Research in children in the emergency department

Published on 23/06/2015 by admin

Filed under Emergency Medicine

Last modified 22/04/2025

Print this page

This article have been viewed 1386 times

29.1 Research in children in the emergency department

Franz E. Babl, Meredith Borland, Andrew J. Davidson

Introduction

Research is an important part of emergency medicine as it provides the scientific basis for optimal patient care. Key elements for conducting high quality, ethical research are the development of a good research question, use of an appropriate study design, adherence to good clinical research practice and an understanding of the ethical basis for research. Study design, the quality of the conduct of the study and its ethics are all intricately linked.

Increasing numbers of emergency physicians, nurses and allied health personnel are involved in research, and trainees are now required to complete research projects during training. Yet few emergency clinicians have formal research training. In addition, over the past years both national and local regulatory requirements have become more complex. Research funding is often difficult to obtain in both the emergency and paediatric setting. Hospitals and departments often have to focus on clinical care with limited resources for dedicated staff, time for research, research assistants or infrastructure for studies. Hence, there is a critical and overdue requirement for the development of paediatric emergency medicine within university academic settings, where research is highly valued and an intrinsic part of daily business.

In addition, serious outcomes and adverse events are rare in children and data collected at paediatric tertiary institutions may not be applicable to other settings. Informed consent is difficult to obtain in the emergency setting and the ethics of research in children, as a particularly vulnerable group, creates an additional degree of complexity.

However, despite these difficulties, a number of strategies can be used to overcome the perceived barriers and achieve quality research in children in the emergency department.

Research science

All research should have a sound scientific basis. Getting the science right is essential before starting any project.

Research question

The most crucial component of every project is the research question. The question defines all the other elements of the research design, including the hypothesis and objective of the project.

A good study question should be:

• original or add significantly to what is known;

• relevant and important;

• feasible, based on resources, skills, time, subject availability;

• plausible, that is there should be a scientific basis for the question;

• clearly defined.

Determining these factors requires clinical perspective and a detailed literature search. In clinical research the most relevant or important questions are those that actually change clinical practice.

A question can be defined in terms of the acronym PICOT:

• population (who should be in the study?);

• indicator (what is the intervention or exposure of interest?);

• comparator (what is the gold standard? comparison vs baseline vs control group?);

• outcome (what is the outcome of interest?);

• timeframe (over what time period?).

The outcome measures are often the most difficult to determine and must be clearly defined, usually with a single primary outcome to answer the study question and further secondary outcomes, which may be multiple, to expand on this question. These should be determined in advance, not after study results are in.

Literature review and level of evidence

The literature review should provide the background to the study question. Literature databases like Pubmed, Medline, Google scholar internet search engines, EMBASE and CINAHL (Cumulative Index to Nursing and Allied Health Literature) are useful but may initially be overwhelming. Helpful starting points can be standard textbooks, the Cochrane library, a search of BestBets (www.bestbets.org), BMJ Clinical Evidence (http://clinicalevidence.bmj.com) and the assistance of a medical librarian.

It is important to grade the importance of medical research evidence. There are many grading systems in use internationally. A commonly used example from National Health and Medical Research Council of Australia (NHMRC) is shown in Table 29.1.1.¹ Systematic reviews often use such a grading system as the basis for clinical management recommendations. The current standard of research evidence is the randomised clinical trial (RCT), and the highest level of evidence is meta-analysis of RCTs.

Level Study design I Evidence obtained from a systematic review of all relevant randomised controlled trials II Evidence obtained from at least one properly designed randomised controlled trial III-1 Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method) III-2 Evidence obtained from comparative studies (including systematic reviews of such studies) with concurrent controls and allocation not randomised, cohort studies, case-control studies, or interrupted time series with a control group III-3 Evidence obtained from comparative studies with historical control, two or more single arm studies, or interrupted time series without a parallel control group IV Evidence obtained from case series, either post-test or pretest/post-test

Adapted from NHMRC 1999.

Types of studies

Studies can be grouped in a number of ways. Studies can be descriptive, analytic or interventional. Intervention studies can either assess the efficacy of the intervention (does it work in a study?) or the effectiveness (does it work in the everyday ED situation?) (Table 29.1.2).

