Pediatr Drugs (2015) 17:69–76 DOI 10.1007/s40272-014-0110-4
CURRENT OPINION
Ethics of Research in Pediatric Emergency Medicine Gal Neuman • Itay Shavit • Doreen Matsui Gideon Koren
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Published online: 5 December 2014 Ó Springer International Publishing Switzerland 2014
Abstract Clinical research in the pediatric emergency department (ED) has been rapidly growing in the past decade, and has resulted in some of the most important milestone studies in the pediatric medical literature. However, it presents a unique ethical goal and requires that additional challenges, such as the acute medical condition, fear and anxiety, unfamiliar physician(s), fatigue, and lack of time be addressed in addition to the standard ethical requirements. These may impair several fundamental elements of research, including the patient enrollment process, informed consent/assent, randomization, and others. Every
This article is part of the topical collection on Ethics of Pediatric Drug Research. G. Neuman (&) G. Koren Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G1X8, Canada e-mail: [email protected] G. Neuman Division of Pediatric Emergency Medicine, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G1X8, Canada I. Shavit Department of Pediatric Emergency Medicine, Meyer Children’s Hospital, Rambam Health Care Campus, Haifa, Israel D. Matsui Children’s Health Research Institute, University of Western Ontario, London, ON, Canada G. Koren University of Toronto, Toronto, ON, Canada
possible attempt must be made to reduce or minimize the risks to which the children are exposed, and one must be cognizant of the special needs of children and their families in the ED. Nevertheless, we are also obliged to find ethical ways to include them in appropriate research endeavors that aim to improve treatments for conditions unique to the ED. This paper explores and overviews the most recent literature in order to characterize the nature of ethical challenges complicating clinical research in pediatric emergency medicine, and then suggests some ethically sound solutions such as deferred/waived consent, designated research staff, and alternative study designs. Finally, a few examples of prospective, blinded randomized trials involving drugs in pediatric emergency medicine are provided, with special emphasis on how the investigators are overcoming the obvious ethical challenges.
Key Points Clinical research in pediatric emergency medicine is associated with difficult ethical challenges for both the researchers and the participants, given the acute, time-sensitive, and stressful situation it usually involves. Ethical challenges in the pediatric emergency room often need to be addressed with unique strategies such as using waived or deferred consent, designated research staff, and/or alternative study designs. Several well designed, prospective randomized controlled trials have shown the effectiveness of these strategies in overcoming ethical challenges in the emergency department setting.
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1 Introduction Pediatric emergency medicine (PEM) has developed as an independent subspecialty in pediatrics in the last 10–15 years, with the fundamental understanding that the child needs totally different diagnostic and management approaches, and therefore s/he is not just a young adult. Consequently, research in PEM has been steadily growing and evolving in recent years. The importance of research in PEM stems from the fact that the emergency department (ED) deals with disease states seen and treated only there. Moreover, specific populations, such as low-income families without adequate medical care, can be studied only in the ED. Not surprisingly, some important milestones in pediatric research have emerged in PEM research networks; good examples of these are the US-based Pediatric Emergency Care Applied Research Network (PECARN) [1], and the Pediatric Emergency Medicine Collaborative Research Committee [http://www.caymansim.com/pemcrc/], as well as the Canadian network, Pediatric Emergency Research Canada (PERC) [http://perc.srv.ualberta.ca/]. All of these are national research networks that constantly provide new evidence that improves the daily practice in PEM. Recent examples of therapeutic progress include traumatic brain injuries, pediatric fractures, procedural sedation and analgesia, fever, bronchiolitis, diabetic ketoacidosis, and acute sickling episodes [2–6]. In this article, we aim to highlight specific ethical issues associated with research in PEM. This is followed by discussion of several unique strategies to overcome these ethical challenges. 2 Ethical Principles of Pediatric Research In order to understand and address the challenges associated with research in PEM, one needs to put them in the context of ethical principles that need to be satisfied when conducting research in pediatric patients. 2.1 Respect for Person and Self-Determination While for adults this principle means that informed consent must be obtained from the subject involved in the research, for children, who are considered incapable of giving formal informed consent, the families/caregivers must be involved and provide consent for the child to participate. Standard principles of informed consent include information, comprehension, and voluntariness [7]. ‘Information’ in this context means all details that the research subject, or his/ her family, need to know in order to understand the circumstances and provide an informed consent.
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‘Comprehension’ means that the legal guardian must be able to understand the information, which leads to the need to use appropriate language and jargon, and taking into account the level of spoken language and literacy of the guardian. The language and jargon are of special importance in the ED, as they often serve multilingual communities and a wide socioeconomic range. ‘Voluntariness’ means that there will be an active attempt to prevent coercion. While the principle of informed consent applies to families in the ED who need to give permission or authorization for their children to be involved in research, the child himself or herself should also assent to participation and have the right to dissent or veto, when possible. Generally, meaningful assent is believed to occur at approximately 7 years of age, when concrete operational thinking emerges [8], although the US Department of Health and Human Services (DHHS) has left the decision regarding ability to assent to the local institutional review boards (IRBs) [9]. Importantly, the age cut-off for patient assent varies among countries, and in some jurisdictions it is based on the patient’s cognitive ability rather than his or her age. There are unique situations where obtaining consent in the ED is not possible, such as when the patient’s status is severe and does not allow time for informed consent, or when a child is brought to the ED without a parent or guardian. These situations will be dealt with later in the section ‘Suggestions to Overcome Ethical Challenges Associated with Research in PEM’. 2.2 No Harm (Non-Maleficence) The major ethical principle of ‘no harm’ means that risk to the patient, associated with participation in the research must be carefully evaluated, and the relevant risk–benefit ratio assessed. The risk needs to be stratified, i.e., minimal risk, minor increment over minimal risk, or more than minor increment over minimal risk [10]. According to the US DHHS, the risks of harm are minimal if they are not greater in probability and magnitude than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Examples relevant to the ED include physical examination and obtaining blood or urine specimens [10]. The definition of minor increment over minimal risk is more complex. A case-by-case decision must be made considering the four perspectives suggested by Levine [11]: common sense estimation of risk, estimation based on the investigator’s previous experience with similar interventions or procedures, statistical information, and trying to put oneself in the situation of the proposed subject. A classification of research based on level of risk has been proposed: greater
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than minimal risk but with a prospect of direct benefit to the individual subject; and minor increase over minimal risk but with no prospect of direct benefit, but a likelihood of generalizable information. There is a consensus that, as the risk to the child increases, the requirements of protection of the child, the stringency of consent, benefits to the child, and the requirements regarding significance of research must also increase. A common example relevant to the ED is pharmacokinetic studies of medications that the child may need for his/her therapy. 2.3 Justice This principle requires that special precautions must exist for vulnerable groups. Attempts must be made to avoid assigning an excessive burden of research to any particular group, such as children with mental or physical handicaps, or children of particular (usually younger) age groups who are vulnerable by virtue of inability to dissent or consent. On the other hand, justice also requires that children, including those with emergent medical conditions, are entitled to benefit from research and not be excluded. In the ED, the issue of justice may arise, for example, when children are excluded from research based on status of their medical insurance, socioeconomic class, or race. 2.4 Privacy Patient confidentiality must be protected in all research, as in any other field of clinical research. In the ED, one has to ensure that, despite the hectic and often chaotic environment, no information is disclosed to other individuals who may happen to share the same space.
