Active compression-decompression cardiopulmonary resuscitation (CPR) with decreased intrathoracic pressure in the decompression phase can lead to improved haemodynamics compared with standard CPR. We aimed to assess effectiveness and safety of this intervention on survival with favourable neurological function after out-of-hospital cardiac arrest. In our randomised trial of 46 emergency medical service agencies (serving 2·3 million people) in urban, suburban, and rural areas of the USA, we assessed outcomes for patients with out-of-hospital cardiac arrest according to Utstein guidelines. We provisionally enrolled patients to receive standard CPR or active compression-decompression CPR with augmented negative intrathoracic pressure (via an impedance-threshold device) with a computer-generated block randomisation weekly schedule in a one-to-one ratio. Adults (presumed age or age ≥18 years) who had a non-traumatic arrest of presumed cardiac cause and met initial and final selection criteria received designated CPR and were included in the final analyses. The primary endpoint was survival to hospital discharge with favourable neurological function (modified Rankin scale score of ≤3). All investigators apart from initial rescuers were masked to treatment group assignment. This trial is registered with ClinicalTrials.gov, number NCT00189423. 2470 provisionally enrolled patients were randomly allocated to treatment groups. 813 (68) of 1201 patients assigned to the standard CPR group (controls) and 840 (66) of 1269 assigned to intervention CPR received designated CPR and were included in the final analyses. 47 (6) of 813 controls survived to hospital discharge with favourable neurological function compared with 75 (9) of 840 patients in the intervention group (odds ratio 1·58, 95 CI 1·07-2·36; p=0·019]. 74 (9) of 840 patients survived to 1 year in the intervention group compared with 48 (6) of 813 controls (p=0·03), with equivalent cognitive skills, disability ratings, and emotional-psychological statuses in both groups. The overall major adverse event rate did not differ between groups, but more patients had pulmonary oedema in the intervention group (94  of 840) than did controls (62  of 813; p=0·015). On the basis of our findings showing increased effectiveness and generalisability of the study intervention, active compression-decompression CPR with augmentation of negative intrathoracic pressure should be considered as an alternative to standard CPR to increase long-term survival after cardiac arrest. US National Institutes of Health grant R44-HL065851-03, Advanced Circulatory Systems.
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Our results show that treatment with active compression-decompression CPR with enhancement of negative intrathoracic pressure during the decompression phase significantly increases survival to hospital discharge with favourable neurological function compared with standard CPR after an out-of-hospital cardiac arrest of presumed cardiac cause ( ). Furthermore, overall survival increased by nearly 50% by 1 year in the intervention group compared with controls. Consistency of benefit was independent of sex, age, date of enrolment, and study site. Neurological function was much the same between groups at 90 days and 365 days after the out-of-hospital cardiac arrest. panel There was no increase in the number of patients with severe neurological impairment in either group. There were no differences in overall major adverse event rates between groups, although occurrence of pulmonary oedema was increased by 50% in the device group, which was coexistent with the increase in survival with favourable neurological function. The clinical relevance of this finding is unclear: the percentage increase in pulmonary oedema (46%) was proportional to the increase in survival in the intervention group (53%). Our findings strongly support the need for rapid deployment of all CPR interventions to maximise possible benefits. Our investigation builds on previous studies 7–12,15,16,27–31 showing that active compression-decompression CPR and a means to lower intrathoracic pressure during the chest recoil phase transforms the chest into an active bellows to more effectively circulate blood during CPR to the heart and the brain and increase short-term survival. Our study shows that teaching and implementation of active compression-decompression CPR and impedance-threshold device skills in urban, suburban, and rural emergency medical services is practicable. Because the US study sites we investigated have much the same practices as do most emergency medical service systems in the USA and because study devices have been successfully integrated into emergency services at locations in Germany and France, this approach should be expandable to any emergency medical service system that follows present European Resuscitation Council or American Heart Association guidelines. We first noted the significant difference in clinical outcomes between intervention groups at the time of hospital discharge; return of spontaneous circulation and hospital admission rates did not differ between groups. On the basis of preclinical and clinical studies showing greater blood flow to the heart and brain with active compression-decompression CPR and augmentation of lower intrathoracic pressure, 7,10–12,14,27–29 we suggest that improved cerebral perfusion during CPR in the intervention group resulted in reduced cerebral ischaemia but that recovery and restoration of brain function might take more time than does the recovery of cardiac function. These findings also support the idea that improved perfusion outside the hospital in the intervention group could result in more stable candidates for cardiac catheterisation than were found in the standard CPR group, resulting in more patients in the intervention group being provided cardiac catheterisation. Our study has several limitations. First, emergency medical service rescuers were not blinded to the CPR method; however, assessors of the primary outcome and neurological tests were masked to intervention status, which restricted potential bias. Second, we could not establish the relative contribution of active compression-decompression CPR alone, the impedance-threshold device alone, or the rescuer feedback elements including the timing lights, metronome, and force gauge to the positive study outcome. Data from studies in animals and human beings suggest that every component is necessary to record benefits with this combined approach. 