Harvard, Boston Children's scientists develop model to improve sepsis treatment

Scientists at the Wyss Institute at Cambridge, Mass.-based Harvard University and Boston Children's Hospital are developing a model for clinical monitoring designed to measure sepsis responses in pigs, according to a paper published in Advances in Critical Care Medicine.

Standard sepsis treatment involves giving patients antibiotics and fluids. Despite the prevalence of sepsis in hospitalized patients, no new therapies have been developed in the last three decades because sepsis treatments frequently fail in clinical trials.

Mice and baboons are regularly used to test drug candidates in preclinical trials. However, these animals are poor models for how humans respond to sepsis since they are often resistant to the pathogens that cause sepsis-inducing infections in humans.

The researchers chose to use pigs as their model since pigs' immune systems and blood clotting is similar to humans and their large size allows their vitals to be monitored in real time. However, even in studies involving pigs, the animals' responses to sepsis are not currently measured with the same criteria used in human clinical practice.

To solve this issue, the scientists developed a new approach for clinical monitoring created to measure sepsis responses in pigs. The scientists looked at several physiological signs and organ failure in pigs rather than analyzing whether the pigs died to help provide a more accurate preview of how sepsis drugs affect humans. Animal models are typically evaluated by whether the animal dies as a result of illness.

To evaluate sepsis in living infected pigs in a manner similar to human clinical assessment, the researchers created a swine-specific Sepsis-3 protocol with swine-specific Sequential Organ Failure Assessment, a measure that classifies the severity of sepsis.

To analyze the responses of the pigs' various organs in real time, the scientists infused Escherichia coli bacteria into 18 young Yorkshire pigs' blood and used the new protocols for evaluation. The researchers gave six pigs the bacteria while conscious, six while under anesthesia and six did not receive the bacteria but had the same procedures (four conscious and two anesthetized).

The scientists found increases in the total swine-specific SOFA scores among the conscious and anesthetized pigs were largely due to kidney and blood clotting failure, with two of the conscious animals developing acute kidney failure.

Of the anesthetized animals, three pigs were categorized as experiencing septic shock, which is the highest severity level in the ss-SOFA system. These findings suggest the effects of anesthesia need to be considered when evaluating responses to sepsis.

"Our system goes beyond simply measuring the effects of pathogen injection on inflammation and animal survival," said Mike Super, PhD, co-author and lead senior staff scientist at the Wyss Institute. "Because it mimics the life-threatening organ failure that is also seen in sepsis patients, it also might provide a better prediction of how sepsis therapies will perform in humans."

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