3 Ethical Issues of Research in the ED In addition to general ethical issues that have already been discussed regarding research in children, special problems pose additional challenges to research undertaken in PEM, especially regarding consent and justice. These complexities stem from two main factors: (1) the population being studied—children, who are considered incapable of providing formal informed consent and thus depend on their primary caregivers in this respect; (2) the circumstances under which the research is conducted—acute, unfamiliar medical conditions, unfamiliar setting and medical personnel, fear, anxiety, uncertainty, and, in many occasions, fatigue of both the child and his/her caregivers. All these factors may impair the family’s ability to fully understand the essence of the specific research in which they may be involved, and to provide uncoerced informed consent. In addition, time shortage and involvement of multiple staff
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(clerks, nurses, physicians, social workers, security personnel, etc.) are factors that further limit the ability to conduct ethically sound research in the PEM setting. Most importantly, children often have acute and sometimes painful medical or surgical conditions that provoke stress and anxiety for them and their families. In extreme cases, acute, life-threatening situations occur, and research is often also needed in those circumstances. Is it possible under such circumstances to ensure that a high-quality risk–benefit discussion takes place prior to participation? Is it possible for the research staff to avoid the risk of coercion? Requests for enrollment are coercive if the families and patient perceive that they should say yes because their lives are in the hands of the researcher. Adequate consent is also threatened in the ED by medical conditions such as coma or respiratory or cardiac arrest, which obviously render incompetent the patient who otherwise has been competent to give consent or assent. The suddenness of the episode as well as the unfamiliar nature of the medical condition and the ED setting may all contribute to these feelings. To what extent do fear and anxiety compromise the ability of parents to make optimal decisions regarding their children’s participation in ED research? One of the significant challenges is in the process of patient enrollment. Difficulty enrolling patients into clinical research in the ED setting has been described, particularly in children, the elderly, and other subpopulations [12]. A significant limiting factor for enrolling patients is the timing, given the high acuity setting in the ED [13]. However, it is our experience that many guardians are quite capable of considering requests for research participation rationally under many (but not all) of the circumstances that occur in the ED. Recently published data on parental perception of clinical research in pediatric EDs have shown that most parents understand the importance of such research in improving the treatment of children, and are willing to let their children participate in clinical research [14]. This provides a unique opportunity to enroll patients who are otherwise unlikely to be enrolled in clinical research [15]. Another challenge is in obtaining informed consent. In the ED, the family is usually not known to the researcher. Without the benefit of a long-standing relationship, the researcher is less able to judge parental ability to comprehend the information necessary to give informed consent/assent. On the other hand, this unfamiliarity removes the risk of coercion typical of parents who feel dependent on the physician treating their child for a chronic condition. In addition to fear, anxiety, and strangeness of setting, many families are also battling fatigue in the ED. They may have completed a full day of work and perhaps also a lengthy wait in the ED. Fatigue may further impair the
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ability to give truly informed and uncoerced consent/ assent.
