The paradox of informed consent issues in paediatric status epilepticus research

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

Raising the D-dimer threshold for ruling out pulmonary embolism: A single-site, observational study with a historical comparison

Objective: The objective of this study was to assess the impact of introduction of a new pulmonary embolism (PE) diagnostic guideline with a raised D-dimer threshold. Methods: This is a single-site, observational, cohort study with a historical comparison. The new guideline raised the D-dimer threshold to 1000 ng/mL for most patients with a Wells' score of 4 or less. Patients investigated for PE with a D-dimer level and/or definitive imaging in 6-month periods before and after the introduction of the guideline were eligible. Patients with D-dimers of 500–1000 ng/mL were prospectively followed up at 3 months for missed PE. Results: During the pre-intervention period, 688 patients were investigated for PE, 366 (53.2%) received definitive imaging and 39 PE were diagnosed (5.7% overall, 10.7% of those imaged). For the 121 patients with D-dimers ≥500 and <1000 ng/mL, 87 (71.9%) were imaged with 7 (5.8%) having a PE diagnosed. Post intervention there were 930 patients, of which 426 (45.8%) received definitive chest imaging and there were 50 patients with PE diagnosed (5.4% overall, 11.7% of those imaged). For the 185 patients with D-dimers ≥500 and <1000 ng/mL, 60 (32.4%) were imaged with 5 (2.7%) having PE diagnosed. No cases of missed PE were identified at 3 months. Conclusion: The introduction of the new guideline was associated with a reduction in overall imaging rates without evidence of missed PE. Further evaluation in other settings is recommended

Early high flow nasal cannula therapy in bronchiolitis, a prospective randomised control trial (protocol): A Paediatric Acute Respiratory Intervention Study (PARIS)

Background Bronchiolitis imposes the largest health care burden on non-elective paediatric hospital admissions worldwide, with up to 15 % of cases requiring admission to intensive care. A number of previous studies have failed to show benefit of pharmaceutical treatment in respect to length of stay, reduction in PICU admission rates or intubation frequency. The early use of non-invasive respiratory support devices in less intensive scenarios to facilitate earlier respiratory support may have an impact on outcome by avoiding progression of the disease process. High Flow Nasal Cannula (HFNC) therapy has emerged as a new method to provide humidified air flow to deliver a non-invasive form of positive pressure support with titratable oxygen fraction. There is a lack of high-grade evidence on use of HFNC therapy in bronchiolitis. Methods/Design Prospective multi-centre randomised trial comparing standard treatment (standard subnasal oxygen) and High Flow Nasal Cannula therapy in infants with bronchiolitis admitted to 17 hospitals emergency departments and wards in Australia and New Zealand, including 12 non-tertiary regional/metropolitan and 5 tertiary centres. The primary outcome is treatment failure; defined as meeting three out of four pre-specified failure criteria requiring escalation of treatment or higher level of care; i) heart rate remains unchanged or increased compared to admission/enrolment observations, ii) respiratory rate remains unchanged or increased compared to admission/enrolment observations, iii) oxygen requirement in HFNC therapy arm exceeds FiO2 ≥ 40 % to maintain SpO2 ≥ 92 % (or ≥94 %) or oxygen requirement in standard subnasal oxygen therapy arm exceeds >2L/min to maintain SpO2 ≥ 92 % (or ≥94 %), and iv) hospital internal Early Warning Tool calls for medical review and escalation of care. Secondary outcomes include transfer to tertiary institution, admission to intensive care, length of stay, length of oxygen treatment, need for non-invasive/invasive ventilation, intubation, adverse events, and cost. Discussion This large multicenter randomised trial will allow the definitive assessment of the efficacy of HFNC therapy as compared to standard subnasal oxygen in the treatment of bronchiolitis

A comprehensive systematic review of stakeholder attitudes to alternatives to prospective informed consent in paediatric acute care research