5,6,11,14,16,30 The study initially included a third arm—standard CPR plus an impedance-threshold device study arm—to assess the relative contribution of the impedance threshold device only to the anticipated benefit of the combination of active compression-decompression CPR plus an impedance-threshold device versus standard CPR. However, due to slower than anticipated enrolment rates for the entire study and limited funding for the study, enrolment in this third study arm was discontinued early in the course of the study. Another potential limitation of our study was that study enrolment was stopped early because of low funding and extra data could have changed the primary findings. Nevertheless, differences between treatment groups were consistent throughout the study ( figure 5 ). Finally, some surviving patients refused to provide consent for further participation or release of data. However, because of the unique circumstances and limitations associated with obtaining of informed consent under emergency circumstances, collection of follow-up data for all patients is a challenge for all studies such as ours. Thus, compared with standard CPR, active compression-decompression CPR with augmentation of negative intrathoracic pressure results in significantly increased survival to hospital discharge with favourable neurological function, which was observed to 1 year after out-of-hospital cardiac arrest. Contributors TPA, RGH, DET, DY, and KGL designed the study. TPA, RJF, MAW, BDM, RAS, RMD, and MLO obtained the data. RGH did the statistical analysis. All authors participated in the data analysis and interpretation processes and in the review of the final report. Study personnel Data and Safety Monitoring Board —L Brent Mitchell (Chairman; Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada), Dianne M Bartels and Patricia Grambsch (University of Minnesota, Minneapolis, MN, USA), Daniel Hankins (Mayo Clinic Medical Transport, Rochester, MN, USA), James Malec (Rehabilitation Hospital of Indiana/Indiana University School of Medicine, Indianapolis, IN, USA), Jay W Mason (University of Utah, Salt Lake City, UT, USA), and Paul Molinari (Twin Cities Anesthesia Associates, Minneapolis, MN, USA). Clinical Events Committee —Carson Harris (Chairman), Avi Nahum, and Dennis Zhu (Regions Hospital, St Paul, MN, USA). Data Co-ordination —Terry Arend Provo, Cindy Setum, Lucinda Klann, Nathan Burkhart, and Caleb Sorenson (Roseville, MN, USA). Conflicts of interest TPA, RJF, MAW, BDM, RAS, RMD, and MLO all received grant funds to their respective institutions for services related to patient enrolment, follow-up and data management for this clinical study; RGH received consulting fees for statistical analyses (US National Institutes of Health [NIH] R44-HL065851-03 ). KGL was co-inventor of the impedance-threshold device and active compression-decompression cardiopulmonary resuscitation device, and founded Advanced Circulatory Systems in 1997 after the University of Minnesota (MN, USA) declined the opportunity to apply for patent protection on the impedance threshold device. All investigators feel KGL contributed substantially to this study and therefore should be listed as an author rather than incorporating his role within the activities of the sponsor, Advanced Circulatory Systems. In his role as the Chief Medical Officer of Advanced Circulatory Systems, KGL participated with the other investigators in obtaining the NIH grant funding (KGL was the principal investigator on the Small Business Innovation Research grant), the study design, data interpretation, writing and the decision to submit the paper for publication. KGL was not involved in any patient care or assessment of patient neurological status during the 1-year follow-up. Outside the present study, TPA has board membership for Take Heart America and Citizen CPR Foundation, has consulted for JoLife Medical and Medtronic Foundation, and has received grants/grants pending from the NIH Immediate Trial, NIH Resuscitation Outcomes Consortium, NIH Neurological Emergency Treatment Trials Network, and NIH Medical College of Wisconsin K12 Research Career Development Program. RJF has received payment for one lecture from Advanced Circulatory Systems. MAW has consulted for Baxter and Vitacare, has received grants/grants pending from the NIH Immediate Trial, payment for lectures or speakers' bureau membership from Vitacare and Sub Zero, and royalties from Cook Critical Care. BDM has board membership for Take Heart Minnesota and has received grants/grants pending from the NIH Neurological Emergency Treatment Trials Network. DET has received grants/grants pending from the Predict HD study , NINDS-6375 , NINDS-40068 and NIMH-01579 , and royalties as a textbook editor. Acknowledgments We thank the many first responders, firefighters, emergency medical technicians, and paramedics at all sites who took care of the patients, and without whom survival from out-of-hospital cardiac arrest would not be possible (see webappendix pp 5–9 ). The study was funded by the US National Institutes of Health and the federal grant ( R44-HL065851-03 ) was used by Advanced Circulatory Systems to fund the study.
The protocol was approved by the US National Institutes of Health (funding source) and a representative of this institute was on the data and safety monitoring board. The sponsor (Advanced Circulatory Systems) helped investigators to obtain government funding, design the study, interpret the data, write the report, and decide to submit the report for publication. The sponsor was not involved in any patient care or assessment of patient neurological status during the 1-year follow-up. The decision to submit the paper was made by all co-authors with no input from the National Institutes of Health. The corresponding author had full access to all the data in the study; all other authors could request examination of any of the data elements. All authors reviewed and approved the final version of the manuscript and had final responsibility for the decision to submit for publication.