4 Suggestions to Overcome Ethical Challenges Associated with Research in Pediatric Emergency Medicine (PEM) Although these threats to research make the ED a less than ideal setting for clinical research, there may be some ways to overcome them and to give children with emergent medical conditions a reasonable opportunity to participate in and benefit from clinical research. Examples of these include deferred consent, designated research staff, and alternative study designs. At the end of this section, examples of prospective controlled trials are provided as well as the ways in which the researchers overcame the ethical challenges. 4.1 Waived or Deferred Consent In 1996, the US FDA and the US DHHS introduced regulations allowing emergency research, under specific circumstances, to be conducted without voluntary prospective consent of the patient. The secretary of Health and Human Services authorized this waiver in response to growing concerns that regulations made high-quality research in emergency circumstances difficult or impossible to conduct, despite being increasingly needed (Office for Protection From Research Risks Report 97-01. Washington, DC: Department of Health and Human Services; 1996) [16]. These regulations became known as the Final Rule, and clinical trials approved under the rule are referred to as ‘‘research with exception from informed consent.’’ Before 1996, much of what was learned about potentially lifesaving advancements was grounded in events that occurred in wartime situations, and no provision in federal regulations governed any exception from the informed consent requirement for greater than minimal risk research. In 2008, the UK also introduced provisions for deferring consent for minors participating in clinical trials or requiring urgent treatment [17]. These new guidelines recognize the unmet need for treatment options in acute, life-threatening situations and address a need to update requirements for the protection of human subjects with diminished autonomy (here defined as an individual’s ability to voluntarily choose to participate or continue to participate as a research subject) [18]. Under certain conditions, the Final Rule contains provisions for an additional layer of protection of patients’ rights not required of other studies, but only when research was undertaken with consent waived. Among these conditions: the situation is life-threatening; obtaining informed
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consent is not feasible; there may be direct benefit to research subjects; the research could not be performed without a consent waiver; and there is a defined therapeutic window. Key elements in the Final Rule are additional protection requirements, including community consultation, public disclosure before and after the study, and study oversight by an independent data safety monitoring committee [19]. Community consultation has been shown to be a useful tool to assess the targeted population’s approach to emergency research studies proposing a waiver of informed consent. The concept of waived informed consent has been tested in two studies among families who visited the ED in regards to deferred/waived consent, showing that, overall, the parental approach toward this strategy was positive, favoring societal benefit over individual right for selfdetermination [20, 21]. Thankfully, these acute and lifethreatening situations are relatively rare in PEM, and, under most circumstances, sufficient time is available for the caregiver and the family to discuss the issue of participation in research in more detail, even if not at the time of the actual enrollment but later on, as in ‘deferred consent’. Nevertheless, deferred consent should be regarded as a viable solution in the appropriate circumstances, and parents appear to support it when necessary [22, 23]. A recent systematic review of waived consent in pediatric resuscitation research has found that, overall, 68 % of subjects who were surveyed supported the concept. Caregivers were more likely to support it when the circumstances were anchored in reality (e.g., critical care unit personnel) [24]. To address the incapacity to obtain truly informed consent due to the acute nature of the medical condition, in some instances it may be best to wait until the child has been stabilized and to receive deferred consent. If possible, fear and anxiety should be addressed prior to introducing research, with the investigators considering the potential guardian’s level of fear and anxiety prior to approaching him or her. An attempt should be made to establish reasonable rapport with patients and families seen in the ED. 4.2 Designated Research Staff To address fear and anxiety, which may occasionally interfere with the family’s ability to provide informed consent, special communication skills and sensitivity are required from the researchers to be able to discuss participation in research with the families. On some occasions, designated research staff, who are not the actual researchers and are not part of the ED team on shift and therefore naturally have more time to spend with each recruited family, may conduct the actual recruitment of the patients, including the initial approach, general explanations, providing handouts with information on the specific
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study, and addressing concerns. Importantly, the researcher himself or herself should be the ultimate address for any of the patient’s concerns. An example for such an approach is a student volunteer program for research, which was recently shown to be effective in facilitating the enrollment of patients into prospective trials in a PED in a tertiary hospital [25]. 4.3 Alternative Study Designs In order to conduct research in the ED, it is imperative to reduce the risks to the child as much as possible when designing the study protocol. In some unique situations, where randomized controlled trials may not be possible due to ethical limitations (e.g., treating children with placebo in acute life-threatening situations), alternative study designs may be appropriate.
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management intervention can reduce healthcare utilization and improve self-assessed health status in frequent ED visitors. One group of patients received the standard care (i.e., no follow-up), and the second group received the experimental care (i.e., case management by a study nurse, based on bi-weekly supportive telephone calls). Patients from the second group who declined the intervention were included in the analysis, and patients from the first group were not asked for consent or offered the study intervention (hence the Zelen design). The study showed that telephonebased case management by a nurse reduced the total number of outpatient visits, the number of ED visits, the number of days patients were admitted to hospitals, and the total healthcare costs for hospital admissions. Patient selfassessed health status improved for the patients who received the case management intervention [28]. 4.3.2 Observational, Non-Randomized Studies
4.3.1 The Zelen Design Although less than ideal, the Zelen design has been proposed to compare best standard control with experimental treatment [26]. In the Zelen design, subjects are randomized to two groups: one receives standard therapy and the second is asked whether they will accept experimental therapy. The results of all subjects in the second group, regardless of the actual treatment received, are compared with those of the first group. However, consent is only required in the second group, and subjects who refuse the experimental treatment receive the control treatment instead. The advantage is that it allows the subjects, in this case the family, to know what treatment they are getting. Consent is needed only if an experimental treatment is offered. The question arises whether justice is maintained for the standard therapy group, who are not offered the chance of the experimental treatment, purely on the basis of the study design. Although this study design should make enrolling patients easier and likely increase the sample size, more patients will be required because some children in the experimental group will actually receive the standard (control) treatment but will still be counted as if they had received the experimental treatment, thus reducing the power of the study. To date, most of the examples for published studies with the Zelen design are not related to clinical research in emergency medicine. A 2004 review of the literature has shown that, of all studies found with Zelen methodology, eight were screening trials; 13 were surgical trials; 12 were drug studies; 15 were ‘service configuration’ trials; and ten were education trials [27]. One study related to emergency medicine has also been published [28]. In that prospective randomized study, the investigators aimed to determine whether a nurse-managed telephone-based case-
