Moving Emergency Medicine Research ForwardMoving Emergency Medicine Research Forward https://pediatricsnationwide.org/wp-content/uploads/2022/04/AdobeStock_234101667_web-crop-1024x614.jpg 1024 614 Abbie Miller Abbie Miller https://pediatricsnationwide.org/wp-content/uploads/2023/05/051023BT016-Abbie-Crop.jpg
- April 20, 2022
- Abbie Miller
Utilizing exception from informed consent studies and a national network of emergency medicine experts, clinician-scientists are advancing research to uncover best practices and improve care.
Exception from informed consent (EFIC) is a special rule set utilized by the U.S. Food and Drug Administration (FDA) to support research in emergency situations.
The word exception is particularly important when talking about EFIC studies.
“Often, people mistakenly say exempted from informed consent,” says Manish Shah, MD, MS, chief of Academic Development and Strategy in the Division of Pediatric Emergency Medicine at Texas Children’s Hospital. “But that is incorrect. While the treatment may be administered before informed consent can be obtained due to the critical needs of the patient, informed consent must still be obtained to use the data collected from the patient.”
The exception to the informed consent is in the timing, not in the requirement of having informed consent. Researchers still have an obligation to notify research participants that they have been enrolled in a study at the earliest feasible opportunity, and they must still give them choices about ongoing participation once that notification has been made.
EFIC CAN ONLY BE USED IF:
The person’s life is at risk
Available treatments are unproven or unknown and collection of valid scientific evidence is necessary to determine the safety and effectiveness of a therapy
• The person could benefit from the study
It is not possible to get permission from the person because of the condition, or from the parent/guardian because of the short amount of time to treat the medical problem
There is no reasonable way to identify prospectively individuals likely to become eligible for participation
The clinical investigation could not practicably be carried out without the exception
“We have clinical research coordinator coverage seven days a week for just this reason,” says Julie Leonard, MD, MPH, principal investigator in the Abigail Wexner Research Institute at Nationwide Children’s Hospital and professor of Pediatrics at The Ohio State University College of Medicine. “We make sure our teams discuss the trial with the caregivers as soon as possible. If they decide to withdraw, we don’t use their data. But usually, families are happy to be part of the trials.”
Before an EFIC study, researchers must provide information about the study to the community and gather community feedback. This helps to increase awareness about the study before families even need emergency care. In some cases, investigators may offer an opt-out option for individuals who know ahead of time that they may likely need services and also know that they do not want to be part of the study. For most studies however, the decision to withdraw from ongoing participation is offered after care has been initiated.
Power in Numbers: Connecting Researchers Through Networks
Nationwide Children’s currently has two emergency medicine EFIC studies open and enrolling. Both are multicenter studies running through the Pediatric Emergency Care Applied Research Network (PECARN). PECARN is a federally funded multi-institutional network for research in pediatric emergency medicine. It operates through seven geographic nodes with sites in each node that represent academic, community, urban, general and children’s hospitals, as well as emergency medical service (EMS).
“The tools, resources and opportunities for collaboration in PECARN have been instrumental in driving these large EFIC studies,” says Dr. Leonard. “Nationwide Children’s Hospital is the lead site for the Great Lakes EMS for Children Research Node of PECARN and has been a key collaborator in studies that have changed the emergency management of children with serious injuries and illnesses.”
An upcoming multicenter study takes EFIC out of the emergency department and into the field. The Pediatric Dose Optimization for Seizures in EMS (PediDOSE) trial is investigating the administration of medication by EMS to stop seizures.
“Far too often, a child is still seizing when they arrive at the emergency department. As many as 1 in 3 children come to the emergency department for seizures are still seizing when they arrive,” says Dr. Shah, who is the leader of the national study.
How does this happen? Well, it all comes down to math. When EMS arrives at the scene, they first assess the child, check their airway and pulse, then administer medication to treat the seizure.
“We typically don’t have another paramedic on the scene with us and are also supervising the basic emergency technician on the scene while they are checking vital signs. In addition, parents are very stressed if the seizure is a new onset,” says Joseph Zarbaugh, paramedic and firefighter for the Columbus Division of Fire. “As the paramedic, I’m working to get the medication ready to administer.”
The medication given by a paramedic is typically a benzodiazepine — often midazolam. According to emergency medicine physicians, midazolam administered via nasal spray or injection is preferred, but paramedics frequently give it intravenously. Additionally, different bottles may have different concentrations.
In order to find the correct dose, the EMS personnel must measure the seizing child with a tape to estimate weight, then use that weight to calculate the dose in milligrams, and then convert that dose to milliliters.
