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  5. Biokinetic modeling of hemolysis and renal injury in cardiopulmonary bypass patients: Establishing safety acceptance criteria for blood damage caused by medical devices
  1. Advancing Regulatory Science

Biokinetic modeling of hemolysis and renal injury in cardiopulmonary bypass patients: Establishing safety acceptance criteria for blood damage caused by medical devices

CERSI Collaborators: University of Maryland Baltimore (UMB): Paul W. Buehler, Pharm.D., Ph.D.

FDA Collaborators: : Center for Devices and Radiological Health (CDRH): Richard Malinauskas, PhD; David Saylor, PhD

Project Start Date: Nov 13, 2020
Project End Date: July 31, 2023

Regulatory Science Challenge

To meet FDA’s Center for Devices and Radiological Health (CDRH) regulatory requirements, blood-contacting medical devices are evaluated for patient safety. Hemolysis, the breakdown of red blood cells resulting in the release of hemoglobin, is assessed in medical devices by simulating their clinical use in laboratory studies using animal blood. Hemoglobin released from damaged red blood cells into the plasma (i.e., free hemoglobin), is toxic. Therefore, hemolysis can lead to negative health outcomes in patients, such as injury to the kidneys. Due to wide variability in the design, intended use, and testing of blood-contacting medical devices, the FDA and industry have not established safety standards for acceptable levels of free hemoglobin during benchtop testing.

To address this regulatory gap, researchers initiated a study to establish the hemoglobin blood damage levels that affect patients undergoing heart-lung bypass procedures. Researchers collected detailed data on biomarkers (a biological molecule that is an indicator of disease or other conditions, normal or abnormal) of hemolysis and acute kidney injury from individual adult UMB surgical patients to extend computational modeling efforts to establish safety acceptance criteria for blood damage levels.

Project Description and Goals

This project studied the effects of medical devices on red blood cell damage. Extended use of medical devices, such as blood pumps used in heart surgery, can lead to red blood cell damage and leakage of their contents into the body’s circulation. Hemoglobin is the primary component of red blood cells that can lead to tissue toxicity, particularly acute kidney injury. This study had three goals directed at understanding the relationship between medical devices, red blood cell injury, and kidney injury:

Goal 1: Determining the time-varying concentrations of biomarkers of hemolysis in individual adult patients undergoing long-term cardiopulmonary by-pass procedures.

Goal 2: Determining the presence and severity of acute kidney injury using qualified biomarkers associated with free hemoglobin and toxin exposure in patients following complex cardiopulmonary bypass surgery.

Goal 3: Developing a computer-based model of cell-free hemoglobin and protective plasma proteins that can predict the onset and severity of acute kidney injury in surgical patients.

Research Outcomes/Results

Through a collaboration between Dr. Paul W. Buehler (UMB) and the FDA’s Center for Devices and Radiological Health, Office of Science and Engineering Labs, Division of Applied Mechanics, two pre-CERSI funded studies were previously conducted to computationally model free-hemoglobin biokinetics based on limited published patient data, and to relate free-hemoglobin levels to renal injury in acutely exposed guinea pigs (1, 2). These studies provided a unique insight into the relationship between free-hemoglobin and kidney injury and set the groundwork for determining safety levels after extended exposure to some blood-contacting medical devices.

Research Impacts

The FDA regulatory science areas include the following:

Modernize Toxicology to Enhance Product Safety - This project aimed to improve FDA’s ability to establish clinically validated in vitro and in vivo safety acceptance criteria for hemolysis levels caused by a variety of blood-contacting medical devices in complex cardio-pulmonary bypass surgeries with durations of 2-4 hours.

The anticipated impacts of this research are to:

  1. Promote a better understanding of toxicity mechanisms by red blood cell-free hemoglobin generated during medical device use.
  2. Develop computational models that are predictive of human toxicological response.
  3. Provide novel testing strategies to identify when hemoglobin levels become high enough to warrant therapeutic intervention.
  4. Help establish safety acceptance criteria for blood-contacting medical devices to assist device innovation by accelerating evaluation by industry and the FDA.

Related Publications

  1. Saylor DM, Buehler PW, Brown RP, Malinauskas RA. Predicting Plasma Free Hemoglobin Levels in Patients Due to Medical Device-Related Hemolysis. ASAIO J 2019;65: 207-18.
  2. Baek JH, Yalamanoglu A, Brown RP, Saylor DM, Malinauskas RA, Buehler PW. Renal Toxicodynamic Effects of Extracellular Hemoglobin After Acute Exposure. Toxicol Sci 2018;166: 180-91.
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