In addition, given the wide variety in clinical practice among PEM physicians and departments, it is not unusual to conduct a prospective observational, non-randomized study to compare different procedures or diagnostic tools for given conditions. Although inferior in their design (e.g., results may be biased by confounders that were not taken into account or could not be adjusted for), such studies have led to some very important breakthroughs that have changed practice in PEM. An important example is a prospective cohort study by Kuppermann et al. [2], which validated clinical decision rules in children presenting to ED with minor head injuries. In that study, a site investigator collected data from the patient’s chart, including history, vital signs, and physical examination results, without interfering with the natural medical assessment performed by the ED physician on that shift. All decisions, including computed tomography (CT) of the head, were made at the discretion of the ED physician without any relation to the study, which was observational in nature and did not alter any standard-of-care interventions. Informed consent was waived. The clinical decision rule was validated only at the end of the study period, following the analysis of the data, when the authors could establish the clinical predictors for the need for head CT in children with traumatic brain injury [2]. This study, and others, provided a sound basis for progress in measuring different outcomes before and after the implementation of such clinical decision rules [29]. 4.3.3 Cluster Randomized Trials Another approach to cases where consent for randomization cannot be achieved in the ED is the option of block or cluster randomization, where randomization is made on a
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cluster basis (i.e., groups of patients) rather than on an individual basis. This design allows the researcher to perform the randomization prior to the actual enrollment of the patient and without consent for randomization. This method is occasionally used despite its obvious statistical downsides. Recent examples include a study that compared success rates of pulled elbow reduction in children, comparing nurses with physicians [30], and an ongoing study that utilizes block randomization of community EDs to evaluate the impact of clinical pathways for the treatment of acute pediatric gastroenteritis and asthma (http://www. clinicaltrials.gov, NCT01815710). Historically, researchers have justified the use of this design in an attempt to avoid the need for informed consent for randomization (but not for participation in a study); however, this approach is now often discouraged [31]. 4.4 Prospective Randomized Trials Involving Drugs in PEM Prospective, controlled double-blind studies are taking place in the emergency setting. An important example of a prospective interventional drug study in the emergency setting is a study that, at the time of writing this article, is recruiting patients (http://www.clinicaltrials.gov, NCT01429415). The main objective of the study is to examine whether, in children with acute asthma remaining in moderate to severe respiratory distress despite maximized initial bronchodilator and steroid therapy, there is a reduction in hospitalization rate from the ED in those who receive nebulized magnesium with salbutamol versus those receiving salbutamol only. Children aged 2–17 years, with moderate to severe asthma, not responding to bronchodilators and steroids, are included and then randomized into two groups: one group is receiving inhaled salbutamol and inhaled magnesium, and the other group is receiving inhaled salbutamol and inhaled hypertonic saline as placebo. Clearly, the ethical challenge is overcome by limiting the intervention to patients who have already received maximized therapy, and by administering the same ‘baseline’ medication (salbutamol) in both groups, with the addition of the study drug in one group only, so that none of the patients receives less than standard therapy. Informed consent is obtained in this study. Another example is the therapeutic approach to acute abdominal pain in children. Historically, generations of physicians were taught that one should not administer morphine as an analgesic agent for acute abdominal pain as it ‘‘may mask signs of acute appendicitis.’’ In fact, although endlessly cited in older surgical textbooks, there has never been any evidence to support this assertion, and many children who
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presented to ED with acute abdominal pain did not receive proper analgesia because of this diagnostic concern. In the early 2000s, several studies were published examining this point, leading to practice changes [32–34]. For example, in 2005, a prospective, double-blind placebo-controlled study conducted by Green et al. [34] assessed the effect of intravenous morphine administration for pain management in children presenting to ED with acute abdominal pain, and compared it with placebo. The results of this study have shown that morphine effectively reduces the intensity of pain among children with acute abdominal pain and does not appear to impede subsequent diagnosis of appendicitis. The obvious ethical challenge, which stems from the need to recruit a child who is acutely ill and in pain to a study, is to explain to their guardians that the child may be randomized to not receive any analgesia, and to receive their informed consent, was justified by the fact that not providing opioid analgesia was the standard of care at the time of the study. Looking retrospectively, the important results of this study justified some of the ethical challenges that may have arisen. Another example is procedural sedation and analgesia (PSA) in the ED. Historically, ketamine, opioids, nitrous oxide, and benzodiazepines were used in the ED. Over the past few years, the drug propofol, which is considered by the FDA as an anesthetic agent, has been increasingly used. It is now accepted that this drug can be safely administered to children in the ED by emergency physicians [35]. However, until the mid-2000s, propofol was rarely used in EDs due to its potential for serious adverse reactions and its high risk. These reactions include prolonged apnea, cardiodepression, and even ‘propofol syndrome,’ a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse [36, 37]. An important study to ascertain the safety of propofol involved 25,433 patients [38]. In this study, all ED procedures using propofol were successfully completed. A collaborative group of PEM researchers prospectively recorded data on pediatric sedations; these data were electronically uploaded to the Pediatric Sedation Research Consortium (PSRC) database (the PSRC was created in 2004 as a collaborative group of institutions). Participating researchers were required to obtain IRB approval for data collection, parental consent, patient assent in appropriate cases, and to agree to a standardized methodology for consecutive data collection [38]. This process of unanimous and consistent data collection supports a standardized, well-organized learning process with the goal of improving patient care in the pediatric ED, without ethical breaches. This is particularly important when the study involves potentially high-risk medications or procedures.
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5 Summary Ethical research in the pediatric ED requires that additional challenges, such as the acute medical condition, fear and anxiety, unfamiliar physician(s), and fatigue be addressed in addition to the standard ethical requirements. Every possible attempt must be made to reduce or minimize the risks to which the children are exposed. Nonetheless, while one must be cognizant of the special needs of children and their families in the ED, we are also obliged to find ethical ways to include them in appropriate research endeavors that aim to improve treatments for conditions unique to the ED. Acknowledgments G. Neuman, I. Shavit, D. Matsui, and G. Koren declare no relevant conflicts of interest. No sources of funding were used to support the writing of this manuscript.
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76 30. Dixon A, Clarkin C, Barrowman N, Correll R, Osmond MH, Plint AC. Reduction of radial-head subluxation in children by triage nurses in the emergency department: a cluster-randomized controlled trial. CMAJ. 2014;186(9):E317–23. doi:10.1503/cmaj. 131101. 31. Weijer C, Grimshaw JM, Eccles MP, et al. The Ottawa statement on the ethical design and conduct of cluster randomized trials. PLoS Med. 2012;9(11):e1001346. doi:10.1371/journal.pmed. 1001346. 32. Kim MK, Strait RT, Sato TT, Hennes HM. A randomized clinical trial of analgesia in children with acute abdominal pain. Acad Emerg Med. 2002;9(4):281–7. 33. Kokki H, Lintula H, Vanamo K, Heiskanen M, Eskelinen M. Oxycodone vs placebo in children with undifferentiated abdominal pain: a randomized, double-blind clinical trial of the effect of analgesia on diagnostic accuracy. Arch Pediatr Adolesc Med. 2005;159(4):320–5. doi:10.1001/archpedi.159. 4.320.