The ethics of medical research

Following atrocities during the Second World War, written codes of medical ethics have been developed such as the Nuremberg Code ², the Declaration of Helsinki³ and the Belmont Report.⁴ The key principles developed in these documents still underpin most ethical guidelines.

Key principles

The key principles of research ethics include respect for persons, beneficence and justice as well as ‘research merit and integrity’.

Respect for persons recognises the value of autonomy to an individual. Participants must have the power to make their own decisions, if possible. Having respect for persons requires due regard for beliefs, customs and cultural heritage of individuals as well as respecting privacy and confidentiality. Consent is the key element of respect. The consent to participate in a research project must be free and informed. Free consent implies a voluntary choice not influenced by external coercion, pressure or inducement. Informed consent implies that the participant has sufficient information and adequate understanding of the proposed research, and, particularly in the paediatric context, is sufficiently mature to understand the consequences of the decision to take part in the study.

The principle of beneficence includes the concept of maximising possible benefits and minimising possible harm while avoiding unnecessary burdens. Non-therapeutic research or research where the risk of harm is possibly greater than the risk of benefit is not beneficent.

The principle of justice implies there should be no inequality in sharing the burden or risks and the benefits of research. The most obvious examples of injustice are where research benefits or risks are unevenly distributed amongst the wealthy and poor, or conducting research exclusively in minority populations to benefit non-minority populations.

Ethics of research involving children

Due to the exploitation of children prior to the Nuremberg Code there is added complexity relating to research in children. This relates to the key component of informed consent. The age at which a child develops the maturity to understand, give informed consent or accept risk for altruistic reasons is not predefined by chronological age. There is variability in this, based on complexity of the proposed intervention. It is important to note that ethical standards and criteria for study participation evolve over time, and what is acceptable now may be controversial or unacceptable in the future, just as previous standards may now be considered questionable. This is particularly so in relation to children.

Assent by the child is a requirement used in some countries (e.g. USA) from the age of approximately 7 years for studies involving children, although formal consent is still required from the legal guardians.

There are in general four recruitment scenarios for children presenting to the ED who may be enrolled in research studies:⁵

Infants/toddlers without the capacity to understand or take part in discussions regarding a research project and whose parents/guardians are approached for consent.

Children able to understand some relevant information and take part in limited discussion about the research, but whose consent is not required. Only parent/guardian consent is required for these children.

Young people of developing maturity, able to understand the relevant information but whose relative immaturity means they remain vulnerable. The consent of these young people is required, but is not sufficient to authorise research, therefore requiring additional parent/guardian consent.

Young people mature enough to understand and consent, and not vulnerable through immaturity in ways that warrant additional consent from a parent or guardian.

As children have limited capacity to consent, the degree of risk they can be exposed to needs careful consideration. In general, risk is classified in degrees, and the degree of risk acceptable depends on the importance of the study, and the likelihood of any direct benefit to the child. For example, the risk of complications from placing an intravenous cannula may be unacceptable in a child when studying a minor condition such as otitis media but acceptable in the setting of determining the effectiveness of a chemotherapy agent. In order that some important research involving children may legitimately be carried out, most jurisdictions deem that it is acceptable to have some degree of risk for the child who is unable to consent where there is no direct benefit accruing to that child, provided certain limitations are adhered to.

In addition, in the ED setting there is the added complexity relating to recruitment for a study at the time of an acute injury or illness. This makes it more difficult to fully assess the child’s maturity level and understanding and to appreciate the potential for researchers to apply covert pressure to a reluctant child. Enrolment may also be curtailed by parents/guardians being unwilling or unavailable to consent during the stress of the presentation to the ED.

Ethics review process

The implementation of national guidelines and principles to individual projects is left to the discretion of committees administered locally by research institutions or hospitals. Research other than low or negligible risk research must be reviewed by a local ethics committee. Ethics committees are usually composed of representatives from clinical (doctors, nurses etc), research and community (lay people and clergy) groups. All research must be approved in writing by the sponsoring institution before it can commence. Research requiring Human Research and Ethics Committee (HREC) approval may not start until there is clear written approval from the committee.

