It is a tired yet true aphorism that children aren’t little adults, but medicine hasn’t always been able to put its (scientific) money where its (anecdotal) mouth is. That has changed in recent years, with the care of a child brought to the ED today far more likely to be guided by evidence-based pediatric emergency care research than it was in the past.
“Over the past few decades, the evidence generated to guide the care of acutely ill and injured children in emergency departments globally has transitioned from retrospective case reports to large prospective research studies,” reported Nathan Kuppermann, MD, the Bo Tomas Brofeldt Endowed Chair and a distinguished professor of emergency medicine at the University of California-Davis School of Medicine, in the keynote address at the Society for Academic Emergency Medicine annual meeting this past May.
“This has further evolved into large, well-organized, and well-funded pediatric emergency care research network,” said Dr. Kuppermann. Not only are there two such networks in the United States, but similar ones exist in Canada, Europe, Australia, and New Zealand. These networks have not only generated high-grade, precise, and generalizable evidence on which to base care of acutely ill and injured children, they have also organized the implementation of this evidence to the bedside.”
That wasn’t always the case, he acknowledged, even though pediatric emergency department visits make up roughly 20 percent of all ED visits every year; that was 30 million children 18 and younger in 2015 alone. And 17 percent of all U.S. children sought emergency care at least once that year, according to a 2018 statistical brief from the Agency for Healthcare Research and Quality (AHRQ).
“Our research in general emergency medicine evolved earlier than pediatric emergency medicine,” Dr. Kuppermann said. “It’s a newer field, first of all. The first boards in pediatric emergency medicine were held in 1992, more than a decade after general emergency medicine had its first boards. Many of our grandmothers and grandfathers of pediatric emergency medicine are still practicing; that’s how young the field is.
Developing the Network
But pediatric emergency medicine is racing to catch up, he said, noting that practicing general emergency medicine requires completing a residency, while a pediatric emergency medicine specialist must finish a fellowship after residency. “That means that all pediatric emergency medicine subspecialists, by definition, have received some training in research during the course of completing a fellowship,” he said.
Research networks are even more important in pediatric emergency medicine than in the field generally, Dr. Kuppermann noted. “Bad outcomes are less common in children than in adults. Often, you can do informative single-center research studies in adults, but to have enough power in a pediatric study, you frequently need to collaborate,” he said.
He and several colleagues developed a shoestring all-volunteer pediatric emergency research network under the auspices of the American Academy of Pediatrics in the mid-1990s. The Pediatric Emergency Medicine Collaborative Research Committee of the AAP had no budget to do prospective, randomized trials; their studies were mostly retrospective chart reviews.
But they published an attention-grabbing study in 2001, led by Dr. Kuppermann and his wife, Nicole Glaser, MD, a professor of pediatrics at UC Davis, on risk factors for cerebral edema in children with diabetic ketoacidosis. (N Engl J Med. 2001;344:264; https://bit.ly/3IbS4Wz.) The group was approached by the Health Resources and Services Administration as that study was ongoing for discussions on how to further develop the network.
“They wanted to know how we could take PEC research to the next level,” Dr. Kuppermann said. “We said, ‘That’s easy. We need money!’” HRSA issued a request for applications to create a PEC research network within its Emergency Medical Services for Children (EMSC) program in 2001, marking the genesis of the Pediatric Emergency Care Applied Research Network (PECARN), the first federally-funded multi-institutional network pediatric emergency care research in the United States. (https://pecarn.org.) HRSA/EMSC funds the PECARN infrastructure, including the data coordinating center, principal investigators at each site, and administrators of the network, but does not fund the research projects themselves.
Building the Evidence
Getting off the ground meant PECARN had to look for studies that were relatively easy to conduct and not too expensive. They found what they were looking for in the question of administering steroids to babies with bronchiolitis, the leading cause of hospitalization for infants in the United States, which accounts for more than 100,000 hospital admissions each year. Small studies in the mid-2000s had suggested that treatment with steroids such as dexamethasone decreased that hospitalization rate.
“People had started using steroids on very young infants with bronchiolitis,” said Dr. Kuppermann, PECARN’s principal investigator. “But you don’t want to give steroids to young developing brains if you don’t need to. So we applied for a grant and enrolled 600 patients at approximately 20 PECARN hospitals to study steroids in bronchiolitis.”
That study found that the hospital admission rate for both groups was identical at about 40 percent. (New Engl J Med. 2007;357:331; https://bit.ly/3llRYSH.) The placebo group did as well as the group treated with steroids.
The bronchiolitis study helped put PECARN on the map. “Then we started getting bigger grants. One led to another and another,” Dr. Kuppermann said. A 2009 trial focused on using CT scanning in pediatric head trauma helped establish rules identifying which children with head trauma required CT scans and which ones were at very low risk of brain injuries and could avoid a CT. (Lancet. 2009;374:1160.)
