence (200, 200, and 360 J for monophasic or 150,150, and 150 J for biphasic) of up to 3 defibrillation shocks was then delivered. If 3 consecutive shocks failed to defibrillate or if the AED did not advise that a shock be delivered, the local protocols according to European Resuscitation Council guidelines were followed.28 29
A daily schedule of randomly selected AED types was distributed on a quarterly basis. At the change of crew shifts in the morning, the carrying case of the selected AED type was tagged, clearly indicating which AED had to be used for the entire day. If the AED was being used in a mission at the designated time, then randomization was delayed until immediately after that mission was completed and the AED was returned.
The biphasic AEDs (ForeRunner AED; Agilent Technologies Heartstream Operation) delivered 150-J impedance-compensated biphasic waveforms from a 100-μF capacitor. This waveform adjusts the duration of each phase in response to patient impedance measured during each shock, providing the desired total waveform duration, tilt, and energy delivery.10 11 12 13 25
Monophasic waveforms were delivered by AEDs designed to conform to the defibrillation waveform requirements of AAMI/ANSI Standard DF-2.30 The monophasic AEDs delivered either monophasic truncated exponential (MTE) or monophasic damped sine (MDS) defibrillation waveforms, depending on the device model in use at each investigational site. MTE AEDs included Heartstart 3000 and Heartstart 911 (Laerdal Medical Corporation). MDS AEDs included Heartstart 2000 (Laerdal Medical Corporation) and LifePak 200 (Physio-Control).
The primary end point of the study was the percentage of patients with VF as the initial monitored rhythm who were defibrillated in the first series of ≤3 shocks. Secondary end points included defibrillation with ≤2 shocks, first-shock defibrillation, and survival to hospital admission and discharge. Other predetermined observations included return of spontaneous circulation (ROSC), response times, and neurological status at discharge.
The sample size was based on historical data from the investigators, which suggested that 70% of monophasic-waveform patients would be defibrillated within 3 shocks. The detection of a 22% increase or a 28% decrease in the primary end point with 80% power and a significance level of 0.05 would therefore require 48 patients per arm. With the estimation that VF would be the initial monitored rhythm in 40% of the sudden cardiac arrest victims,31 a total enrollment of 240 was anticipated.
ECG and shock data were obtained from the recording systems within the AEDs. Patient data were collected from the incident reports and follow-up reports. Neurological status was scored according to the Glasgow-Pittsburgh Cerebral Performance Category (CPC) and Overall Performance Category (OPC) by study investigators at each site at patient discharge from the hospital.32
Postshock ECGs were classified by the investigator at each site and reviewed by an independent Data and Safety Monitoring Board (DSMB). VF was defined as a disorganized rhythm with a median peak-to-peak amplitude of ≥100 μV. Any rhythm with an amplitude of <100 μV was defined as asystole. An episode of VF was required to persist ≥5 seconds before transition to a non-VF rhythm. The subsequent recurrence of VF was considered a new episode.
Defibrillation was defined as the termination of VF for ≥5 seconds, without regard to hemodynamic factors.33 By definition, rhythms that occurred after successful shocks included supraventricular and paced rhythms, ventricular standstill (asystole), bradycardia, and idioventricular rhythms. Non-VF ventricular tachyarrhythmias were defined as successful defibrillation rhythms if they self-terminated within 30 seconds from shock delivery.
Data and Safety Monitoring
Each case report form was sent independently from the centers to the independent DSMB. Members of the DSMB (D.C., L.B., W.D.W.) reviewed all case reports to ensure patient safety and integrity of the data and selected source data (eg, original ECGs) as deemed necessary to resolve apparent discrepancies, by judgment of the chairman (D.C.). The DSMB conducted a separate analysis of the major study end points. The data were formally analyzed after the accumulation of the first 10% of the data and each successive 25% thereafter, based on the equivalent group sequential test for the primary hypothesis. The board reviewed each case at the conclusion of the study. Discrepancies were discussed until an agreement was reached on all cases.
Continuous variables are expressed as mean±SD and compared with the use of t tests. Ordinal variables (discharge destination, CPC, OPC) were compared by the Kruskal-Wallis rank sums test. Discharge destination was assigned a rank of 1 for home, 2 for rehabilitation facility, and 3 for extended care facility. Proportions were compared by log-likelihood ratio χ2 tests and include ≈95% CIs of differences. Tests were 2-tailed and were computed with the JMP software application developed by the SAS Institute. A P value of ≤0.05 was considered statistically significant.
