Published online before print November 9, 2007, doi: 10.1161/CIRCULATIONAHA.107.186228
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(Circulation. 2007;116:2501-2512.)
© 2007 American Heart Association, Inc.
ILCOR Consensus Statements |
Scientific Knowledge Gaps and Clinical Research Priorities for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Identified During the 2005 International Consensus Conference on ECC and CPR Science With Treatment Recommendations
A Consensus Statement From the International Liaison Committee on Resuscitation (American Heart Association, Australian Resuscitation Council, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, and the New Zealand Resuscitation Council); the American Heart Association Emergency Cardiovascular Care Committee; the Stroke Council; and the Cardiovascular Nursing Council
Key Words: AHA Scientific Statement • cardiopulmonary resuscitation • death, sudden
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Introduction |
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New guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) were published in November 2005.1,2 Publication followed a systematic evaluation of scientific evidence that culminated in the 2005 International Consensus Conference on ECC and CPR Science With Treatment Recommendations hosted by the American Heart Association (AHA) in January 2005.3,4 The new treatment recommendations from this meeting incorporated scientific advances made after publication of the 2000 guidelines and were published with the expectation that their worldwide implementation would help improve rates of survival from cardiac arrest and other life-threatening cardiopulmonary emergencies.
A new cycle of evidence evaluation has begun and is expected to be completed in 2010 with the publication of new and revised treatment recommendations. These recommendations will once again reflect the scientific knowledge gained during the intervening period. As the cycle begins, a unique opportunity exists to identify areas in greatest need of clinical research, with the expectation that key questions asked today may be answered in time for the 2010 guidelines. To this end, valuable information was obtained during the evidence evaluation process that led to the 2005 guidelines. Experts appointed to review specific resuscitation topics were asked not only to summarize the existing science but also to identify knowledge gaps. As a result, experts identified knowledge gaps in 276 preassigned topics. We have compiled and organized these knowledge gaps and, through a process of consultation and consensus, identified areas of priority for clinical research.
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Methods |
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Member organizations of the International Liaison Committee on Resuscitation (ILCOR), which includes the AHA, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Resuscitation Council of Southern Africa, the Australia and New Zealand Committee on Resuscitation, and the InterAmerican Heart Foundation, planned the process of evidence evaluation for the January 2005 evidence-based consensus conference on CPR and ECC.3 ILCOR representatives established task forces on basic life support, advanced life support, neonatal resuscitation, pediatric resuscitation, interdisciplinary topics, and acute coronary syndromes. The AHA established 2 additional task forces on stroke and first aid. Each task force identified topics that required evidence evaluation and appointed international experts to review these topics with strict attention to conflicts of interest and transparency of process.5,6 Each topic was assigned to a minimum of 2 reviewers who represented 2 different ILCOR member organizations, and most assigned reviews were completed. The result was that a total of 281 experts prepared 403 worksheets on 276 topics. Each reviewer was instructed to search a minimum of 5 databases (Medline, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, EMBASE, and AHA/EndNote [a library of references compiled by the AHA using EndNote that includes all citations used in previous resuscitation publications]) and to use a standardized evaluation form to rate the level and quality of evidence.7 The original worksheets are available on the Internet at http://www.c2005.org under "View the Evidence Evaluation Worksheet Data Supplement." Reviewers were also instructed to identify knowledge gaps within their assigned topics, which resulted in 1 or more gaps being identified in 199 of the 276 topics. These knowledge gaps were used to develop the present consensus statement.
The knowledge gaps were collated to minimize duplication, classified by specific task force topics, and submitted to the corresponding task force chairs for further review, editing, and identification of the 10 to 15 most important research priorities within each topic. The comprehensive lists of knowledge gaps with their corresponding research priorities have been posted in the online-only Data Supplement at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.186228/DC1 in the form of Appendixes 1 through 8. These research priorities were then organized into 4 categories: (1) resuscitation, (2) acute coronary syndromes, (3) stroke, and (4) first aid. Additional input was sought from resuscitation experts, and the revised lists were returned to the task force chairs for final update, revision, and approval.