G. Neuman et al. 34. Green R, Bulloch B, Kabani A, Hancock BJ, Tenenbein M. Early analgesia for children with acute abdominal pain. Pediatrics. 2005;116(4):978–83. doi:10.1542/peds.2005-0273. 35. Godwin SA, Burton JH, Gerardo CJ, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2014;63(2):247–258.e18. doi:10.1016/j.annemergmed. 2013.10.015. 36. Marik PE. Propofol: therapeutic indications and side-effects. Curr Pharm Des. 2004;10(29):3639–49. 37. Metzner J, Domino KB. Risks of anesthesia or sedation outside the operating room: the role of the anesthesia care provider. Curr Opin Anaesthesiol. 2010;23(4):523–31. doi:10.1097/ACO. 0b013e32833b7d7c. 38. Mallory MD, Baxter AL, Yanosky DJ, Cravero JP, Pediatric Sedation Research Consortium. Emergency physician–administered propofol sedation: a report on 25,433 sedations from the pediatric sedation research consortium. Ann Emerg Med. 2011;57(5): 462–468.e1. doi:10.1016/j.annemergmed.2011.03.008.
CURRENT OPINION
Ethics of Research in Pediatric Emergency Medicine Gal Neuman • Itay Shavit • Doreen Matsui Gideon Koren
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Published online: 5 December 2014 Ó Springer International Publishing Switzerland 2014
Abstract Clinical research in the pediatric emergency department (ED) has been rapidly growing in the past decade, and has resulted in some of the most important milestone studies in the pediatric medical literature. However, it presents a unique ethical goal and requires that additional challenges, such as the acute medical condition, fear and anxiety, unfamiliar physician(s), fatigue, and lack of time be addressed in addition to the standard ethical requirements. These may impair several fundamental elements of research, including the patient enrollment process, informed consent/assent, randomization, and others. Every
This article is part of the topical collection on Ethics of Pediatric Drug Research. G. Neuman (&) G. Koren Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G1X8, Canada e-mail: [email protected] G. Neuman Division of Pediatric Emergency Medicine, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G1X8, Canada I. Shavit Department of Pediatric Emergency Medicine, Meyer Children’s Hospital, Rambam Health Care Campus, Haifa, Israel D. Matsui Children’s Health Research Institute, University of Western Ontario, London, ON, Canada G. Koren University of Toronto, Toronto, ON, Canada
possible attempt must be made to reduce or minimize the risks to which the children are exposed, and one must be cognizant of the special needs of children and their families in the ED. Nevertheless, we are also obliged to find ethical ways to include them in appropriate research endeavors that aim to improve treatments for conditions unique to the ED. This paper explores and overviews the most recent literature in order to characterize the nature of ethical challenges complicating clinical research in pediatric emergency medicine, and then suggests some ethically sound solutions such as deferred/waived consent, designated research staff, and alternative study designs. Finally, a few examples of prospective, blinded randomized trials involving drugs in pediatric emergency medicine are provided, with special emphasis on how the investigators are overcoming the obvious ethical challenges.
Key Points Clinical research in pediatric emergency medicine is associated with difficult ethical challenges for both the researchers and the participants, given the acute, time-sensitive, and stressful situation it usually involves. Ethical challenges in the pediatric emergency room often need to be addressed with unique strategies such as using waived or deferred consent, designated research staff, and/or alternative study designs. Several well designed, prospective randomized controlled trials have shown the effectiveness of these strategies in overcoming ethical challenges in the emergency department setting.
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1 Introduction Pediatric emergency medicine (PEM) has developed as an independent subspecialty in pediatrics in the last 10–15 years, with the fundamental understanding that the child needs totally different diagnostic and management approaches, and therefore s/he is not just a young adult. Consequently, research in PEM has been steadily growing and evolving in recent years. The importance of research in PEM stems from the fact that the emergency department (ED) deals with disease states seen and treated only there. Moreover, specific populations, such as low-income families without adequate medical care, can be studied only in the ED. Not surprisingly, some important milestones in pediatric research have emerged in PEM research networks; good examples of these are the US-based Pediatric Emergency Care Applied Research Network (PECARN) [1], and the Pediatric Emergency Medicine Collaborative Research Committee [http://www.caymansim.com/pemcrc/], as well as the Canadian network, Pediatric Emergency Research Canada (PERC) [http://perc.srv.ualberta.ca/]. All of these are national research networks that constantly provide new evidence that improves the daily practice in PEM. Recent examples of therapeutic progress include traumatic brain injuries, pediatric fractures, procedural sedation and analgesia, fever, bronchiolitis, diabetic ketoacidosis, and acute sickling episodes [2–6]. In this article, we aim to highlight specific ethical issues associated with research in PEM. This is followed by discussion of several unique strategies to overcome these ethical challenges. 2 Ethical Principles of Pediatric Research In order to understand and address the challenges associated with research in PEM, one needs to put them in the context of ethical principles that need to be satisfied when conducting research in pediatric patients. 2.1 Respect for Person and Self-Determination While for adults this principle means that informed consent must be obtained from the subject involved in the research, for children, who are considered incapable of giving formal informed consent, the families/caregivers must be involved and provide consent for the child to participate. Standard principles of informed consent include information, comprehension, and voluntariness [7]. ‘Information’ in this context means all details that the research subject, or his/ her family, need to know in order to understand the circumstances and provide an informed consent.