The site in Mainz, Germany, enrolled 197 patients starting from December 1996; the site in Brugge, Belgium, enrolled 69 patients starting from September 1997; the site at Hamburg, Germany, enrolled 37 patients starting from November 1997; and the site at Helsinki, Finland, enrolled 35 patients starting from July 1998. By the conclusion of the study in December 1998, a total of 338 patients had been enrolled.
Of the 338 patients, 246 had an arrest of cardiac etiology that was not witnessed by EMS personnel and were randomized to an AED. There were no statistical differences between the monophasic and biphasic AED patients in terms of age, sex, weight, primary structural heart diseases, cause or location of arrest, bystanders who witnessed the arrest or performed CPR, or the type of responder. Similarly, these factors were not statistically different when only the 115 patients who presented with VF as their initial monitored rhythm were considered (Table 2⇓). The patients who presented with VF are the subjects of interest for this study of AED efficacy. All analyses and discussions from this point on focus exclusively on these patients.
The time from the emergency call to the first shock was 8.9±3.0 minutes overall and did not differ between treatments: 8.7±3.2 for monophasic versus 9.2±2.9 for biphasic (P=0.51).
Resuscitation of VF Patients
The defibrillation efficacy of the 150-J biphasic waveform was superior to that of the 200- to 360-J monophasic waveforms (Table 3⇓, Figure 1⇓). Four patients in the monophasic group were not treated with the AED due to low-amplitude VF not being detected by the AED. For the primary end point of defibrillation within the first shock series, 53 of 54 (98%) VF patients were defibrillated with 150-J biphasic shocks compared with 42 of 61 (69%) patients defibrillated with 200- to 360-J monophasic shocks (P<0.0001).
More patients were defibrillated with the initial biphasic shock than with the initial monophasic shock (96% compared with 59%, P<0.0001), and ultimately all patients treated with biphasic AEDs were defibrillated while under EMS care, whereas this was not true for those treated with monophasic AEDs or a combination of monophasic AEDs and backup manual monophasic defibrillators (100% compared with 84%, P=0.003).
A higher percentage of patients (76%) achieved ROSC after 150-J biphasic-waveform defibrillation compared with higher-energy monophasic-waveform defibrillation (54%) (Figure 1⇑, P=0.01). Rates of survival to hospital admission and to hospital discharge did not differ between the treatments.
Outcomes of Discharged Patients
Destination of discharge did not differ between the treatments (Figure 2⇓). CPC at hospital discharge favored patients treated with 150-J biphasic shocks (Figure 2⇓). Among survivors to hospital discharge, 87% of patients resuscitated with 150-J biphasic shocks had good cerebral status compared with only 53% after resuscitation with higher-energy monophasic shocks (P=0.04, 95% CI 6% to 62%). OPC did not differ between the treatments (Figure 2⇓).
Improved Defibrillation Efficacy
The high defibrillation efficacy of the particular 150-J impedance-compensating biphasic waveform observed in the present study is consistent with previous reports but strengthens the finding by providing randomized data from out-of-hospital emergency care.26 27 The concurrent controls substantiate the magnitude of the improvement in defibrillation efficacy obtained with this biphasic waveform compared with conventional escalating-energy monophasic-waveform methods. In addition to the improved defibrillation rates of individual biphasic shocks or shock sequences, it is noted that all patients who received treatment with 150-J biphasic shocks were eventually defibrillated during the resuscitation attempt and without resort to backup manual defibrillators, which was not true for the higher-energy monophasic waveforms. Dynamic control of waveform parameters via impedance compensation with a 150-J biphasic shock provides consistently high defibrillation rates without the need for escalating energies. This finding is key to encouraging the further evolution of small, low cost, and widely available AED technology with dynamic waveform control techniques.
Impact on Patient Survival
Despite a statistically significant increase in ROSC after defibrillation with 150-J biphasic shocks, no differences in survival to admission to or discharge from hospital were established. The present study was statistically powered to show differences in defibrillation efficacy, not in patient survival. Our objective was to assess the relative performances of the AEDs. The determination of statistical differences in short- or long-term patient survival would require a prohibitively large study to mitigate the uncontrolled variables associated with EMS system influences and postresuscitation treatment.