Background: A challenge of performing research in the paediatric emergency and acute care setting is obtaining valid prospective informed consent from parents. The ethical issues are complex, and it is important to consider the perspective of participants, health care workers and researchers on research without prospective informed consent while planning this type of research. Methods: We performed a systematic review according to PRISMA guidelines, of empirical evidence relating to the process, experiences and acceptability of alternatives to prospective informed consent, in the paediatric emergency or acute care setting. Major medical databases and grey sources were searched and results were screened and assessed against eligibility criteria by 2 authors, and full text articles of relevant studies obtained. Data were extracted onto data collection forms and imported into data management software for analysis. Results: Thirteen studies were included in the review consisting of nine full text articles and four abstracts. Given the heterogeneity of the methods, results could not be quantitatively combined for meta-analysis, and qualitative results are presented in narrative form, according to themes identified from the data. Major themes include capacity of parents to provide informed consent, feasibility of informed consent, support for alternatives to informed consent, process issues, modified consent process, child death, and community consultation. Conclusion: Our review demonstrated that children, their families, and health care staff recognise the requirement for research without prior consent, and are generally supportive of enrolling children in such research with the provisions of limiting risk, and informing parents as soon as possible. Australian data and perspectives of children are lacking and represent important knowledge gaps

Factors infuencing variation in investigations after a negative CT brain scan in suspected subarachnoid haemorrhage: A qualitative study

Introduction Variation in the approach to the patient with a possible subarachnoid haemorrhage (SAH) has been previously documented. The purpose of this study was to identify factors that influence emergency physicians’ decisions about diagnostic testing after a normal CT brain scan for ED patients with a headache suspicious of a SAH. Methods We conducted an interview-based qualitative study informed by social constructionist theory. Fifteen emergency physicians from six EDs across Queensland, Australia, underwent individual face-to-face or telephone interviews. Content analysis was performed whereby transcripts were examined and coded independently by two co-investigators, who then jointly agreed on the influencing factors. Results Six categories of influencing factors were identified. Patient interaction was at the forefront of the identified factors. This shared decision-making process incorporated ‘what the patient wants’ but may be biased by how the clinician communicates the benefits and harms of the diagnostic options to the patient. Patient risk profile, practice evidence and guidelines were also important. Other influencing factors included experiential factors of the clinician, consultation with colleagues and external influences where practice location and work processes impose constraints on test ordering external to the preferences of the clinician or patient. The six categories were organised within a conceptual framework comprising four components: the context, the evidence, the experience and the decision. Conclusions When clinicians are faced with a diagnostic challenge, such as the workup of a patient with suspected SAH, there are a number of influencing factors that can result in a variation in approach. These need to be considered in approaches to improve the appropriateness and consistency of medical care.No Full Tex

Qualitative evaluation of a deferred consent process in paediatric emergency research: a PREDICT study

Background: A challenge of conducting research in critically ill children is that the therapeutic window for the intervention may be too short to seek informed consent prior to enrolment. In specific circumstances, most international ethical guidelines allow for children to be enrolled in research with informed consent obtained later, termed deferred consent (DC) or retrospective consent. There is a paucity of data on the attitudes of parents to this method of enrolment in paediatric emergency research. Objectives: To explore the attitudes of parents to the concept of DC and to expand the knowledge of the limitations to informed consent and DC in these situations.MethodChildren presenting with uncomplicated febrile seizures or bronchiolitis were identified from three separate hospital emergency department databases. Parents were invited to participate in a semistructured telephone interview exploring themes of limitations of prospective informed consent, acceptability of the DC process and the most appropriate time to seek DC. Transcripts underwent inductive thematic analysis with intercoder agreement, using Nvivo 11 software. Results: A total of 39 interviews were conducted. Participants comprehended the limitations of informed consent under emergency circumstances and were generally supportive of DC. However, they frequently confused concepts of clinical care and research, and support for participation was commonly linked to their belief of personal benefit. Conclusion: Participants acknowledged the requirement for alternatives to prospective informed consent in emergency research, and were supportive of the concept of DC. Our results suggest that current research practice seems to align with community expectations.</jats:sec

Traumatic brain injury in young children with isolated scalp haematoma

Objective Despite high-quality paediatric head trauma clinical prediction rules, the management of otherwise asymptomatic young children with scalp haematomas (SH) can be difficult. We determined the risk of intracranial injury when SH is the only predictor variable using definitions from the Pediatric Emergency Care Applied Research Network (PECARN) and Children’s Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE) head trauma rules.Design Planned secondary analysis of a multicentre prospective observational study.Setting Ten emergency departments in Australia and New Zealand.Patients Children 5 cm haematoma in any region of the head) rule-based definition of isolated SH in both childre