The primary objectives of an HREC are to assess the ethical principles by which research projects in humans are proposed and conducted, protecting the welfare and rights of the research participants and to facilitate research that is or will be of benefit to the researcher’s community or to humankind. HRECs may also consider all matters relating to project design, technical feasibility and any other ethical implications associated with each project. The ethics review process is not perfect and may be frustrating but a wise researcher engages with the ethics committee in a positive and helpful manner.

Many small projects can be undertaken as clinical audits and would be regarded by the community as an essential part of clinical practice, such as an analysis of the types of clinical presentations that did not wait to be seen. These projects should still be presented to the HREC, but in most institutions should undergo an expedited review, without the need for a full ethics submission and the consequent delay. In this circumstance, it is still important to plan the research project fully, as the project will not be of benefit to anyone if a researcher has not collected and analysed the data in a systematic and rigorous manner.

HREC approval is often contingent on other processes. The hospital lawyer and hospital insurer may have to sign off on high-risk projects; the trials may need registration and Therapeutic Goods Administration (TGA) notification may be required in clinical drug or device studies. A study can only be commenced once HREC approval has been obtained and only HREC approved study documents may be used during a study.

The practice and governance of research

Well-conducted clinical research is far more likely to discover the truth. There are basic professional standards in the conduct of research which must be met during this process.

Research documents

Good documentation is a key to a successful study. Documents should be kept together, be complete, dated, and secured. There should be a clear trail of all data from the point of data collection, collation into database through to publication. This trail may be scrutinised if there is any question about the veracity of a research finding. Clear documentation is also essential to reduce the chance of error and to keep the project running smoothly.

Research protocol

The key document for any study is the research protocol. It sets out why a trial should be run, acts as an operations manual and is the scientific design document for the trial. It is submitted to the HREC at the time of approval application along with the case report forms, patient information statement and consent form. The research protocol outlines in detail the research question being asked, background and rationale for the study, the design and methodology by which the question will be addressed, secondary objectives, primary and secondary outcomes, statistical considerations including sample size and power calculations. There should also be a discussion of any ethical implications of the study being undertaken. Templates for protocols can be found on the websites of a number of organisations such as the TGA.⁶

Case report forms (CRF)

The CRF is designed to record all of the required information as defined in the protocol for accurate analysis. Badly designed CRFs negatively affect the quality of data analysis and the ability of the project to answer the research question. CRFs should be designed concurrently with the protocol, preferably with input from a biostatistician and should be piloted prior to study commencement. All data collected for the study should be recorded directly, promptly, accurately and legibly.

Patient information statement and consent form

In order to gain informed consent from a potential research participant, research projects require patient information statements in plain language and consent forms that must be approved by the ethics committee prior to their use. They are intended to outline the proposed study in language lay people can understand. Good patient information statements are difficult to write and poorly written ones may cause delays in obtaining ethics approval.⁷

Study document file

The study document file should be kept in the ED administrative area and contain copies of all documentation relevant to the study in an orderly and systematic fashion. Good data handling and record keeping ensures a ‘paper and electronic trail’ that testifies to the accuracy of the reported data, as a study may be audited even years after it has finished.

The research team

Research is a team effort, even for a small trainee-led project. Good research practice involves having an effective team of researchers and collaborators (such as nurses, junior doctors, allied health workers) with a clear understanding of who is responsible for what and who reports to whom. Even in small studies, biostatisticians should be involved early in the design stage. They will help guide researchers to determine study design and sample size in addition to their role in database creation and data analysis.

Depending on the size and type of study, teams may include, in addition to clinicians, expert researchers, statisticians, pharmacists and/or technicians, health economists, trial coordinators, data manager, data entry staff and research nurses or assistants.

Larger studies may require several groups or committees such as a trial management group (to manage the trial on a day-to-day basis), trial steering committee, data monitoring and/or safety committee and data management committee. These committees should have regular minuted meetings.