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‘Comprehension’ means that the legal guardian must be able to understand the information, which leads to the need to use appropriate language and jargon, and taking into account the level of spoken language and literacy of the guardian. The language and jargon are of special importance in the ED, as they often serve multilingual communities and a wide socioeconomic range. ‘Voluntariness’ means that there will be an active attempt to prevent coercion. While the principle of informed consent applies to families in the ED who need to give permission or authorization for their children to be involved in research, the child himself or herself should also assent to participation and have the right to dissent or veto, when possible. Generally, meaningful assent is believed to occur at approximately 7 years of age, when concrete operational thinking emerges [8], although the US Department of Health and Human Services (DHHS) has left the decision regarding ability to assent to the local institutional review boards (IRBs) [9]. Importantly, the age cut-off for patient assent varies among countries, and in some jurisdictions it is based on the patient’s cognitive ability rather than his or her age. There are unique situations where obtaining consent in the ED is not possible, such as when the patient’s status is severe and does not allow time for informed consent, or when a child is brought to the ED without a parent or guardian. These situations will be dealt with later in the section ‘Suggestions to Overcome Ethical Challenges Associated with Research in PEM’. 2.2 No Harm (Non-Maleficence) The major ethical principle of ‘no harm’ means that risk to the patient, associated with participation in the research must be carefully evaluated, and the relevant risk–benefit ratio assessed. The risk needs to be stratified, i.e., minimal risk, minor increment over minimal risk, or more than minor increment over minimal risk [10]. According to the US DHHS, the risks of harm are minimal if they are not greater in probability and magnitude than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Examples relevant to the ED include physical examination and obtaining blood or urine specimens [10]. The definition of minor increment over minimal risk is more complex. A case-by-case decision must be made considering the four perspectives suggested by Levine [11]: common sense estimation of risk, estimation based on the investigator’s previous experience with similar interventions or procedures, statistical information, and trying to put oneself in the situation of the proposed subject. A classification of research based on level of risk has been proposed: greater
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than minimal risk but with a prospect of direct benefit to the individual subject; and minor increase over minimal risk but with no prospect of direct benefit, but a likelihood of generalizable information. There is a consensus that, as the risk to the child increases, the requirements of protection of the child, the stringency of consent, benefits to the child, and the requirements regarding significance of research must also increase. A common example relevant to the ED is pharmacokinetic studies of medications that the child may need for his/her therapy. 2.3 Justice This principle requires that special precautions must exist for vulnerable groups. Attempts must be made to avoid assigning an excessive burden of research to any particular group, such as children with mental or physical handicaps, or children of particular (usually younger) age groups who are vulnerable by virtue of inability to dissent or consent. On the other hand, justice also requires that children, including those with emergent medical conditions, are entitled to benefit from research and not be excluded. In the ED, the issue of justice may arise, for example, when children are excluded from research based on status of their medical insurance, socioeconomic class, or race. 2.4 Privacy Patient confidentiality must be protected in all research, as in any other field of clinical research. In the ED, one has to ensure that, despite the hectic and often chaotic environment, no information is disclosed to other individuals who may happen to share the same space.
3 Ethical Issues of Research in the ED In addition to general ethical issues that have already been discussed regarding research in children, special problems pose additional challenges to research undertaken in PEM, especially regarding consent and justice. These complexities stem from two main factors: (1) the population being studied—children, who are considered incapable of providing formal informed consent and thus depend on their primary caregivers in this respect; (2) the circumstances under which the research is conducted—acute, unfamiliar medical conditions, unfamiliar setting and medical personnel, fear, anxiety, uncertainty, and, in many occasions, fatigue of both the child and his/her caregivers. All these factors may impair the family’s ability to fully understand the essence of the specific research in which they may be involved, and to provide uncoerced informed consent. In addition, time shortage and involvement of multiple staff
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(clerks, nurses, physicians, social workers, security personnel, etc.) are factors that further limit the ability to conduct ethically sound research in the PEM setting. Most importantly, children often have acute and sometimes painful medical or surgical conditions that provoke stress and anxiety for them and their families. In extreme cases, acute, life-threatening situations occur, and research is often also needed in those circumstances. Is it possible under such circumstances to ensure that a high-quality risk–benefit discussion takes place prior to participation? Is it possible for the research staff to avoid the risk of coercion? Requests for enrollment are coercive if the families and patient perceive that they should say yes because their lives are in the hands of the researcher. Adequate consent is also threatened in the ED by medical conditions such as coma or respiratory or cardiac arrest, which obviously render incompetent the patient who otherwise has been competent to give consent or assent. The suddenness of the episode as well as the unfamiliar nature of the medical condition and the ED setting may all contribute to these feelings. To what extent do fear and anxiety compromise the ability of parents to make optimal decisions regarding their children’s participation in ED research? One of the significant challenges is in the process of patient enrollment. Difficulty enrolling patients into clinical research in the ED setting has been described, particularly in children, the elderly, and other subpopulations [12]. A significant limiting factor for enrolling patients is the timing, given the high acuity setting in the ED [13]. However, it is our experience that many guardians are quite capable of considering requests for research participation rationally under many (but not all) of the circumstances that occur in the ED. Recently published data on parental perception of clinical research in pediatric EDs have shown that most parents understand the importance of such research in improving the treatment of children, and are willing to let their children participate in clinical research [14]. This provides a unique opportunity to enroll patients who are otherwise unlikely to be enrolled in clinical research [15]. Another challenge is in obtaining informed consent. In the ED, the family is usually not known to the researcher. Without the benefit of a long-standing relationship, the researcher is less able to judge parental ability to comprehend the information necessary to give informed consent/assent. On the other hand, this unfamiliarity removes the risk of coercion typical of parents who feel dependent on the physician treating their child for a chronic condition. In addition to fear, anxiety, and strangeness of setting, many families are also battling fatigue in the ED. They may have completed a full day of work and perhaps also a lengthy wait in the ED. Fatigue may further impair the
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ability to give truly informed and uncoerced consent/ assent.
