A significant nationwide trial comparing two early therapies for the management of patients with sepsis, the body’s catastrophic reaction to an uncontrolled infection, was headed by Vanderbilt University Medical Center.
A vasopressor, a medication that causes the blood vessels to constrict, and/or intravenous (IV) fluids are frequently used to treat the dangerously low blood pressure that can result from sepsis. Vasopressors or IV fluids should be used as the primary treatment for sepsis-induced low blood pressure, however this question has been debatable for decades without a definitive conclusion.
In the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial, investigators compared these two approaches for treating sepsis. The outcomes of the trial, which were reported in the New England Journal of Medicine, showed that survival rates were essentially comparable whether high amounts of fluid were administered during resuscitation or smaller volumes of fluid were administered when more vasopressors were used.
“Sepsis is one of the most common causes of death worldwide,” said Wesley H. Self, MD, MPH, Senior Vice President for Clinical Research at VUMC and senior author of the study. “There have never been good data to inform us on what volume of fluid we should be giving to our sickest septic patients and when we should be starting vasopressors,” he said.
“The CLOVERS trial results are important because they provide strong data showing that supporting blood pressure with either IV fluids or vasopressors can result in similar outcomes,” Self said. “To me, these results emphasize that rapidly achieving a normal blood pressure and systemic perfusion may be more important than the method used to achieve that normal blood pressure.”
The United States sees at least 1.7 million adult cases of sepsis annually, and at least 350,000 people pass away from the condition, according to the Centers for Disease Control and Prevention. Approximately one in three people who die in U.S. hospitals have sepsis.
Sepsis is just one of hundreds of acute illnesses. We should be doing the same type of research for gastrointestinal bleeds and acute respiratory failure and trauma, and not just in the hospital but in the clinic. We can’t recommend and prescribe treatments without knowing for certain how well they work. We have to compare them to see which is best.
The CLOVERS trial enrolled 1,563 adults with septic shock at 60 medical centers across 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 run 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, clinicians debated about whether prioritizing fluid for resuscitation or initiating vasopressor therapy earlier was best for patients with septic shock,” Rice said. “This trial demonstrates that both are acceptable treatment options and result in similar clinical outcomes. The CLOVERS trial represents the first trial to address this question in patients with septic shock, and the results are highly informative for clinicians caring for these patients,” he said.
“The two approaches that we compared in the study are common in current clinical practice, but if you had two physicians treating a patient, they might not agree on the best approach,” Semler said. “The trial aimed to determine if one of the approaches produced better outcomes than the other. It’s difficult to make progress in the treatment of sepsis. Studies over the past 30 years have evaluated new drugs to treat sepsis, but none have worked. We think optimizing the use of treatments we already have may be a key to improving outcomes for patients with sepsis.”
“VUMC’s Center for Learning Healthcare and others are pushing researchers to not just look at potential new drugs, but to compare existing treatments to understand how to best use them.”
Semler said there are still many unanswered questions about the treatment of patients with sepsis, including:
- Is it possible to personalize the amount of IV fluid given to each patient? Could it be that some patients need more and some need less?
- There are different types of fluids. Which should be used?
- What vasopressor should be used and when should it be started?
- What is the target blood pressure that should be achieved?
- Which antibiotics result in the best outcomes?
Semler said that questions like these are the focus of the Center for Learning Healthcare, which brings together clinicians, health system operations leaders and researchers to generate evidence in the course of health care delivery to continuously improve the quality, value and safety of health care offered to patients.
The specific interventions used may not have a significant impact on the outcome of sepsis treatment, and that other factors (such as the severity of the patient’s condition or the timing of treatment) may be more important.
“Sepsis is just one of hundreds of acute illnesses. We should be doing the same type of research for gastrointestinal bleeds and acute respiratory failure and trauma, and not just in the hospital but in the clinic,” Semler said. “We can’t recommend and prescribe treatments without knowing for certain how well they work. We have to compare them to see which is best.”