Databases and analysis

Good data management should be carefully planned from before the first data are collected though to the analysis of data; otherwise implausible values and inconsistencies are carried through to the analysis phase, where it is very difficult to correct errors. A database is a computer software program (e.g. EpiData) where data is entered and stored in a table or file, which is called the data file. Each study patient should have a unique identifier different from the patient’s hospital number to ensure confidentiality. Even for simple databases, a ‘coding manual’ should be created to explain variable names, describe the variables and their units, specify the number of decimals, etc. Studies are often performed over a period of time and what seems obvious at the beginning of the process may become cryptic at the analysis stage. Data must be kept securely with password protection and limited access by nominated and HREC-approved researchers, and be regularly backed up.

Reporting guidelines

The reporting of clinical trials has a recommended, standardised approach, outlined by the CONSORT Statement, an evidence based format aimed at improving the quality and integrity of reporting for RCTs. CONSORT consists of a checklist and flow diagram for reporting a RCT.⁸ The flow diagram provides readers with a clear picture of the progress of all participants in the trial, from the time they are randomised until the end of their involvement. Both documents are also very helpful at the design stage of the trial and ensure that the research protocol is comprehensive and logical.

There are also a number of reporting guidelines for other types of studies. Information about reporting guidelines, including key checklists and flow diagrams, is listed at the EQUATOR website.⁹

Key regulatory documents

The National Statement on Ethical Conduct in Human Research ⁵

The peak medical research bodies in Australia (NHMRC, Australian Research Council (ARC) and the Australian Vice Chancellors’ Committee (AVCC)) produce this joint statement which is Australia’s primary source of guidance promoting ethically sound review and conduct of human research with national standards to guide institutions, researchers and HRECs.

International Conference on Harmonisation of Good Clinical Practice guidelines (ICH-GCP)¹⁰

This is an international document accepted in Australia. It was developed through a drive to regulate requirements for a single market for pharmaceuticals. ICH-GCP is also known as GCP or GCRP (good clinical research practice). It is an overarching ethical and quality standard for the design, conduct, performance, recording, analysis, monitoring, auditing and reporting of clinical research. It also includes protection of human rights as a subject in clinical trial.

Australian Code for the Responsible Conduct of Research ¹¹

Having been jointly authored by ARC, AVCC, and NHMRC, this code is designed to guide institutions and researchers in how to achieve and maintain responsible research practice.

All research in Australia must abide by the National Statement. The National Statement requires that research is conducted in accordance with the Australian Code of Conduct. However, this document does not provide an exhaustive description of how to conduct research. The TGA has published a more detailed document describing how research should be performed in Australia which in turn requires that researchers follow relevant sections of the ICH GCP.¹⁰

The aim of these documents is not only to increase the scientific quality and hence the veracity of findings but also to ensure research is conducted in an ethically responsible manner and that the findings are verifiable. Being compliant with these documents assures the public that the data and reported results are credible and accurate and that the rights, integrity and confidentiality of human research subjects have been protected.

Project registration

Since July 2005 all clinical trials must be registered on a Clinical Trials Register before the enrolment of the first participant. The guidelines of the International Committee of Medical Journal Editors (ICMJE) state that any trial must be registered in order to be published in any of their comprehensive list of journals.¹² The purpose of trial registration is a greater efficiency by reducing unnecessary duplication of research effort, better compliance, and a greater assurance that all clinical trials reports are reported, including those with negative results. There are several clinical trial registers worldwide including the Australian and New Zealand Clinical Trial Registry (ANZCTR).¹³

Privacy and confidentiality

Clinical research almost invariably involves the use of personal information. Patients provide information with the expectation that it will be treated confidentially and the unauthorised disclosure of such information may be a risk to the subject which should be considered in any research project. Similar to medical records in general, patient privacy laws apply to research records.