4 Suggestions to Overcome Ethical Challenges Associated with Research in Pediatric Emergency Medicine (PEM) Although these threats to research make the ED a less than ideal setting for clinical research, there may be some ways to overcome them and to give children with emergent medical conditions a reasonable opportunity to participate in and benefit from clinical research. Examples of these include deferred consent, designated research staff, and alternative study designs. At the end of this section, examples of prospective controlled trials are provided as well as the ways in which the researchers overcame the ethical challenges. 4.1 Waived or Deferred Consent In 1996, the US FDA and the US DHHS introduced regulations allowing emergency research, under specific circumstances, to be conducted without voluntary prospective consent of the patient. The secretary of Health and Human Services authorized this waiver in response to growing concerns that regulations made high-quality research in emergency circumstances difficult or impossible to conduct, despite being increasingly needed (Office for Protection From Research Risks Report 97-01. Washington, DC: Department of Health and Human Services; 1996) [16]. These regulations became known as the Final Rule, and clinical trials approved under the rule are referred to as ‘‘research with exception from informed consent.’’ Before 1996, much of what was learned about potentially lifesaving advancements was grounded in events that occurred in wartime situations, and no provision in federal regulations governed any exception from the informed consent requirement for greater than minimal risk research. In 2008, the UK also introduced provisions for deferring consent for minors participating in clinical trials or requiring urgent treatment [17]. These new guidelines recognize the unmet need for treatment options in acute, life-threatening situations and address a need to update requirements for the protection of human subjects with diminished autonomy (here defined as an individual’s ability to voluntarily choose to participate or continue to participate as a research subject) [18]. Under certain conditions, the Final Rule contains provisions for an additional layer of protection of patients’ rights not required of other studies, but only when research was undertaken with consent waived. Among these conditions: the situation is life-threatening; obtaining informed
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consent is not feasible; there may be direct benefit to research subjects; the research could not be performed without a consent waiver; and there is a defined therapeutic window. Key elements in the Final Rule are additional protection requirements, including community consultation, public disclosure before and after the study, and study oversight by an independent data safety monitoring committee [19]. Community consultation has been shown to be a useful tool to assess the targeted population’s approach to emergency research studies proposing a waiver of informed consent. The concept of waived informed consent has been tested in two studies among families who visited the ED in regards to deferred/waived consent, showing that, overall, the parental approach toward this strategy was positive, favoring societal benefit over individual right for selfdetermination [20, 21]. Thankfully, these acute and lifethreatening situations are relatively rare in PEM, and, under most circumstances, sufficient time is available for the caregiver and the family to discuss the issue of participation in research in more detail, even if not at the time of the actual enrollment but later on, as in ‘deferred consent’. Nevertheless, deferred consent should be regarded as a viable solution in the appropriate circumstances, and parents appear to support it when necessary [22, 23]. A recent systematic review of waived consent in pediatric resuscitation research has found that, overall, 68 % of subjects who were surveyed supported the concept. Caregivers were more likely to support it when the circumstances were anchored in reality (e.g., critical care unit personnel) [24]. To address the incapacity to obtain truly informed consent due to the acute nature of the medical condition, in some instances it may be best to wait until the child has been stabilized and to receive deferred consent. If possible, fear and anxiety should be addressed prior to introducing research, with the investigators considering the potential guardian’s level of fear and anxiety prior to approaching him or her. An attempt should be made to establish reasonable rapport with patients and families seen in the ED. 4.2 Designated Research Staff To address fear and anxiety, which may occasionally interfere with the family’s ability to provide informed consent, special communication skills and sensitivity are required from the researchers to be able to discuss participation in research with the families. On some occasions, designated research staff, who are not the actual researchers and are not part of the ED team on shift and therefore naturally have more time to spend with each recruited family, may conduct the actual recruitment of the patients, including the initial approach, general explanations, providing handouts with information on the specific
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study, and addressing concerns. Importantly, the researcher himself or herself should be the ultimate address for any of the patient’s concerns. An example for such an approach is a student volunteer program for research, which was recently shown to be effective in facilitating the enrollment of patients into prospective trials in a PED in a tertiary hospital [25]. 4.3 Alternative Study Designs In order to conduct research in the ED, it is imperative to reduce the risks to the child as much as possible when designing the study protocol. In some unique situations, where randomized controlled trials may not be possible due to ethical limitations (e.g., treating children with placebo in acute life-threatening situations), alternative study designs may be appropriate.
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management intervention can reduce healthcare utilization and improve self-assessed health status in frequent ED visitors. One group of patients received the standard care (i.e., no follow-up), and the second group received the experimental care (i.e., case management by a study nurse, based on bi-weekly supportive telephone calls). Patients from the second group who declined the intervention were included in the analysis, and patients from the first group were not asked for consent or offered the study intervention (hence the Zelen design). The study showed that telephonebased case management by a nurse reduced the total number of outpatient visits, the number of ED visits, the number of days patients were admitted to hospitals, and the total healthcare costs for hospital admissions. Patient selfassessed health status improved for the patients who received the case management intervention [28]. 4.3.2 Observational, Non-Randomized Studies
4.3.1 The Zelen Design Although less than ideal, the Zelen design has been proposed to compare best standard control with experimental treatment [26]. In the Zelen design, subjects are randomized to two groups: one receives standard therapy and the second is asked whether they will accept experimental therapy. The results of all subjects in the second group, regardless of the actual treatment received, are compared with those of the first group. However, consent is only required in the second group, and subjects who refuse the experimental treatment receive the control treatment instead. The advantage is that it allows the subjects, in this case the family, to know what treatment they are getting. Consent is needed only if an experimental treatment is offered. The question arises whether justice is maintained for the standard therapy group, who are not offered the chance of the experimental treatment, purely on the basis of the study design. Although this study design should make enrolling patients easier and likely increase the sample size, more patients will be required because some children in the experimental group will actually receive the standard (control) treatment but will still be counted as if they had received the experimental treatment, thus reducing the power of the study. To date, most of the examples for published studies with the Zelen design are not related to clinical research in emergency medicine. A 2004 review of the literature has shown that, of all studies found with Zelen methodology, eight were screening trials; 13 were surgical trials; 12 were drug studies; 15 were ‘service configuration’ trials; and ten were education trials [27]. One study related to emergency medicine has also been published [28]. In that prospective randomized study, the investigators aimed to determine whether a nurse-managed telephone-based case-