“Doing math in a high-stress situation is a challenge for caring for children having seizures at the scene,” says Zarbaugh. “There are a lot of moving parts on the scene, and emergencies involving children are even more stressful.”
Paramedics like Zarbaugh do these calculations in high-pressure and time-sensitive situations: while the child is having a seizure and the family members are present and upset and every second counts. In these circumstances, it’s no wonder that some children receive incorrect doses. And if you’re erring on the side of caution, you probably are going to underdose the benzodiazepine. Overdosing puts the heart and lungs at risk. Underdosing prolongs the risk of damage to the brain. It’s a hard line to walk.
The idea behind the PediDOSE trial is to optimize the timing, the amount, and the method of giving the medication: It does this by emphasizing the use of a nasal spray or intramuscular injection only — no intravenous administration. The patient care protocol also lowers the priority of getting a blood glucose test until after the first dose of medication is administered. And finally, it eliminates the need for complex math. Children are given one of four age-based doses instead of a calculated weight-based dose.
“We know children are getting underdosed in these emergency situations,” says Dr. Leonard, principal investigator for the Nationwide Children’s study site. “We want to find out if the protocol can change that.”
Notably, the age-based doses in the protocol are safe doses that are already used in various medical settings.
“Our team thought very carefully about the dose ranges,” says Dr. Shah. “We are confident they are optimal based on standardized growth charts for children.”
The PediDOSE trial will be launched in 20 cities across the United States, including Columbus, Ohio, where it will be rolled out as a collaboration between Nationwide Children’s and Columbus Division of Fire. In each city, each participating EMS agency will first follow their current protocol, but will then switch to the new protocol at some point over the next years.
Researchers will then compare the data from all sites to see if more children arrive at the ED with their seizures stopped when treated under the new protocol versus the EMS agencies’ current protocols. Zarbaugh is optimistic that the trial will lead to improvements in emergency care for children.
“Anything that reduces resources and complexity in a high-stress environment is going to afford a better outcome on emergency calls,” he says. “Caring for children in general is especially stressful for EMS. Anything that can simplify and streamline their care will be a positive outcome, and a welcome improvement for both the EMS and the children we treat.”
PROMPT Bolus Study
Each year, 100,000 children arrive at emergency departments with severe sepsis. More than 2,500 of them die, 25 times more than the number of children who die from the flu each year.
Previous research has shown that quickly hydrating children who come to the ED with sepsis is critical to improving their outcomes. The two main choices for hydration are normal saline and lactated ringers. Normal saline is just what it sounds like — a saltwater solution. Lactated ringers is similar to normal saline, but is considered a balanced crystalloid solution because it contains other electrolytes that more closely approximate those found in blood and tissues.
In recent years, adult studies have shown a slight but significant benefit of lactated ringers over normal saline, but to date, no evidence exists to show if this might be true for children.
“Both normal saline and lactated ringers are effective for hydrating pediatric patients with sepsis,” says Julia Lloyd, MD, attending emergency medicine physician and site principal investigator at Nationwide Children’s for the PROMPT Bolus study. “But is one safer? We don’t know. Adult studies show clinical evidence for lactated ringers in adults, with a small but meaningful reduction in major adverse kidney events and hospital mortality. However, no trial has compared the effectiveness of different crystalloid fluid types for resuscitation in children with sepsis, and the two largest observational pediatric studies reported conflicting results.”
The PROMPT Bolus (PRagMatic Pediatric Trial of Balanced vs nOrmaL saline flUid in Sepsis) study is designed as a randomized trial to compare the two options. The protocol, first developed as a pilot at Children’s Hospital of Philadelphia and later published in the Academy of Emergency Medicine, has now been extended to a national study through PECARN.
Using EFIC, the pilot study had 85% enrollment of eligible patients; of those, 98% completed the study. PROMPT Bolus will enroll children (age 6 months to 18 years) who come into the ED with suspected sepsis. These children will be randomly assigned to two groups: normal saline or lactated ringers. All other tests, medicines and care will be given according to the normal routines of the hospital.
“If a patient is coming in with sepsis, they’re going to receive one of these two fluids anyway,” says Dr. Lloyd. “The difference with the study is that an envelope will tell us which to give and enable us to collect the data needed to find out if one is better than the other or if they really are equally effective.”
This article appears in the 2022 Spring/Summer print issue. Download the full issue.
Balamuth F, Kittick M, McBride, Woodford AL, Vestal N, Casper TC, Metheney M, Smith K, Atkin NJ, Baren JM, Dean JM, Kuppermann N, Weiss SL. Pragmatic pediatric trial of balanced versus normal fluid in sepsis: the PRoMPT BOLUS randomized controlled trial pilot feasibility study. Academy of Emergency Medicine. 2019 Dec;26(12):1346-1356.
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