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Results |
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Research Priorities in Resuscitation of Adults, Children, and Neonates
The research priorities for adults, children, and neonates (Table 1
) were combined because of substantial overlap among these age groups. The overlap was most evident in topics related to adult and pediatric resuscitation. Age-related differences and unique research priorities in the neonatal group were noted under each research priority. The original lists of knowledge gaps and priorities for each age group—as indicated in Methods—can be found in the online-only Data Supplement. The research priorities were grouped into broad categories, which, wherever possible, paralleled the sequence of interventions during a resuscitation episode. The categories included "medical emergency teams"; "recognition of cardiac arrest and its causes"; "body position"; "electrical defibrillation"; "blood flow generation"; "airway management"; "ventilation"; "oxygenation"; "pharmacological interventions"; "metabolic, temperature, and postresuscitation management"; "physiological monitoring and feedback"; "ethical issues"; "education and training"; and "outcomes."
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"Medical Emergency Teams" acknowledged the need to assess the potential impact of these teams on in-hospital cardiac arrest through early recognition of physiological deterioration and timely intervention. "Recognition of Cardiac Arrest and Its Causes" highlighted the need to develop better methods to recognize cardiac arrest and establish its origin and mechanism in order to tailor resuscitation efforts. "Body Position" focused on the relationship between positioning and airway management (especially in victims with a suspected cervical spine injury) and on development of alternative positions for performance of CPR.
"Electrical Defibrillation" identified the need to establish the optimal energy and sequence of electrical shocks, duration of chest compressions before and between electrical shocks, impact of real-time ventricular fibrillation waveform analysis, short- and long-term effects of electrical shocks on the myocardium (especially in children), and issues related to home and public-access defibrillation, as well as defibrillation by first responders. "Blood Flow Generation" highlighted the need to define settings in which compression-only CPR is more effective, to understand and optimize the various determinants of blood flow during manual and mechanical chest compression, to assess the impact of airway impedance threshold devices, and to develop strategies for minimizing interruptions during chest compressions while effectively integrating the various resuscitation interventions.
"Airway Management" focused on techniques to secure upper-airway patency, methods to provide ventilation (comparing bag-mask ventilation with ventilation through an advanced airway), techniques to confirm and monitor advanced airway placement, and issues of training in airway management. In the neonatal area, research priorities focused on assessing the effectiveness of various upper-airway interventions and ventilation, including techniques on meconium suctioning, administration of surfactant, and administration of drugs. "Ventilation" emphasized the need to define age-related compression-to-ventilation ratios and tidal volumes and to develop methods for providing real-time feedback that minimize adverse effects of ventilation on venous return. "Oxygenation" focused on defining oxygen needs during basic life support and delivery room resuscitation in neonates.
"Pharmacological Interventions" highlighted the need to assess the outcome effects of drugs for which proof of ultimate survival benefit is lacking, such as vasopressor agents, antiarrhythmic drugs, and atropine. Additional research priorities included assessment of β-adrenergic blockers, with consideration of selectivity and duration of action, fibrinolytic drugs and other agents that interfere with coagulation and blood clot formation, novel vasopressor agents, and novel compounds targeting reperfusion injury, such as mitochondrial ATP-sensitive K+ channel openers, opioid receptor agonists, Na+-H+ exchanger inhibitors, and erythropoietin. Research priorities were also identified in routes and timing of drug delivery. "Metabolic, Temperature, and Postresuscitation Management" acknowledged the need to evaluate the effectiveness and management of hypothermia during and after resuscitation. Other research priorities included blood glucose management and use of vasoactive and inotropic drugs during the postresuscitation phase. For neonatal resuscitation, research priorities also included the effects of barriers on heat exchange. "Physiological Monitoring and Feedback" focused on critical needs for real-time monitoring of physiological variables during and after cardiac resuscitation for directive and corrective action.
