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Cardiac Arrest Research Leading the Way to Individualized CPR
mccannn [at] email.chop.edu (By Nancy McCann)
Children’s Hospital of Philadelphia investigators are moving beyond the one-size-fits-all cardiopulmonary resuscitation (CPR) guidelines by extending blood pressure-directed CPR through the development of next generation strategies and noninvasive monitors that can guide CPR on a second-to second basis, modulating it to each individual. They are also developing stabilizing therapeutics that aim to limit brain injury from lack of oxygen during cardiac arrest.
Each year, thousands of hospitalized children experience cardiac arrest. While survival outcomes of in-hospital pediatric cardiac arrest have improved over the last decade, fewer than 50 percent of these children will live to be discharged with their families. For those who do survive, devastating brain injury will complicate care.
“We know we can save children with good CPR,” said Todd Kilbaugh, MD, anesthesiologist, intensivist, and co-director of the Center for Pediatric Resuscitation at CHOP, “but now we want to develop drugs and therapeutics that will stabilize their injury both from their heart and their brain. We do this by creating a window into the brain with the use of noninvasive and minimally invasive techniques, allowing us to see the brain and heart in real time, at a level that we’ve never been able to do.”
As leaders in pediatric resuscitation science, Dr. Kilbaugh and Robert Sutton, MD, MSCE, critical care physician and co-director of the Center for Pediatric Resuscitation at CHOP, are building the framework for a new resuscitation training and research program for resuscitation science at the Research Institute.
The primary goal of CHOP’s translational resuscitation program is to create a syndicate of many researchers in order to accelerate novel, first-in-human clinical trials of therapeutics, diagnostics, and devices through collaborative scientific platforms that range from basic science to understand mitochondria genomics, to neuro diagnostics, to computational biology.
“The investment in the new Center for Resuscitation Science and the focus on resuscitation and CPR, illustrates how CHOP is pushing the cutting edge every single day,” Dr. Kilbaugh said. “If you can keep patients alive long enough to get them the therapies they need, and at the same time limit neurologic injury and give them a return to the same life — that’s the goal.”
Noninvasive Methods for Monitoring CPR Quality
When an in-hospital pediatric cardiac arrest occurs, clinicians are able to monitor blood pressure directly and in real-time — if the patient has an arterial line in place — making high quality CPR possible. The major limitation: Only about half of the children who arrest in hospitals have a catheter in their arteries.
To address this shortcoming and extend the idea of physiologic-directed CPR, Drs. Sutton and Kilbaugh are investigating using noninvasive monitors — some already in clinical use — to determine if they can be used to monitor CPR quality.
Take for instance the pulse oximeter, or as Dr. Sutton refers to it, “the little E.T. phone home red light that attaches to your finger.” It’s a noninvasive method for monitoring a person’s oxygen saturation. Any child requiring emergent medical care will be monitored with a pulse oximeter, Dr. Sutton said.
“When we’re doing CPR on kids, we always feel good if the pulse ox gets a reading because you need a pulse to have a pulse ox tracing,” said Dr. Sutton, also associate professor of Anesthesiology and Critical Care, at the Perelman School of Medicine in the University of Pennsylvania. “We think the CPR is good if we can generate a reading, but we really don’t know exactly what this means.
“That’s what our CPR-NOVA project is all about: using NOn-invasive waVeform Analytics (NOVA) through a collaboration with Villanova University to look at characteristics in pulse ox tracings, such as amplitude, or height of the tracing, and use sophisticated machine learning analytics to infer what the blood pressure would be,” Dr. Sutton said. “With development, there is a real possibility that a provider could receive near instant feedback regarding the quality of their CPR based on a patient’s physiologic response.”
This ancillary research will leverage the existing infrastructure of the National Institute of Child Health and Human Development-funded Collaborative Pediatric Critical Care Research Network (CPCCRN) and the unique hemodynamic waveform database of the National Heart, Lung, and Blood Institute-funded parent grant — the ICU-Resuscitation (ICU-RESUS) Project, which Dr. Sutton is also leading. The ICU-RESUS clinical trial aims to determine if a novel patient-centric resuscitation care improvement bundle, consisting of bedside CPR training and multidisciplinary reviews of each cardiac arrest, improves CPR quality and survival outcomes in a multicenter trial. In its final year, this trial will provide the clinical evidentiary support for disseminating the blood pressure directed CPR approach.
