Wake Forest University School of Medicine has received a five-year, $3.8 million grant from the National Heart, Lung and Blood Institute to study a new approach to treating septic shock, a life-threatening condition that remains the leading cause of death in intensive care units worldwide.
The clinical trial will be led by Ashish K. Khanna, M.D., professor of anesthesiology and surgery (hypertension) and vice-chair of research in the department of anesthesiology, division of critical care medicine, and Mark C. Chappell, Ph.D., professor of hypertension and surgery.
Septic shock occurs when an infection triggers an overwhelming immune response, causing dangerously low blood pressure and reduced oxygen delivery to organs. Even with advanced critical care, mortality rates remain close to 40%.
“You have a very short window to treat these patients before they decline,” Chappell said.
Today, nearly all patients with septic shock receive the same first-line therapy: fluids and norepinephrine, a drug that tightens blood vessels to raise blood pressure. However, early research suggests that some patients may benefit more from Angiotensin II, a medication that works through a different biological pathway.
Under normal conditions, the body relies on the Renin-Angiotensin System, a hormone pathway, to maintain blood pressure. During septic shock, this system attempts to compensate but often fails.
“It’s like having a flat tire,” Chappell said. “You keep pumping air in, but there’s a leak and the pressure keeps falling.”
In many patients, renin levels rise, indicating the system is trying to activate, but the body cannot produce enough Angiotensin II to restore blood pressure. This imbalance may also impair immune function.
For the study, researchers will enroll 78 patients at Atrium Health Wake Forest Baptist Medical Center in Winston-Salem, Atrium Health High Point Medical Center in High Point and Massachusetts General Hospital in Boston. After initial therapy with fluids and norepinephrine, participants will be randomly assigned to receive either Angiotensin II or additional norepinephrine.
Researchers will measure how well each treatment restores the Renin-Angiotensin System (RAS), track immune function and monitor safety. They will also explore whether Angiotensin II helps white blood cells clear infection more effectively than standard care.
“If Angiotensin II not only raises blood pressure but also corrects a key RAS imbalance and boosts immunity, it could truly change how we treat these patients,” Khanna said.
Earlier studies in mice suggested Angiotensin II improves bacterial clearance by enhancing neutrophils, a type of white blood cell. A 2017 New England Journal of Medicine trial, where Khanna was a lead author, showed that more than 70% of patients with vasodilatory septic shock responded to Angiotensin II, and those with high renin levels had better survival rates. Additional analyses found renin and angiotensinogen that form Angiotensin II were stronger predictors of poor outcomes than lactate, the current standard biomarker.
“Renin tells us the system is trying to activate,” Chappell said. “Lactate shows tissues aren’t getting oxygen, but it doesn’t guide treatment. Renin might help us match patients to the right therapy.”
Khanna said the trial will answer three key questions:
- Does Angiotensin II repair the damaged blood pressure system better than norepinephrine?
- Which parts of the system are most linked to risk of death?
- Does Angiotensin II boost immune response?
If results are promising, they could lead to a larger trial and bedside tests for renin levels. Patients with high renin could receive Angiotensin II as primary therapy, moving toward a precision medicine approach.
“The biggest misconception about septic shock is that one size fits all,” Khanna said. “We owe our patients better outcomes. Matching treatment to each patient’s profile could be the key.”