"Ethical Issues" included evaluating the effects of the presence of family members during a resuscitation attempt, initiation and discontinuation of life support, and the impact of advance directives. "Education and Training" identified the need to assess the impact of methods for CPR self-instruction, training status of lay responders, methods to promote acquisition and retention of resuscitation skills, and risks associated with training. Finally, "Outcomes" emphasized the need to develop methods to assess quality of life in survivors of cardiac arrest and to identify valid surrogate measurements of ultimate outcome. For children, identification of therapeutic end points for shock resuscitation was deemed a priority.
Research Priorities in Acute Coronary Syndromes
Categories of research priorities in acute coronary syndromes (Table 2) included "Prehospital and Emergency Department Assessment," "Antiplatelet Drugs," "Heparin," "β-Adrenergic Blockers," and "Reperfusion Strategies." "Prehospital and Emergency Department Assessment" focused on the use of the 12-lead ECG in patients with ST-segment–elevation myocardial infarction. "Antiplatelet Drugs" emphasized the need to determine the optimal dose of clopidogrel and the time dependency of prehospital administration of glycoprotein IIb/IIIa receptor inhibitors. "Heparin" focused on prehospital and emergency department formulation of the drug and dosing for ST-segment–elevation and non–ST-segment–elevation myocardial infarction. "β-Adrenergic Blockers" focused on prehospital use. "Reperfusion Strategies" included prehospital administration of fibrinolytic drugs and various strategies for triage of patients for percutaneous coronary intervention.
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Research Priorities in Stroke
Categories of research priorities in stroke (Table 3) included "Stroke Centers," "Pharmacological Interventions," "Metabolic Management," "Neuroprotective Therapies," "Transient Ischemic Attack," and "Intracerebral Hemorrhage." "Stroke Centers" identified the need to assess the safety and efficacy of stroke centers and to determine appropriate triage protocols. "Pharmacological Interventions" highlighted blood pressure management, use of intravenous recombinant tissue plasminogen activator, and local procedures for clot extraction. "Metabolic Management" included the need to define optimal strategies for control of blood glucose and oxygen supplementation. "Neuroprotective Therapies" focused on hypothermia and pharmacological agents and their interaction with concomitant interventions. "Transient Ischemic Attack" identified the need for risk stratification and triage. "Intracerebral Hemorrhage" focused on the management of spontaneous bleeding and bleeding associated with oral anticoagulation.
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Research Priorities in First Aid
Categories of research priorities in first aid (Table 4) included "Bleeding," "Joint Injury," "Skin Burns," "Bone Fracture," "Spinal Injury," "Local Cold Injury," "Snake Bite," "Oral Poisoning," "Allergic Reaction," and "Oxygenation." "Bleeding" highlighted the need to evaluate the safety and efficacy of tourniquets and of novel technologies for control of bleeding. "Joint Injury" and "Skin Burns" highlighted various issues related to cold therapy. "Bone Fracture" identified the need to assess the impact of straightening fractures and stabilization of injured extremities. "Spinal Injury" identified issues related to recognition of spinal injury by first aid responders and immobilization techniques. "Local Cold Injury" focused on identifying optimal methods to rewarm body parts. "Snake Bite" emphasized the need for data regarding the safety and efficacy of compressive wrapping for elapid and nonelapid snake bites. "Oral Poisoning" focused on charcoal administration and its use by the public. "Allergic Reaction" identified issues of recognition and assisting victims with self-administration of epinephrine. "Oxygenation" related to the safety and efficacy of administration of oxygen to dyspneic victims.