Impact on Patient Outcome
Although the rate of survival to discharge from hospital did not differ between treatments, among patients who survived to be discharged, those treated with the biphasic waveform were more likely to be in good condition (eg, to have a CPC of “good”) than were those treated with monophasic waveforms. Discharge destinations and OPCs were consistent with these findings in favoring biphasic patients, although the differences were not statistically significant. Improved neurological status has previously been associated with shorter overall resuscitation times in the treatment of sudden cardiac arrest victims34 but not with defibrillation energy or waveform. It is our hypothesis that the superior neurological status observed at hospital discharge after resuscitation with 150-J biphasic defibrillation shocks is associated with shorter time to ROSC and resultant better postresuscitation cardiac output during the critical interval immediately after severe ischemic compromise. This hypothesis is supported by the significantly higher rate of ROSC obtained with the biphasic waveform. Furthermore, studies in animals have demonstrated that both defibrillation waveform and energy dose affect postresuscitation myocardial function.18 19 20 21 22 23 In these studies, both stroke volume and ejection fraction were significantly depressed for many hours after high-energy monophasic shocks to a much greater degree than after 150-J biphasic shocks. Increasing the number of neurologically intact survivors from out-of-hospital sudden cardiac arrest may directly depend on reducing the compromise of cardiac output associated with high-energy defibrillation.
Randomization of treatment was conducted on the basis of date rather than on the basis of patient and responders were not blinded to the AED type. The AEDs were all commercially available devices, with each of the 5 models differing in its user interface, analysis algorithm, and therapy waveform. The EMS personnel were familiar with the monophasic devices at the outset of the study, whereas the biphasic devices were newly introduced. These choices were made due to practical and ethical considerations. The urgency of immediate intervention precluded concealment. Training, budget, and regulatory constraints precluded the development and use of novel devices solely for the purposes of the study. Our method is, however, superior to the alternative day technique used in other recent resuscitation trials.35 36
In designing our nonblinded study, we considered that unintended randomization errors might favor one mode of defibrillation or the other. Bias in selection of the type of defibrillator used would then be difficult to disprove. It was for this reason that an intention-to-treat analysis was included in the protocol and in this report.
The control AEDs used in the present study deployed either MTE (79%) or MDS (21%) shocks, reflecting the distribution of AED types in service at the time of the study. There is some evidence that MTE waveforms have lower defibrillation rates than MDS waveforms.37 Thus, the observed defibrillation efficacy of the control group may depend in part on the distribution of monophasic AED types. However, a subset analysis that compared the efficacy of each waveform substantiates the benefits of the biphasic waveform over each of the monophasic waveforms (P. Martens, MD, unpublished data, 2000), as does a comparison of this biphasic AED with only MDS AEDs in a similar smaller study (K.-G. Kanz, unpublished data, 1999).
In summary, the results of the present study show that an appropriately dosed low-energy impedance-compensating biphasic-waveform strategy results in superior defibrillation performance in comparison with escalating, high-energy monophasic shocks in out-of hospital cardiac arrest. Moreover, the 150-J biphasic-waveform AED results in a higher rate of ROSC and better neurological status at the time of hospital discharge.
Investigators and participating institutions are given in the order of the number of patients enrolled:
Thomas Schneider, MD; Benno Wolcke, MD; Gerhard Tauscher, Study Coordinator; Heinke Teichmann, Clinic of Anaesthesiology, The Johannes Gutenberg-University Medical School, Mainz, Germany; Patrick R. Martens, MD; Francis Cooman, MD; Martin De Meyer, RN, Emergency Medical Department, St Jan Hospital, Brugge, Belgium; Luc Charles, Project Coordinator, Fire Brigade, Brugge, Belgium; Hans-Richard Paschen, MD, EMS Medical Director, Hamburg Fire Brigade, Hamburg, Germany; and Markku Kuisma, MD, Janne Aaltonen, MD, Jouni Pousi, RN, Helsinki City EMS, Helsinki, Finland.
This work was supported by a grant from Agilent Technologies Heartstream Operation. B. Gliner and Dr Russell were employees of and Dr Weaver was an advisor to Heartstream during the study. Prof Chamberlain’s Honorary Chair in Cardiff is supported (expenses only) by a grant from the Laerdal Foundation.
- Received March 3, 2000.
- Revision received May 15, 2000.
- Accepted May 16, 2000.
- Copyright © 2000 by American Heart Association
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