New Data Show Two Common Strategies for Early Treatment of Low Blood Pressure in Sepsis Are Equally Effective

Written by: Jacqueline Mitchell Contact: Chloe Meck,

JANUARY 21, 2023

Third Leading Cause of Death Claims 350,000 Lives Annually in the United States

BOSTON – The third leading cause of death in the United States after heart disease and cancer, sepsis is a life-threatening response to infection that occurs when the immune system begins to attack the body’s own tissues. Sepsis can lead to tissue damage, organ failure and death.

As sepsis becomes more severe, it is often accompanied by low blood pressure, also called hypotension. Physicians commonly rely on one of two methods to treat patients with low blood pressure caused by sepsis: either administering intravenous (IV) fluids to increase blood volume or drugs called vasopressors which raise blood pressure by constricting dilated blood vessels. While each treatment has known advantages and potential downsides, limited data exist to guide specific use of intravenous fluids or vasopressors in the early care of patients with low blood pressure in sepsis.

In a trial conducted by the National Heart, Lung, and Blood Institute sponsored Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, a team led by Nathan I. Shapiro, MD, MPH, of Beth Israel Deaconess Medical Center (BIDMC) and Ivor S. Douglas, MD, of the University of Colorado and Denver Health Medical Center, compared the two strategies for early treatment of sepsis-induced hypotension in more than 1,500 patients treated at 60 US medical centers. The findings, published in the New England Journal of Medicine, found that neither treatment resulted in significantly lower or higher mortality before discharge home by day 90.

“Early recognition of sepsis allows for the delivery of therapies, which highlights the need for prompt action,” said Shapiro, an emergency medicine physician at BIDMC. “Both the administration of large volumes of fluid with later use of vasopressor medications (a fluid liberal approach), as well as administering less intravenous fluids and relying on vasopressor medications earlier (a fluid restrictive approach) are common practices during the initial phase of sepsis management. However, the lack of robust data to guide whether liberal or restrictive approaches in early sepsis care leads to better outcomes has contributed to practice variability. The goal of this trial was to provide evidence to assist physicians in selecting the best treatment approach.”

Between March 2018 and January 2022, the study team enrolled 1,563 adult patients 18 years and older at 60 US medical centers. Participants were randomly assigned in a 1:1 ratio to receive either a fluid liberal treatment protocol (uses larger amounts of fluids and later vasopressor use) or a fluid restrictive (lesser amounts of fluids with early vasopressor use). The trial’s protocol allowed for bedside clinicians to titrate the resuscitation based on the clinical condition of the patient and specified that each patient’s clinical team could override the assigned care instructions at any time if it was judged to be in the best interest of the patient. Patients in both groups other received standard of care treatments for underlying infections and organ failures related to sepsis.

“The goal of initial fluid liberal therapy is to increase depleted or functionally reduced intravascular volume often present in sepsis, which can counter the organ damage that can occur,” said Shapiro, who is also a professor of emergency medicine at Harvard Medical School. “However, fluid administration may also lead to excess fluid in the lungs and other organs. Meanwhile, vasopressor agents are commonly used to treat sepsis-induced hypotension by constricting blood vessels, but this also comes with certain risks, such as increased cardiac workload and arrhythmias.”

The researchers evaluated for mortality from any cause before patient discharge home by day 90. Amongst survivors, they evaluated how many days patients were free from ventilator use, renal-replacement therapy, and vasopressor use, how many days they were out of the ICU and how many days they were out of the hospital. They also collected data on adverse effects, such as the onset of new arrhythmias or complications related to catheter use.

A total of 781 patients were assigned to the fluid liberal group; 782 underwent fluid restrictive treatment. Results between the groups were strikingly similar, with death occurring in 109 (14.0 percent) in the restrictive group and 116 (14.9 percent) in the liberal group. Likewise, the number of adverse events was similar in each group.

“We detected no significant difference in mortality before discharge home by day 90, suggesting that for the types of patients enrolled in this trial, the prioritization of either a vasopressor predominant or fluid predominant approach resulted in similar patient-centered outcomes,” Shapiro said. “It is possible that subgroups may exist — defined according to more sophisticated methods with the use of clinical or biologic measurements — where there is a preferential treatment for one approach or the other. Future initiatives may assess for these types of subgroups and differential treatment effects.”

Co-authors included Daniel Talmor, MD, of BIDMC; Douglas Hayden, PhD, Weixing Huang, MSPH, Poying Lai, MS, Katherine Oldmixon, RN, Nancy Ringwood, BSN, and B. Taylor Thompson, MD, of Massachusetts General Hospital; Jay S. Steingruber, MD, of Baystate Medical Center; Adit A. Ginde, MD, MPH, of University of Colorado School of Medicine; Roy Brower, MD, and Theodore Iwashyna, MD, of Johns Hopkins University School of Medicine; Samuel M. Bown, MD, and Colin K Grissom, MD, of Intermountain Medical Center and the University of Utah; Matthew Exline, MD, of the Ohio State University Wexner Medical Center; Michelle N. Gong, MD, of Montefiore Medical Center; C. Terry Howe, MD, and Akram Khan, MD, of Oregon Health and Science University; Alan E. Jones, MD, of University of Mississippi Medical Center; Kathleen D. Liu, MD, of University of California San Francisco; Chadwick D. Miller, MD, of Wake Forest Baptist Medical Center; Pauline K. Park, MD, of University of Michigan Medical Center; Todd W. Rice, MD, Matthew W. Semler, MD, and Wesley H. Self, MD, MPH, of Vanderbilt University Medical Center; and Donald M. Yealy, MD, of University of Pittsburgh School of Medicine.

The lists of the members of the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) Investigators and the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network are provided in the supplementary appendix available on the New England Journal of Medicine website.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is the official hospital of the Boston Red Sox.

Beth Israel Deaconess Medical Center is a part of Beth Israel Lahey Health, a health care system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, more than 4,800 physicians and 36,000 employees in a shared mission to expand access to great care and advance the science and practice of medicine through groundbreaking research and education.