As the study team collects blood pressure waveforms in the ICU-RESUS project, they also note the simultaneously recorded blood pressure and the simultaneously recorded pulse ox tracing. The next step is to apply machine learning to find characteristics in the pulse oximeter tracings that are associated with good blood pressures.
“Once we know those characteristics, that algorithm could be built into a module that can go to the bedside of every patient in-and-out of hospital and be used to monitor the quality of resuscitation in kids — a great example of how the Center plans to translate quickly promising lab findings to the bedside of patients,” said Dr. Sutton, chair of the Resuscitation Committee and medical lead of the Preventing Codes Outside the ICU Initiative at CHOP. These operational leadership roles help Dr. Sutton ensure that promising research findings reach patients.
Individualized CPR Leads to Mitochondrial Targeted Therapeutics
Dr. Kilbaugh’s NIH supported research, “Improving Pediatric Cardiac Arrest Survival and Neurologic Outcome,” focuses on developing innovative techniques to target resuscitation with noninvasive imaging with fellow CHOP collaborators, Daniel Licht, MD; Wesley Baker, PhD; Tiffany Ko, PhD; Misun Hwang, MD; and Ryan Morgan, MD, MTR. It also concentrates on how to tie together cardiac arrest with the physiologic needs of the patient’s brain and then to develop mitochondrial targeted therapeutics for neuro protection and brain regeneration.
The research team’s fundamental idea is that mitochondria play a significant role in controlling cell injury within the brain. If mitochondria are healthy, then the brain cells tend to persevere and overcome injury. Dr. Kilbaugh is learning where these mitochondria are injured during cardiac arrest, in order to develop pharmacologic approaches that can target mitochondrial deficits in the brain after cardiac arrest. Stabilizing and healing the brain by supporting mitochondrial health could lead to better neurologic outcomes.
“The grant takes a look at how well we deliver high quality CPR to each individual,” said Dr. Kilbaugh, also on faculty at Perelman School of Medicine at Penn. “We do that by creating a window into the brain for the use of noninvasive techniques — both optical and contrast enhanced ultrasound, which allows the clinician to view the microvascular circulation in the brain. Then we develop therapeutics that are targeted at mitochondrial health within the brain.
“We’re also developing diagnostics to understand each individual’s brain injury by measuring biomarkers of brain injury that leak into the peripheral bloodstream,” Dr. Kilbaugh added. “Dr. Sutton and I create living-innovation incubators to access the wealth of talent at CHOP, the University of Pennsylvania, and collaborators across the globe.”
Biomedical Optical Devices to Monitor Cerebral Health
Named a Frontier Program in 2019, Biomedical Optical Devices to Monitor Cerebral Health, co-led by Drs. Kilbaugh, Licht, and Baker, has the goal of developing an optical device that could revolutionize cardiac resuscitation by providing real-time feedback to the person performing CPR. The instrument, via a small rubber pad that sticks to the patient’s forehead, will be able to sense oxygen demand, oxygen delivery, and metabolic alterations within the brain using optical light, and then relay that information back to the care provider.
“We envision it would provide a green light/red light to rescuers on whether their chest compressions adequately perfuse the brain,” said Dr. Baker, a physicist in the Wolfson Family Laboratory for Clinical and Biomedical Optics.
The research team is also developing this technology to be used with Extracorporeal Membrane Oxygenation (ECMO) — a mechanical pump that provides life-sustaining oxygenation to the body via a modified cardiopulmonary bypass machine to critically ill patients who do not respond to conventional management.
They aim to develop an algorithm that continually adjusts, through artificial intelligence, the ECMO pump delivery based on feedback from optical monitoring of cerebral blood flow and metabolism. Through ensuring optimal brain perfusion on an ongoing basis, the biomedical optical device would individualize the ECMO treatment and could improve neurologic outcomes.
“Ultimately, our goal is to limit neurologic injury and return (recovered cardiac arrest patients) home — to their families and lives — the same children before they were entrusted into our care,” said Dr. Kilbaugh, medical director of the ECMO Center at CHOP.