Fibrinogen in traumatic haemorrhage: A narrative review

Haemorrhage in the setting of severe trauma is associated with significant morbidity and mortality. There is increasing awareness of the important role fibrinogen plays in traumatic haemorrhage. Fibrinogen levels fall precipitously in severe trauma and the resultant hypofibrinogenaemia is associated with poor outcomes. Hence, it has been postulated that early fibrinogen replacement in severe traumatic haemorrhage may improve outcomes, although, to date there is a paucity of high quality evidence to support this hypothesis. In addition there is controversy regarding the optimal method for fibrinogen supplementation. We review the current evidence regarding the role of fibrinogen in trauma, the rationale behind fibrinogen supplementation and discuss current research.Griffith Health, School of Medical ScienceNo Full Tex

A Randomized Trial of High-Flow Oxygen Therapy in Infants with Bronchiolitis

BACKGROUND: High-flow oxygen therapy through a nasal cannula has been increasingly used in infants with bronchiolitis, despite limited high-quality evidence of its efficacy. The efficacy of high-flow oxygen therapy through a nasal cannula in settings other than intensive care units (ICUs) is unclear. METHODS: In this multicenter, randomized, controlled trial, we assigned infants younger than 12 months of age who had bronchiolitis and a need for supplemental oxygen therapy to receive either high-flow oxygen therapy (high-flow group) or standard oxygen therapy (standard-therapy group). Infants in the standard-therapy group could receive rescue high-flow oxygen therapy if their condition met criteria for treatment failure. The primary outcome was escalation of care due to treatment failure (defined as meeting ≥3 of 4 clinical criteria: persistent tachycardia, tachypnea, hypoxemia, and medical review triggered by a hospital early-warning tool). Secondary outcomes included duration of hospital stay, duration of oxygen therapy, and rates of transfer to a tertiary hospital, ICU admission, intubation, and adverse events. RESULTS: The analyses included 1472 patients. The percentage of infants receiving escalation of care was 12% (87 of 739 infants) in the high-flow group, as compared with 23% (167 of 733) in the standard-therapy group (risk difference, −11 percentage points; 95% confidence interval, −15 to −7; P<0.001). No significant differences were observed in the duration of hospital stay or the duration of oxygen therapy. In each group, one case of pneumothorax (<1% of infants) occurred. Among the 167 infants in the standard-therapy group who had treatment failure, 102 (61%) had a response to high-flow rescue therapy. CONCLUSIONS: Among infants with bronchiolitis who were treated outside an ICU, those who received high-flow oxygen therapy had significantly lower rates of escalation of care due to treatment failure than those in the group that received standard oxygen therapy. (Funded by the National Health and Medical Research Council and others; Australian and New Zealand Clinical Trials Registry number, ACTRN12613000388718.

Nasal high flow in room air for hypoxemic bronchiolitis infants

Background: Bronchiolitis is the most common reason for hospital admission in infants, with one third requiring oxygen therapy due to hypoxemia. It is unknown what proportion of hypoxemic infants with bronchiolitis can be managed with nasal high-flow in room air and their resulting outcomes. Objectives and Settings: To assess the effect of nasal high-flow in room air in a subgroup of infants with bronchiolitis allocated to high-flow therapy in a recent multicenter randomized controlled trial. Patients and Interventions: Infants allocated to the high-flow arm of the trial were initially treated with room air high-flow if saturations were ≥85%. Subsequently, if oxygen saturations did not increase to ≥92%, oxygen was added and FiO2 was titrated to increase the oxygen saturations. In this planned sub-study, infants treated during their entire hospital stay with high-flow room air only were compared to infants receiving either standard-oxygen or high-flow with oxygen. Baseline characteristics, hospital length of stay and length of oxygen therapy were compared. Findings: In the per protocol analysis 64 (10%) of 630 infants commenced on high-flow room air remained in room air only during the entire stay in hospital. These infants on high-flow room air were on average older and presented with moderate hypoxemia at presentation to hospital. Their length of respiratory support and length of stay was also significantly shorter. No pre-enrolment factors could be identified in a multivariable analysis. Conclusions: In a small sub-group of hypoxemic infants with bronchiolitis hypoxemia can be reversed with the application of high-flow in room air only