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PRoMPT BOLUS Resources
What is Exception From Informed Consent (EFIC)?
The U.S. Food and Drug Administration (FDA) is an agency of the federal government that oversees human research protection involving medicines. The FDA has created a set of special rules, called “Exception From Informed Consent” (EFIC), for clinical trials that apply to critically ill patients who require emergent therapy when prospective informed consent is not possible or may put the patient at risk for increased harm by delaying potentially life-saving therapies. Under some circumstances, there may not be time to seek prospective informed consent from every eligible patient and, in some cases, discussing a possible option to enroll in a study may itself cause dangerous delays in a person’s care. Nonetheless, many critically ill patients could benefit from enrollment into an appropriate clinical trial. Therefore, to ensure that clinical trials can be conducted for patients in emergency situations, the FDA established rules for EFIC that require special safeguards to ensure that most people would consider the study to be ethical and appropriate. These special rules allow research studies in certain emergency situations to be conducted without prospective informed consent.
EFIC can only be used when:
- The person’s life is at risk, AND,
- The best treatment is not known, AND
- The study might help the person, AND
- It is not possible to get permission:
- from the person because of his or her medical condition nor
- from the person’s guardian because there is a very short amount of time required to treat the medical problem
Before researchers can start a study using EFIC, they must provide information about the study to the community and get their feedback. We have conducted surveys and performed focus groups with CHOP families for our pilot study, and will extend this work to Pittsburgh for this phase of the study. Please fill out a short on-line survey / Complete una breve encuesta en línea.
Approximately 2,500 non-newborn children die from septic shock each year in the US and thousands more die worldwide. Despite widespread implementation of resuscitation protocols, contemporary studies still report 2-6% mortality for children with septic shock treated in the pediatric ED.
Crystalloids are the standard resuscitative fluid for septic shock. NS and LR are inexpensive, stable at room temperature, and nearly universally available with identical storage volumes and dosing strategies. Notably, both are also of proven clinical benefit in septic shock. However, NS is used in 80-95% of cases of pediatric septic shock, despite data supporting that LR resuscitation may have superior efficacy and safety.
NS contains a supra-physiologic concentration of chloride (1.5X that of plasma) and a strong ion difference (SID) of zero but is isotonic compared to extracellular fluid. Balanced solutions have less chloride, small amounts of additional electrolytes, and a higher SID due to the presence of an anion buffer. The high chloride content and low SID of NS has been associated with acute kidney injury (AKI), acidemia, hyperkalemia, vascular permeability, inflammation, coagulopathy, fluid overload, and death.
Buffered crystalloids, including LR, have demonstrated a 1-4% absolute mortality reduction and up to a 50% lower odds of dialysis compared to NS in observational and non-randomized interventional studies in adult sepsis. Nevertheless, because definitive conclusions have not been able to be drawn from existing observational and non-randomized studies, NS overwhelmingly remains the most commonly used fluid based on historical precedent (particularly in pediatrics).
In pediatrics, a recent propensity-matched analysis of 2,398 patients in the PHIS database found a 2% lower mortality for children receiving LR versus NS. Conversely, in our matched analysis of 4,234 children with septic shock from 382 hospitals in the Premier Healthcare Alliance, we could not demonstrate superiority of LR or NS. However, we noted that highly selective use of LR made it impossible to fully eliminate confounding factors and we concluded that these retrospective data are best used to support equipoise rather than declare NS and LR to be of equal benefit. To definitively test the comparative effectiveness of NS versus LR, a well-powered randomized controlled trial (RCT) is necessary.
Frequently Asked Questions
Sepsis is a potentially life threatening response to infection that
- Affects over 70,000 children in the United States every year
- Can happen to someone of any age
- Can cause damage to many of the body’s organs
- Can prevent a person from being able to function normally or independently
- Can limit awareness and cause coma
- Can cause death
Sepsis is treated with emergency therapies that include antibiotics and fluids, usually given through an IV. The most common place for sepsis to be treated when it occurs in the community is in an emergency department (ED).
If a child is enrolled in PRoMPT BOLUS, they will be randomly assigned during their ED visit (like the flip of a coin) to receive either NS or LR IV fluids as part of their sepsis treatment. They will then receive study fluid as their treatment fluid during the remained of their ED visit and for up to 48 hours of their hospitalization if they are admitted to the hospital. The child’s doctors will determine when to give fluid and how much fluid to give, just as they would for a child not in the study.
Both NS and LR are electrolyte solutions- forms of salt water- that are safe, FDA-approved, and commonly used to treat sepsis. At CHOP, about half of children admitted to the Pediatric Intensive Care Unit (PICU) are treated with NS and half are treated with LR. The chemical composition of NS and LR are slightly different in that NS has only sodium and chloride, while LR contains less sodium, less chloride, and also has small amounts of other electrolytes like calcium and potassium.
Although both NS and LR are safe, FDA-approved, and commonly used to treat sepsis, nobody knows for sure whether one fluid is more effective and safer to treat sepsis than the other. Several prior studies have suggested that LR may be superior to NS, but a clear determination cannot be made without a large clinical trial. In pediatrics, NS is generally the preferred fluid used to treat sepsis but LR is also commonly used, especially for children in Pediatric Intensive Care Units (PICU). However, nobody yet knows for sure which fluid is safer or more effective.
Because both fluid types are effective, safe, and recommended for treatment of sepsis, all children in this study will receive standard care, regardless of which fluid is given. But because, as part of this study, you will be randomly assigned (like a “flip of a coin”) to receive either NS or LR rather than your doctor selecting which fluid to give you, you may receive a fluid that you might not have otherwise received. If there are differences in effectiveness and safety between these two fluids, then length of stay in hospital or other outcomes may be different depending on the fluid you receive and one fluid may have higher mortality than the other.
NO. Decisions about when and how much fluid a child receives, as well as any other medications that they might need will not be affected by the study. These will be decided by the treatment team as they normally would for any child with possible sepsis.
A subject is free to withdraw from study participation at any time by contacting the study team either in person or by email: ProMPTBOLUS@email.chop.edu
We encourage you to contact us with any questions/concerns and/or complete an online survey, so that we may work together to share information about patient enrollment through EFIC and learn from each other.
If you would like to opt your child out of the study so that they would not be included if they developed possible sepsis, please fill out this form. Any patient who has opted out will be mailed a bracelet that they must wear for the duration of the study so that they will not be enrolled even if they present any study site.