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Discussion |
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The clinical research priorities identified in the present statement are the result of a process of consensus and consultation among experts and reflect unresolved clinical problems related to resuscitation and emergency management of acute coronary syndromes, stroke, and first aid. New scientific information is needed regarding prevention, recognition, treatment, monitoring, outcomes evaluation, ethics, and education. These research priorities are being published to help guide decision making by scientists, researchers, institutional review boards, funding agencies, policymakers, and all those concerned with advancing resuscitation and emergency management of acute coronary syndromes, stroke, and first aid. New information arising from clinical research hopefully may lead to rapid improvement in clinical practice by incorporation of the new information into the 2010 evidence evaluation process, with subsequent formulation of treatment recommendations. These recommendations do not exclude the possibility that new areas of research may emerge in the interim and take priority over areas identified in the present document.
Studies that examine clinically important events with robust statistical methodology have the greatest potential to impact clinical practice. Hospital discharge with intact neurological function is considered the most meaningful clinical end point in relation to cardiac resuscitation. This end point may be strengthened by standardization of postresuscitation treatment and minimization of uncontrolled variables. If adequately powered and carefully executed, a study with this end point may provide a definitive answer to a specific question and may therefore qualify for level 1 evidence in support of a Class I recommendation.7 Although such studies are optimal, there are reasons beyond cost and feasibility for conducting smaller studies of alternative end points, such as return of spontaneous circulation and hospital admission rate. For example, new concepts may require initial testing in a small group of patients to address safety, refine protocols, and provide initial evidence of efficacy. Other studies may require focus on physiologically relevant measurements as proof of concept before controlled clinical trials can be conducted. Likewise, studies related to acute coronary syndromes, stroke, and first aid may have end points related to preservation of function and reduction of disability. Some of these research priorities will require initial laboratory/animal studies before clinical research is possible. Education studies are also critical for developing more effective methods of translating current and newly acquired knowledge into information that can be used by rescuers and the public.
The most useful clinical advances result from a continuous cycle of scientific discovery, acquisition of knowledge, translational research, and clinical trials followed by dissemination and implementation of new treatment recommendations. Funding is essential to advance this cycle. In the area of resuscitation, past initiatives include the Post-Resuscitation and Initial Utility in Life Saving Efforts conference,8,9 which was charged with developing strategies for future resuscitation research (http://www.nhlbi.nih.gov/meetings/pulse/index.htm). This initiative stimulated new grants for basic science research in resuscitation and for the development of new technology for monitoring and performing resuscitation. Another critical initiative was the establishment of the Resuscitation Outcomes Consortium, which currently encompasses 10 regional clinical centers (8 in the United States and 2 in Canada) and a data coordinating center that provides infrastructure for collaborative resuscitation trials (https://roc.uwctc.org/tiki/tiki-index.php). The AHA supports the National Registry of CardioPulmonary Resuscitation, which is a large, prospective cohort study of patients with in-hospital cardiac arrest (http://www.nrcpr.org). In the United Kingdom, the Resuscitation Council supports the National Audit of Pediatric Resuscitation, which is charged with collection of data on pediatric resuscitation from centers throughout the United Kingdom (http://www.resus.org.uk/pages/naprupdt.htm). Ongoing support as part of established extramural research programs originates from the National Heart, Lung, and Blood Institute and the AHA in the United States; the Institutes of Circulatory Respiratory Health of the Canadian Institutes of Health Research; the Heart and Stroke Foundation of Canada; the British Heart Foundation, the Resuscitation Council, and the Department of Health in the United Kingdom; the Deutsche Stiftung für Herzforschung in Germany; the National Heart Foundation of Australia; and the Laerdal Foundation in Norway.
Despite these important resuscitation-specific initiatives and ongoing nonspecific funding mechanisms, additional support is needed to reduce death due to sudden cardiac arrest. Ischemic heart disease is the leading cause of death in high-income as well as low- and middle-income countries,10 and 
50% of those deaths are attributed to sudden cardiac arrest.11 It is estimated that every year, 330 000 individuals in the United States12 and 700 000 in Europe13 have an episode of sudden cardiac arrest. Efforts to restore life require not only that cardiac activity be reestablished but that injury to vital organs be prevented, minimized, or reversed. Unfortunately, with current resuscitation methods, the rate of hospital discharge with capability for independent living is disappointingly low, ranging from <2%14–17 to between 2% and 10%18–20 in many large urban areas, but rarely exceeding 15%.21,22 Many conditions other than ischemic heart disease can precipitate cardiac arrest, including those related to respiratory conditions, especially in the pediatric population. Accordingly, there is an urgent need for a substantial increase in research funding for resuscitation. Increased funding is also needed for research on the emergency management of acute coronary syndromes, stroke, and first aid.
