Introduction: Status epilepticus (SE) has confounded clinicians for hundreds of years and remains the most common neurological emergency affecting children in emergency departments. Remarkably, management has changed little over the last century, and very little data are available to guide treatment. Potential new therapies are often adopted into clinical care without robust evidence, however clinicians seeking to evaluate the same therapies in methodologically sound studies face high levels of scrutiny as well as regulatory and ethical obstacles. This is partly because of the difficulty of conducting research in this setting, with informed consent issues in time-critical research being a major barrier. This leads to the ethical paradox of using untested therapies in critically ill children without informed consent, but the regulatory and ethical barriers existing in researching these same therapies.
Objectives: The objectives of this thesis are to explore the paradox of informed consent issues in paediatric SE research. The specific objectives of the thesis are: to 1) Identify gaps and opportunities for research from a review of the existing literature on paediatric SE; 2) Inform the future research agenda in the management of paediatric SE by achieving consensus on research priorities among experts in managing this condition, consisting of paediatric neurologists and emergency physicians who treat children; 3) Determine if research priorities identified by experts align with priorities identified by consumers (parents of children with SE); 4) Determine what is known about the public's perceptions and attitudes towards research in a paediatric emergency setting without prospective informed consent; 5) Explore attitudes of the general public to research in emergency settings without prior consent; 6) Explore parental attitudes to a deferred consent process in the emergency department (ED) setting, including the management of SE.
Methods: In this thesis multiple methodologies are used to achieve the stated objectives. The thesis consists of two separate, but interconnected streams. Stream one explores the existing knowledge of paediatric SE, identifies research priorities and explores the feasibility of addressing these knowledge gaps. Stream two explores the barriers to research in paediatric SE, namely issues of consent in time-critical research. At the confluence of these two streams is the discussion highlighting a roadmap for addressing the various knowledge gaps in paediatric SE, for the improved care of this condition. Methodologies used in the thesis include literature reviews (narrative, systematic, perspective), Delphi consensus technique, a cross-sectional population-based survey (with qualitative and quantitative components), and a qualitative study (semi-structured interviews resulting in thematic analysis).
Results: Chapters 2 and 3 of the thesis comprise reviews of the existing literature on the epidemiology, investigation, management of paediatric SE as well as specifically exploring pre-hospital aspects of paediatric SE care. A historical lack of consistency with definitions and classification has been a limitation of existing comparative studies. Consistency in definitions moving forward is essential to future research efforts. The review found an incomplete understanding of the epidemiology of paediatric SE, with a dearth of local data. The fundamental question of whether seizure duration is an independent predictor of poor outcome, when confounding factors such as age and aetiology are controlled for, remains unanswered. Optimal investigation and management of paediatric SE are based on low level evidence. Observational data suggest that treatment is often delayed, but beyond first line care, management guidelines are based on expert opinion only. Definitive evidence on the pre-hospital management of paediatric SE is lacking, and the review highlighted substantial variation in local protocols around Australia and New Zealand.
Chapter 4 reports the results of a Delphi study to achieve consensus on research priorities in paediatric SE among experts (neurologists and emergency physicians). Nine priority research questions are identified, consisting of second line management including levetiracetam (efficacy, dose and timing), use of third line agents, induction of anaesthesia (timing and best agent), management of focal SE, and indicators of "subtle SE". Some of these priorities are unlikely to be addressed in clinical trials with traditional concepts of informed consent, and other methods will be required such as alternative study designs and alternative approaches to consent.
Chapter 5 outlines a protocol for a clinical trial of second line management of paediatric SE. This trial directly addresses two of the nine priorities identified by the Delphi process. The trial epitomises the paradox of informed consent in paediatric SE research as the study intervention (levetiracetam) is being rapidly adopted into clinical care and protocols without any robust evidence of efficacy. The study would not be possible with traditional models of informed consent applied and uses a controversial deferred consent process.
Chapter 6 presents the historical context of informed consent in emergency research, highlighting important principles of the Declaration of Helsinki and the historically inconstant approach taken in emergency medicine as exemplified in the cardiac mega trials. Chapter 7 presents the results of a systematic review of empirical evidence on informed consent issues specific to paediatric emergency medicine. Thirteen studies included in the review found that the public are generally supportive of alternatives to prospective informed consent, with important considerations being the level of risk involved, and informing the parents about the research involvement as soon as possible. Other major themes explored in the review are capacity of parents to provide informed consent, feasibility of informed consent and modified consent processes. There were no Australian studies identified in the review.
Chapter 8 presents results of a national, cross-sectional, population-based survey on attitudes about research without prospective informed consent. This is the first study of its kind in an Australian population, and the results indicate that the public are generally supportive of the concept. Level of risk and the time-critical nature of the intervention are again identified as important considerations.
Chapter 9 reports the results of a novel Australian study on the attitudes and experiences of parents attending the ED with their children on the concepts of deferred or retrospective consent. The qualitative study of 39 parents finds universal support for emergency research and an acknowledgment of the limitations of traditional consent under these circumstances. Participants are generally supportive of deferred consent. Health and research literacy is identified as an important issue, potentially leading to some confusion with difficult concepts.
Discussion: In the modern era of evidence-based medicine, it is not satisfactory for the management of potentially life-threatening conditions such as paediatric SE to be based on inadequate evidence. It should not be acceptable to use untested or experimental therapies for clinical care without consent, when research and evaluation of the same therapies is burdened by regulations and administrative and ethical requirements. The literature reviews and Delphi study presented in this thesis outline many knowledge gaps in the management of paediatric SE and opportunities for further research. Several of the research priorities identified are unlikely to be addressed in adequately powered, traditional randomised controlled trials. Alternative study designs and alternatives to traditional concepts of informed consent will be required. Recent innovations and advances in electronic health information systems and electronic medical records may represent an elegant solution, and present an opportunity to embed data collection on infrequent presentations and conditions into routine practice. The added possibility exists of embedding treatment allocation into such systems where true equipoise exists, resulting in the necessary robust evidence to drive practice change.
Importantly, this could be achieved without exposing patients to any additional risk which represents a recurrent theme of concern in this thesis surrounding research without explicit prospective consent. This research demonstrates that the public recognise the requirement for research without prospective informed consent, with the degree of risk being a key consideration. Policy makers and guidelines need to explicitly address this type of research in regulatory documents, to ensure such research can continue, and the trust of the public and community in maintained. In Australia, guideline documents do not explicitly define requirements for emergency and time-critical research and specific requirements vary by jurisdictions due to local legal requirements. This needs to be addressed as a priority, to ensure that important research into time-critical and life-threatening conditions such as paediatric SE can continue. The involvement of consumers in the process, such as the data presented in this thesis, is essential in maintain the trust of the community.
Conclusion: Paediatric SE is an important cause of morbidity and mortality in children. Care often involves unproven therapies that are introduced into standard care and guidelines. This generally occurs with community acceptance and legal protections for time-critical interventions. Paradoxically, quality research is often thwarted due in part to ethical complexities, including the inability to obtain prospective informed consent in time-critical situations. In situations where there is clinical equipoise, and clear evidence does not exist, a compelling ethical argument can be made that similar standards should be applied to research, especially when considering the additional protections offered under the oversight of a high-quality randomised controlled trial. The data presented in this thesis indicates that the general public do not make a distinction between clinical care and research, providing that there is no exposure to additional risk. This research represents an important first step in the design of a program of research on paediatric SE to address these important clinical issues, in an ethical manner that will be acceptable to the community. A combination of real time registry, learning health systems, and innovative clinical trial designs is required, with consent requirements that are appropriate for the level of risk to participants, and congruent with community expectations
