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

До історії вивчення прісноводної малакофауни Закарпатської області

Freshwater malacofauna of Transcarpathia until today remains poorly understood and our research is aimed to contribute data on solution of this problem. This article presents an analytical review of the available literature data concerning the knowledge of freshwater molluscs fauna of the Transcarpathian region. The list of all species of freshwater molluscs (gastropods and bivalves) that were observed or have been collected by different authors in the territory during the 19-21 centuries is presented. Altogether the list contains 86 species of freshwater gastropods from 13 families and 33 species of bivalves, which belong to 2 families. One species, Viviparus rossmaessleri (Bourguignat, 1880) is only indicated as a possible resident of the area. Status of other species that are mentioned in the analyzed literature require further clarification, as in species of independence, and about the real presence of them in the area. The presence of some of them was confirmed as a result of our revisions of the malacological collections of natural institutions of Ukraine. A significant number of names (species) are listed in this article, by a modern classification (World Register of Marine Species), reduced to synonyms, common species, so such a taxa number, which is indicated in the literature, in our opinion, is overestimated. In this article we do not aim to reduce this list, but only based on literature data, showing the general picture of the composition of the molluscs fauna of this region. Our further work will be aimed at the systematic study of the freshwater molluscs fauna of the Transcarpathian region, based on our own sampling from this area that were carried out during the years 2016-2019. This should add more reliable evidences in assessment of the species diversity of the freshwater malacofauna of the Transcarpathian region. As a result, the whole list of all species of freshwater molluscs available on the territory will be presented, taking into account modern views on their taxonomy.Прісноводна малакофауна Закарпаття до сьогоднішнього часу залишається маловивченою і наші дослідження спрямовані на вирішення цієї проблеми. Дана стаття представляє аналітичний огляд наявних літературних відомостей щодо вивченості прісноводної малакофауни Закарпатської області. У ній наведено перелік всіх видів прісноводних молюсків (черевоногих та двостулкових), які відмічались або були зібрані різними авторами на території дослідження впродовж 19-21 ст. Загалом перелік включає 86 видів прісноводних черевоногих молюсків з 13 родин та 33 види двостулкових, які належать до 2 родин. Один вид, Viviparus rossmaessleri (Bourguignat, 1880), вказується лише як можливий мешканець території дослідження. Решта видів, які згадуються у проаналізованій літературі потребують подальшого уточнення, як щодо видової самостійності, так і щодо реальної наявності їх у регіоні. Значна кількість назв (видів) перерахованих у цій статті, за сучасною системою (World Register of Marine Species), зводиться до синонімів загальноприйнятих видів, тому така їх кількість, яка зазначається в літературі на нашу думку є значно перебільшеною. У цій статті ми не ставимо перед собою мету скоротити цей перелік, а лише, спираючись на літературні матеріали, показуємо загальну картину щодо складу малакофауни регіону. Подальша наша робота буде спрямована на систематичне вивчення прісноводної малакофауни Закарпаття, опираючись на власні збори з території дослідження, які проводились впродовж 2016-2019 років. У подальшому це повинно додати наукової певності в оцінці видового складу прісноводної малакофауни Закарпатського регіону

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

Studies of phase separable soluble polymers

The technique of phase labeling has the ability to greatly enhance synthetic protocol by simplifying purification and increasing efficiency. Traditional insoluble supports offer efficient and simple recovery of the Âphase tagged material but suffer from problems inherent to their heterogeneous nature. A solution to these problems has been to utilize phase separable soluble polymers in the design of Âsmart responsive systems that offer the option of homogenous reaction conditions with heterogeneous separation conditions. The subject of this dissertation focuses on the application of soluble polymeric phase tags in systems where the miscibility between solid-liquid and liquid-liquid systems is thermally induced. Low molecular weight poly(ethylene glycol) (PEG) oligomers were investigated as phase anchors for SCS palladacycle catalysts. The oligomeric PEG chains were sufficient to engender polar phase solubility in a heptane-DMA thermomorphic system. Microwave irradiation of these thermomorphic mixtures of palladium complexes and substrates was a viable scheme to recycle and significantly shorten reaction times for simple Heck reactions of aryl iodides. Soluble polymeric supports possessing a lower critical solution temperature (LCST) were utilized in the sequestration of the S-triazine herbicide, atrazine, from contaminated water samples. The ability of poly(N-isopropylacrylamide) to sequester hydrophobic guests like atrazine was examined. A functionalized PNIPAM derivative containing secondary cyclic amines exhibited superior sequestration ability that was credited to the covalent binding of the atrazine. In order to facilitate the design of tailored, thermally responsive, smart polymers, a high throughput temperature gradient microfluidic device was used to obtain LCST data in a fast, accurate manner. The specific ion effects of various alkali metal halide salts on the LCST of PNIPAM were investigated. The high precision in the measurements enabled more subtle effects such as changes in solvent isotope, polymer microstructure, molecular weight, and importance of end group effects on the LCST of poly(N-alkylacrylamide)s to be evaluated

Prehabilitation for frail patients undergoing colorectal surgery: lessons learnt from a randomised feasibility study

There is substantial interest by clinicians to improve the health outcomes of older and frail patients followingmajor surgery, with prehabilitation a potential and important component of future standard patient care. We studied the feasibility of a randomised controlled trial of pre-operative prehabilitation in frail patients scheduled for colorectal surgery in regional Australia. We conducted a single blind, parallel arm, randomised controlled trial in a regional referral centre where colorectal surgical patients aged over 50 were invited to participate and screened for frailty. Frail patients were randomised to undertake either a 4-week supervised exercise program with dietary advice, or usual care. The primary outcome was 6-min-walk-distance at baseline, pre-surgery (4 weeks later) and at follow-up (4–6 weeks post-operation). Secondary outcomes included physical activity level, health-related quality of life, and post-surgical complications. Feasibility outcomes were numbers of patients reaching each stage and barriers or reasons for withdrawal. Of 106 patients eligible for screening during the 2-year study period, only five were able to be randomised, of which one alone completed the entire study to follow-up. Fewer patients than expected met the frailty criteria (23.6%), and many (22.6%) were offered surgery in a shorter timeframe than the required 4 weeks. Physical and psychological aspects of frailty and logistical issues were key for patients declining study participation and/or not complying with the intervention and/or all outcome assessments. Feasibility for a large randomised controlled trial of prehabilitation for frail colorectal patients was poor (~5%) for our regional location. Addressing barriers, examination of a large, dense population base, and utilisation of a frailty-screening tool validated in surgical patients are necessary for future studies to identify the impact of prehabilitation for frail patients

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