In addition to funding limitations, research on resuscitation and other emergencies faces a critical challenge because it is usually impossible to obtain prospective consent before administration of an investigational intervention. In 1993, the US Food and Drug Administration (FDA) placed a moratorium on resuscitation research because of concern that existing regulations on informed consent were not being met,23 bringing to a virtual halt all interventional resuscitation research in the United States. A series of subsequent initiatives involving discussions between the FDA and industry in 1993, a congressional hearing in May 1994, a coalition conference of academic, medical, and research organizations in October 1994, and an FDA-sponsored public forum in January 1995 concluded in October 1996 with the enactment of parallel regulations by the FDA and the US Department of Health and Human Services that provided an exception to the requirement for informed consent under certain emergency circumstances (21 CFR part 50.24).24,25 These regulations provided a mechanism for conducting research on life-threatening conditions without prior consent through a process of community consultation and public notification (http://www.fda.gov/oc/ohrt/irbs/except.html). These regulations are still debated,26,27 have not gained full acceptance in the community,28 have imposed regulatory burdens for investigators and institutional review boards, and have limited the number of clinical trials on resuscitation.29,30 In Europe, a directive known as the Clinical Trials Directive was introduced in April 2001 by the European Parliament and the Council of the European Union. This directive threatens to significantly restrict resuscitation research by requiring that informed consent be obtained before subjects can be recruited into clinical trials of medical products.31 Investigators from several European countries are currently lobbying for amendments to the directive that could enable a waiver or deferral of consent so that unconscious patients can be enrolled in clinical trials without the delays inherent to obtaining consent.32 However, important randomized studies have been completed recently under the guidance of these new regulations on both sides of the Atlantic.33–37
Initiatives and policies aimed at improving funding and developing regulations to enable research in resuscitation and other emergencies are predicted to have a major impact on developing more effective therapies, saving more lives, driving public health policies, and attracting new investigators to the field. We trust that the present international consensus statement will create incentive and facilitate efforts to expand research in resuscitation and other emergencies.
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Acknowledgments |
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Disclosures
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Footnotes |
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The online-only Data Supplement, which contains 8 Appendixes, is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.186228/DC1.
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This article has been co-published in the December 2007 issue of Resuscitation.
When this document is cited, the American Heart Association requests that the following citation format be used: Gazmuri RJ, Nadkarni VM, Nolan JP, Arntz H-R, Billi JE, Bossaert L, Deakin CD, Finn J, Hammill WW, Handley AJ, Hazinski MF, Hickey RW, Jacobs I, Jauch EC, Kloeck WGJ, Mattes MH, Montgomery WH, Morley P, Morrison LJ, Nichol G, O’Connor RE, Perlman J, Richmond S, Sayre M, Shuster M, Timerman S, Weil MH, Weisfeldt ML, Zaritsky A, Zideman DA. Scientific knowledge gaps and clinical research priorities for cardiopulmonary resuscitation and emergency cardiovascular care identified during the 2005 International Consensus Conference on E and CPR Science With Treatment Recommendations: a consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian Resuscitation Council, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, and the New Zealand Resuscitation Council); the American Heart Association Emergency Cardiovascular Care Committee; the Stroke Council; and the Cardiovascular Nursing Council. Circulation. 2007;116:2501–2512.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on July 10, 2007. A single reprint is available by calling 800-242-8721 (US only) or by writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0420. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifer=3023366.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.americanheart.org/presenter.jhtml?identifier=4431. A link to the "Permission Request Form" appears on the right side of the page.
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