In addition, given the wide variety in clinical practice among PEM physicians and departments, it is not unusual to conduct a prospective observational, non-randomized study to compare different procedures or diagnostic tools for given conditions. Although inferior in their design (e.g., results may be biased by confounders that were not taken into account or could not be adjusted for), such studies have led to some very important breakthroughs that have changed practice in PEM. An important example is a prospective cohort study by Kuppermann et al. [2], which validated clinical decision rules in children presenting to ED with minor head injuries. In that study, a site investigator collected data from the patient’s chart, including history, vital signs, and physical examination results, without interfering with the natural medical assessment performed by the ED physician on that shift. All decisions, including computed tomography (CT) of the head, were made at the discretion of the ED physician without any relation to the study, which was observational in nature and did not alter any standard-of-care interventions. Informed consent was waived. The clinical decision rule was validated only at the end of the study period, following the analysis of the data, when the authors could establish the clinical predictors for the need for head CT in children with traumatic brain injury [2]. This study, and others, provided a sound basis for progress in measuring different outcomes before and after the implementation of such clinical decision rules [29]. 4.3.3 Cluster Randomized Trials Another approach to cases where consent for randomization cannot be achieved in the ED is the option of block or cluster randomization, where randomization is made on a
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cluster basis (i.e., groups of patients) rather than on an individual basis. This design allows the researcher to perform the randomization prior to the actual enrollment of the patient and without consent for randomization. This method is occasionally used despite its obvious statistical downsides. Recent examples include a study that compared success rates of pulled elbow reduction in children, comparing nurses with physicians [30], and an ongoing study that utilizes block randomization of community EDs to evaluate the impact of clinical pathways for the treatment of acute pediatric gastroenteritis and asthma (http://www. clinicaltrials.gov, NCT01815710). Historically, researchers have justified the use of this design in an attempt to avoid the need for informed consent for randomization (but not for participation in a study); however, this approach is now often discouraged [31]. 4.4 Prospective Randomized Trials Involving Drugs in PEM Prospective, controlled double-blind studies are taking place in the emergency setting. An important example of a prospective interventional drug study in the emergency setting is a study that, at the time of writing this article, is recruiting patients (http://www.clinicaltrials.gov, NCT01429415). The main objective of the study is to examine whether, in children with acute asthma remaining in moderate to severe respiratory distress despite maximized initial bronchodilator and steroid therapy, there is a reduction in hospitalization rate from the ED in those who receive nebulized magnesium with salbutamol versus those receiving salbutamol only. Children aged 2–17 years, with moderate to severe asthma, not responding to bronchodilators and steroids, are included and then randomized into two groups: one group is receiving inhaled salbutamol and inhaled magnesium, and the other group is receiving inhaled salbutamol and inhaled hypertonic saline as placebo. Clearly, the ethical challenge is overcome by limiting the intervention to patients who have already received maximized therapy, and by administering the same ‘baseline’ medication (salbutamol) in both groups, with the addition of the study drug in one group only, so that none of the patients receives less than standard therapy. Informed consent is obtained in this study. Another example is the therapeutic approach to acute abdominal pain in children. Historically, generations of physicians were taught that one should not administer morphine as an analgesic agent for acute abdominal pain as it ‘‘may mask signs of acute appendicitis.’’ In fact, although endlessly cited in older surgical textbooks, there has never been any evidence to support this assertion, and many children who
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presented to ED with acute abdominal pain did not receive proper analgesia because of this diagnostic concern. In the early 2000s, several studies were published examining this point, leading to practice changes [32–34]. For example, in 2005, a prospective, double-blind placebo-controlled study conducted by Green et al. [34] assessed the effect of intravenous morphine administration for pain management in children presenting to ED with acute abdominal pain, and compared it with placebo. The results of this study have shown that morphine effectively reduces the intensity of pain among children with acute abdominal pain and does not appear to impede subsequent diagnosis of appendicitis. The obvious ethical challenge, which stems from the need to recruit a child who is acutely ill and in pain to a study, is to explain to their guardians that the child may be randomized to not receive any analgesia, and to receive their informed consent, was justified by the fact that not providing opioid analgesia was the standard of care at the time of the study. Looking retrospectively, the important results of this study justified some of the ethical challenges that may have arisen. Another example is procedural sedation and analgesia (PSA) in the ED. Historically, ketamine, opioids, nitrous oxide, and benzodiazepines were used in the ED. Over the past few years, the drug propofol, which is considered by the FDA as an anesthetic agent, has been increasingly used. It is now accepted that this drug can be safely administered to children in the ED by emergency physicians [35]. However, until the mid-2000s, propofol was rarely used in EDs due to its potential for serious adverse reactions and its high risk. These reactions include prolonged apnea, cardiodepression, and even ‘propofol syndrome,’ a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse [36, 37]. An important study to ascertain the safety of propofol involved 25,433 patients [38]. In this study, all ED procedures using propofol were successfully completed. A collaborative group of PEM researchers prospectively recorded data on pediatric sedations; these data were electronically uploaded to the Pediatric Sedation Research Consortium (PSRC) database (the PSRC was created in 2004 as a collaborative group of institutions). Participating researchers were required to obtain IRB approval for data collection, parental consent, patient assent in appropriate cases, and to agree to a standardized methodology for consecutive data collection [38]. This process of unanimous and consistent data collection supports a standardized, well-organized learning process with the goal of improving patient care in the pediatric ED, without ethical breaches. This is particularly important when the study involves potentially high-risk medications or procedures.
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5 Summary Ethical research in the pediatric ED requires that additional challenges, such as the acute medical condition, fear and anxiety, unfamiliar physician(s), and fatigue be addressed in addition to the standard ethical requirements. Every possible attempt must be made to reduce or minimize the risks to which the children are exposed. Nonetheless, while one must be cognizant of the special needs of children and their families in the ED, we are also obliged to find ethical ways to include them in appropriate research endeavors that aim to improve treatments for conditions unique to the ED. Acknowledgments G. Neuman, I. Shavit, D. Matsui, and G. Koren declare no relevant conflicts of interest. No sources of funding were used to support the writing of this manuscript.
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