Multicentre research

Some of the difficulties in emergency research in children, such as the low frequency of major outcomes or limited applicability of findings, can be overcome by co-operating with other institutions. This recognition has led to a number of cooperative research networks, initially in North America (Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN)), in Australia and New Zealand (Paediatric Research in Emergency Departments International Collaborative (PREDICT)) and now also in Europe (Research in European Paediatric Emergency Departments (REPEDS)). These networks have increased the profile of paediatric emergency medicine, illustrated the similarities and differences in practice across geographical areas and are increasing the evidence base for interventions.¹⁴

Funding research

Finding funding for research is a challenge. In Australia the major large sources are ARC and NHMRC grants, with smaller disease- and specialty-specific competitive funding bodies such as Diabetes Australia Research Trust, National Heart Foundation, and so on. Obtaining such funding requires a robust research question and study design, and a strong track record. Evidence of seed funding and pilot data is also useful. Seed funding may come from professional societies, research institutions and private practice funds. Infrastructure support may come from the hospitals, universities or research institutes. Philanthropic funds are also available, though these are increasingly competitive. Collaboration with other successful groups and researchers is another key to funding success.

Controversies and future directions

Trainees are expected to undertake research during their training. Due to time constraints this encourages low level studies and biases against RCTs or Systematic Reviews. Supervisors should offer research training for trainees.

Most public hospital departments are poorly resourced both financially and with research-specific personnel to undertake research in emergencies in children. There is a pressing need for the development of university departments of paediatric emergency medicine.

The development of cross linkages through research networks such as PREDICT has helped build capacity in emergency departments. It has also provided increased exposure of paediatric emergency research to funding agencies which may be the basis for developing high level research studies with dissemination of both research projects and their results into more emergency departments.

Expansion of cross-linkages between international research networks is being developed and should further enhance the dissemination of evidence based emergency medicine.

1 National Health and Medical Research Council of Australia. Levels of Evidence Guidelines. Available from: http://www.nhmrc.gov.au/guidelines/consult/consultations/add_levels_grades_dev_guidelines2.htm [accessed 29.10.10]

2 National Institutes of Health. Office of Human Subjects Research. Regulations and Ethical Guidelines. Available from: http://ohsr.od.nih.gov/guidelines/nuremberg.html [accessed 29.10.10]

3 World Medical Association Declaration of Helsinki. Ethical Principles of Medical Research involving Human Subjects. Available from: http://www.wma.net/en/30publications/10policies/b3/index.html [accessed 29.10.10]

4 National Institutes of Health. Office of Human Subjects Research. Regulations and Ethical Guidelines. Available from: http://ohsr.od.nih.gov/guidelines/belmont.html [accessed 29.10.10]

5 National Health and Medical Research Council. Australian Research Council. Australian Vice Chancellors’ Committee. National Statement on Ethical Conduct in Human Research. 2007. Available from: http://www.nhmrc.gov.au/PUBLICATIONS/ethics/2007_humans/contents.htm [accessed 29.10.10]

6 Therapeutics Goods Administration. Available from: www.tga.gov.au/docs/pdf/euguide/ich/ich13595.pdf [accessed 29.10.10]

7 Green J.B., Duncan R.E., Barnes G.L., Oberklaid F. Putting the ‘informed’ into ‘consent’: a matter of plain language. J Paediatr Child Health. 2003;39(9):700-703.

8 CONSORT group. The CONSORT Statement. Available from: http://www.consort-statement.org/consort-statement/ [accessed 29.10.10]

9 EQUATOR Network. Introduction to reporting guidelines. Available from: http://www.equator-network.org/resource-centre/library-of-health-research-reporting/reporting-guidelines/ [accessed 20.10.10]

10 . International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use’. ICH Guidelines. Available from: http://www.ich.org/cache/compo/276-254-1.html [accessed 29.10.10]

11 National Health and Medical Research Council. Australian Research Council. Australian Vice Chancellors’ Committee. Australian Code for the Responsible Conduct of Research. 2007. 2007. Available from: http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/r39.pdf [accessed 29.10.10]

12 International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Publishing and Editorial Issues Related to Publication in Biomedical Journals: Obligation to Register Clinical Trials. Available from: http://www.icmje.org/publishing_10register.html [accessed 29.10.10]

13 . Australian and New Zealand Clinical Trials Registry. Available from: www.anzctr.org.au [accessed 20.10.10]

14 Kuppermann N., Holmes J.F., Dayan P.S., et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009;374(9696):1160-1170.

Related

Textbook of Paediatric Emergency Medicine