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Precision, Lifesaving Care

The Question:

How to save more lives from cardiac arrest, circulatory collapse and respiratory distress?

It was a Monday morning in the Emergency Department at the Captain James A. Lovell Federal Health Care Center (FHCC) when the call came in: A 17-year-old girl in cardiac arrest was about to arrive by ambulance.

Dr. Raúl J. Gazmuri, a professor of medicine at Chicago Medical School and chief of the FHCC's ICU, quickly recognized that the barely responsive patient with undetectable blood pressure, despite 40 minutes of mechanical chest compression by paramedics, was not in cardiac arrest. An ultrasound showed a dilated right ventricle, and analysis of blood gases along with expired carbon dioxide showed a very large alveolar dead space — a condition that may occur when a segment of pulmonary circulation is occluded. The swift combination of careful observations and treatments that followed confirmed Dr. Gazmuri's preliminary diagnosis — massive pulmonary embolism. It also saved his patient's life.

Intravenous administration of the drug alteplase (tPA) was key. The drug, which helps break down blood clots, is also used to stop acute ischemic stroke.

"She could have died if she hadn't been diagnosed so quickly," Dr. Gazmuri said. "Who would run a code [resuscitative efforts] for an hour? Or she might have been placed on cardiopulmonary bypass, with more invasive attempts to save her life."

Dr. Gazmuri, an expert in the field of resuscitation and critical care medicine, has presented on and treated other cases of massive pulmonary embolism, an event that if it kills often does so within the first hour after onset of symptoms. He and his FHCC team authored a paper on their experience, "Circulatory collapse, right ventricular dilatation and alveolar dead space: A triad for the rapid diagnosis of massive pulmonary embolism," which appeared in the December 2016 issue of American Journal of Emergency Medicine.

As director of RFU's Resuscitation Institute, Dr. Gazmuri is leading research expected to help generate novel therapeutic interventions for resuscitation from cardiac arrest and circulatory shock. He's in the preliminary stages of developing a biomedical startup based on his research and clinical approaches.

How do we move forward these ideas so that they can help people? A company can cross that barrier and move our approaches to the market. That's the whole incentive.

"We've developed many ideas over the years, in the institute, but also at the bedside and
through critical care that, at most, gets into a scientific journal," he said. "But how do we move
forward these ideas so that they can help people? A company can cross that barrier and move
our approaches to the market. That's the whole incentive."

Dr. Gazmuri is hoping to market a rich portfolio of ideas that includes drugs, some devices and other products — "for lack of a better term," he said — that are educational and that he calls "instant learning at the bedside."

"I have other ideas to add value to what we do at bedside, which is the intersection between quality and cost," he said. "The optimal intersection gives you value."

High on the list are drugs intended to target reperfusion injury during CPR. Reperfusion or reoxygenation injury happens when blood supply returns to the tissue after a period of ischemia or lack of oxygen.

"No one today is targeting reperfusion injury during CPR," Dr. Gazmuri said. "Current CPR drugs do not attempt to reduce injury to the heart and the brain suffered during resuscitation. That's what we've done at the Resuscitation Institute for many, many years."

He's investigating how to limit the entry of sodium into cells that have been ischemic and  are being reperfused during CPR through the use of sodium-hydrogen exchanger isoform-1  (NHE-1) inhibitors. While the inhibitors are not yet available clinically, the drug erythropoietin (EPO) — currently used to boost red blood cell production in chronic kidney disease — has been shown to act in a similar way to make cells more resistant to reperfusion injury.

Studies, including one funded by the Department of Veterans Administration, show it improves survival. The institute applied for and received a use patent and the repurposed drug could lead the planned startup.

"If we are able to succeed with EPO based on our animal work and clinical study, we could improve on the 12 percent out-of-hospital survival rate for cardiac arrest," Dr. Gazmuri said. "We think we can push that number to 20 percent. We're hoping a startup will be a better vehicle to deliver these lifesaving drugs to the community."

He also plans to pursue, under his startup, development of an NHE-1 inhibitor drug for the treatment of cardiac arrest, and a smart compressor that would compress the chest while adjusting the mechanics based on input collected from the patient in real time.

Dr. Gazmuri completed a residency in internal medicine in his native Chile and arrived at RFU in 1986 as a research fellow in the lab of the renowned Dr. Max Harry Weil, often cited as the father of critical care medicine, who was conducting research in CPR.

The fellowship was a defining experience for the young physician, who always wanted to be  an intensivist. Dr. Weil mentored him through his PhD, which he earned from the School of Graduate and Postdoctoral Studies in 1994.

"Dr. Weil was a pioneer," Dr. Gazmuri said. "He challenged the status quo. He was always thinking ahead. He met with us fellows two or three times a week. I was very vocal and we argued back and forth — this little guy from Chile, arguing with the man who developed the field of critical care medicine — and he never told me to shut up. He always wanted to persuade me that he was right. I learned to respect the value of vigorous discussion."

It was in working with Dr. Weil that Dr. Gazmuri embraced the idea of personalized care, focusing on the individual patient, basing care decisions on changes in function observed at bedside. He eventually developed a "precision care" philosophy, which differs from precision medicine, a concept that grew out of the management of cancers.

We want to tailor resuscitation to the individual patient — the same thing that's happening in critical care medicine — bringing all the knowledge to the individual patient at the bedside, delivering what the patient needs at that particular time, no more, no less.

"Precision care takes into account the individual patient at a particular time; for instance,
the ability to recognize that someone who's in cardiac arrest might need a different way of
compressing the chest," he said. "Moving forward, we want to tailor resuscitation to the individual patient — the same thing that's happening in critical care medicine — bringing all the knowledge to the individual patient at the bedside, delivering what the patient needs at that particular time, no more, no less."

Dr. Gazmuri says that "research is an opportunity for serendipity." Based on the effect observed for cardiac arrest, he thought EPO could also improve survival in hemorrhagic shock, a big challenge in tactical combat casualty care, where administration of fluids must be minimized until bleeding is controlled. When EPO failed, he chose a different treatment — vasopressin infusion — which improved survival by nearly 90 percent, experiments showed. The institute will begin studying, under a three-year, $1.9 million Department of Defense (DOD) grant, the efficacy of vasopressin for the simultaneous treatment of hemorrhagic shock and traumatic brain injury, with the expectation that it will allow resuscitation with minimum fluid while also increasing blood pressure to perfuse the brain, preventing further injury.

Dr. Gazmuri's research is also focused on mitochondria, crucial cell organelles that help
regulate energy production, homeostasis and cell death. He and his longtime associate
Jeejabai Radhakrishnan, PhD, a molecular biologist at the Resuscitation Institute, discovered that a mitochondrial protein known as cyclophilin-D is key to the regulation of mitochondrial gene expression. He is collaborating with Professor John K. Buolamwini, BPharm, PhD, chair of pharmaceutical sciences in the College of Pharmacy, to help develop novel drugs.

"The idea is that, maybe in the future, we could manipulate mitochondria to improve oxygen efficiency," Dr. Gazmuri said. "If that's the case it will, perhaps, help someone to more quickly adapt to altitude, increase physical performance and help people with chronic conditions in which oxygen delivery is critical, like coronary artery disease and diabetes, and who might benefit if their tissues were more efficient in the utilization of oxygen."

Two grant applications to continue that work are pending, including one before the DOD.

This article first appeared in the Summer 2017 issue of Helix magazine.

Posted October 20, 2017
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