Sepsis-Induced Hypotension: Study Compares Fluid Strategy Interventions

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Vanderbilt University Medical Center played a leading role in a large national study designed to compare two early interventions in the treatment of patients with sepsis, the body’s severe response to an uncontrolled infection.

Sepsis can cause dangerously low blood pressure, which is usually treated with intravenous (IV) fluids and/or a vasopressor, a drug that causes blood vessels to constrict. Whether treatment of sepsis-induced low blood pressure should be treated primarily with intravenous fluids or vasopressors has been debated for decades with no clear answer.

In the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial, researchers compared these two approaches to treating sepsis. The results of the trial, which were published in the New England Journal of Medicine , demonstrated that both a resuscitation strategy that relied on the administration of large volumes of fluids and one that relied on lower volumes of fluids with increased use of Vasopressors led to almost identical survival .

 “Sepsis is one of the most common causes of death worldwide,” said Wesley H. Self, MD, MPH, senior vice president of clinical research at VUMC and lead author of the study. “There has never been good data to inform us about what volume of fluid we should give to our sickest septic patients and when we should start vasopressors,” he said.

“The results from the CLOVERS trial are important because they provide strong data showing that maintaining blood pressure with intravenous fluids or vasopressors can produce similar results,” Self said. "To me, these results emphasize that rapidly achieving normal blood pressure and systemic perfusion may be more important than the method used to achieve that normal blood pressure."

According to the Centers for Disease Control and Prevention, at least 1.7 million adults in the U.S. develop sepsis each year and at least 350,000 die from the disease. About one in three people who die in U.S. hospitals has sepsis.

The CLOVERS trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) and enrolled 1,563 adults with septic shock at 60 medical centers in the United States over about three years. The trial was designed and conducted by investigators as part of the Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network.

In addition to Self, key VUMC investigators who helped design and execute the trial were Matthew Semler, MD, MSc, and Todd Rice, MD, MSc, both in the Department of Medicine’s Division of Allergy, Pulmonary and Critical Care Medicine.

"Prior to this study, doctors debated whether prioritizing fluids for resuscitation or starting vasopressor therapy earlier was best for patients with septic shock," Rice said. “This trial demonstrates that both are acceptable treatment options and have similar clinical outcomes. The CLOVERS trial represents the first trial to address this question in patients with septic shock, and the results are very informative for physicians caring for these patients,” she said.

“The two approaches we compared in the study are common in current clinical practice, but if two doctors treated a patient, they might not agree on the best approach,” Semler said. “The trial aimed to determine whether one of the approaches produced better results than the other.

“It is difficult to advance in the treatment of sepsis. Studies over the past 30 years have tested new medications to treat sepsis, but none have worked . “We believe that optimizing the use of the treatments we already have can be key to improving outcomes for patients with sepsis.”

VUMC’s Center for Healthcare Learning and others are pushing researchers to not only look for potential new drugs, but to compare existing treatments to understand how to best use them.”

Semler said there are still many unanswered questions about treating patients with sepsis, including:

• Is it possible to customize the amount of intravenous fluid given to each patient? Could it be that some patients need more and others less?
• There are different types of fluids. Which one should be used?
• Which vasopressor should be used and when should it be started?
• What is the target blood pressure to achieve?
• Which antibiotics give the best results?

Semler said questions like these are the focus of the Center for Learning Healthcare , which brings together physicians, health system operations leaders and researchers to generate evidence in the course of healthcare delivery to continually improve quality, value and the safety of medical care offered to patients.

“Sepsis is just one of hundreds of acute illnesses. “We should be doing the same type of research for gastrointestinal bleeding and acute respiratory failure and trauma, and not just in the hospital but in the clinic,” Semler said. “We cannot recommend and prescribe treatments without knowing with certainty how well they work. We have to compare them to see which one is the best.”