And a 2014 study tested the hypothesis that lorazepam may be more effective or safer than diazepam in treating pediatric status epilepticus, as several previous retrospective studies had suggested. (JAMA. 2014;311:1652; https://bit.ly/2ZOwJS0.) But this larger, randomized trial found no evidence of superiority for lorazepam, so either agent could be chosen as a reasonable first-line therapy.
Today, PECARN consists of a data coordinating center and six hospital-based research node centers composed of academic, community, urban, general, and children’s hospitals, each containing three hospital emergency department affiliates and one EMS affiliate. The Pediatric EM Northeast, West, and South (PEM-NEWS), for example, includes Columbia-Morgan Stanley Children’s Hospital in New York, Texas Children’s Hospital in Dallas, Children’s Hospital Colorado in Denver, and Colorado’s Aurora Fire EMS affiliate. It also has an EMS research node, which includes three EMS affiliates.
EDs in the PECARN network serve approximately 1.3 million acutely ill and injured children every year, and the nine EMS affiliates account for more than 113,000 pediatric runs annually. PECARN has published more than 150 articles and obtained more than $150 million in grant funding in addition to HRSA’s funding of its infrastructure over the past 20 years.
Some of the issues now being studied in PECARN include normal saline v. lactated Ringer’s for pediatric sepsis, azithromycin for young children with wheezing, a prediction rule for brain abnormalities in children with acute headaches, a prediction model for pulmonary embolus in children, risk stratification for pediatric cervical spine injury, and pain control in children with long bone fractures.
And the EMS node of PECARN was funded in August 2021 for its largest trial to date, an NIH-supported study of pediatric seizures that will be one of the first pediatric-focused, large-scale NIH projects in the prehospital setting.
“This is a 20-site study and would be impossible without a large-scale network,” said E. Brooke Lerner, PhD, a professor of emergency medicine at the University of Buffalo’s Jacobs School of Medicine and Biomedical Sciences, who leads the PECARN EMS node. “We just don’t have enough patients at any site to do work of this size. Pilot studies show that kids tend to get underdosed for their seizures, so we are trying to move from a weight-based calculation to age-based dosing with the goal of improving dosage so that more kids arrive at the hospital no longer seizing.”
Dr. Lerner said she believed that this will also be the first trial in the pediatric emergency prehospital setting to incorporate a stepped-wedge protocol in which the study is randomized not at the patient level but at a cluster level. “All sites will start with the current protocol, and then in a randomized fashion, sites will switch over to the new protocol,” she explained. “It’s a way for us to look at a process instead of a single event. This approach also makes it easier to do research in the prehospital setting where you typically don’t have a research assistant present.
“You’re much more likely to be successful by flipping from the control protocol to the new protocol at a single point, and don’t have to have someone who’s ready to do either approach at any moment,” she said. “When you have just a couple of people in an ambulance or a fire truck, it’s hard to manage patient-randomized protocols. We think this will give us the ability to do more advanced research in the prehospital setting.”
The EMS node is also awaiting word from the NIH about a respiratory distress study that it plans to start in the coming months. “We have finally reached a critical mass where we have a lot of investigators who are preparing and submitting grants,” Dr. Lerner said. “Pediatric prehospital EMS research is an area that’s clearly lacking in the literature. Where PECARN has reached its maturity in ED-based research, I hope we can achieve the same success and address what we don’t know in the prehospital setting.”
Sister pediatric emergency care networks have been developing around the world, in Canada, Australia, New Zealand, Europe, and Latin America. Representatives from several of the groups met in Amsterdam to develop a collaborative study in 2009 at the height of the H1N1 influenza pandemic. “We were seeing all these kids in the winter with flulike symptoms,” said Dr. Kuppermann. “Which ones actually had H1N1? What were the risk factors for doing poorly? We knew that we needed to focus our disparate efforts.”
That study (BMJ. 2013;347:f4836; https://bit.ly/3rsjuSc) led to the creation of the Pediatric Emergency Research Networks (PERN), an international collaboration of these national and regional groups. PERN will soon release a large study on risk factors for adverse COVID-19 outcomes in children, again, a study that would not have been possible without this large international partnership.
Going forward, Dr. Kuppermann said PECARN needs to add evidence implementation to its robust evidence creation. “We have generated a lot of evidence that is practice-changing, but now we need to study the best ways to implement it in everyday practice. We also need to study health equity and health disparities, and look for ways to mitigate disparities in pediatric emergency care globally. That’s what we’ve all committed to do, not just documenting these disparities, which have already been identified, but alleviating and mitigating them.”
Access the links in EMN by reading this on our website: www.EM-News.com.
Comments? Write to us at [email protected].
Ms. Shawis a freelance writer with more than 20 years of experience writing about health and medicine. She is also the author of Having Children After Cancer, the only guide for cancer survivors hoping to build their families after a cancer diagnosis. You can find her work athttp://www.writergina.com/Home.html. Follow her on Twitter@writergina.