Ebola: Aggressive Hydration Key to Effective Treatment in US

Laurie Barclay, MD

November 13, 2014

The first two Americans diagnosed with Ebola virus disease (EVD), Kent Brantly, MD, and Nancy Writebol, were transferred from Liberia to the United States in August for care that likely contributed to their survival. Now, the treating clinicians and Dr Brantly himself describe the course of care and recovery in a brief report published online November 12 in the New England Journal of Medicine.

"EVD causes a nonspecific febrile illness associated with myalgia, with progression to gastrointestinal symptoms (abdominal pain, nausea, vomiting, and diarrhea)," write G. Marshall Lyon, MD, from the Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, and colleagues. "In the second week of illness, hemorrhagic symptoms and sepsis may develop." The current estimated fatality rate for the Ebola strain responsible for the current infection is 78%, the authors note.

One of the two patients was also diagnosed with and treated for malaria early in the course of EVD. Both patients had significant intravascular volume depletion and electrolyte abnormalities of hypokalemia, hypocalcemia, and hypoalbuminemia, and hyponatremia was also seen in one patient. These symptoms responded to aggressive supportive hydration with 3 to 5 L intravenous fluids daily, given early in the course, and electrolyte correction emphasizing replacement of potassium and calcium.

Although the authors say they think the aggressive hydration was important, they caution that vascular leak syndrome can lead to fluid pooling elsewhere, including plural effusions. Therefore, the investigators suggest that fluid replacement be adjusted on the basis of respiratory status. They note that most intravenous fluids recommended for rehydration lack sufficient potassium, calcium, and magnesium and that rehydration with commercial sports drinks may increase the risk for hypokalemia. They therefore suggest supplementing oral rehydration with oral potassium, calcium, and magnesium, especially in patients with large-volume diarrhea.

Both patients had thrombocytopenia, but neither had coagulopathy. Both had hypoalbuminemia and elevated alkaline phosphatase levels, which tend to be associated with increased mortality risk, as well as serum calcium levels near the levels predicting greater risk for death. One patient had significant liver injury but maintained good hepatic synthetic function and renal function.

Clinical improvement in both patients was associated with a corresponding decrease in viral load found in plasma. Both patients had detectable EBOV RNA until the fourth week of illness, which the investigators suggested could represent persistence of infectious virus, or just detectable RNA.

Experimental Treatments Used

Both patients received treatment with experimental monoclonal antibody (ZMapp, Mapp Biopharmaceutical and LeafBio) and improved both subjectively and objectively soon after receiving the first dose of the antibody cocktail. However, the clinical benefit of antibody therapy is unclear, as these patients simultaneously received other treatment. The investigators recommend controlled clinical trials to evaluate the efficacy of ZMapp for EVD.

Both patients received whole-blood transfusions in Liberia, and Dr Brantly received one unit of whole blood from an EVD survivor. However, the investigators note that controlled clinical trials are needed to determine whether convalescent serum from Ebola survivors is of therapeutic benefit.

"Our limited experience with two patients cannot be extrapolated to all patients with EVD," the study authors conclude. "However, intensive care nursing, aggressive oral and intravenous rehydration, electrolyte supplementation, and transfusion of blood products appeared to be critical for a positive outcome in our patients with EVD."

Challenges of EVD

In an accompanying editorial, Eric J. Rubin, MD, PhD, and Lindsey R. Baden, MD, from the New England Journal of Medicine, describe a third patient, who was transferred from Sierra Leone to Germany and was more profoundly ill. Despite profuse diarrhea requiring 30 L intravenous fluid replacement in the first 72 hours, bacterial sepsis, respiratory failure, and encephalopathy, the patient recovered and was discharged a month later.

The editorial notes the challenge of early diagnosis, as all three patients were treated initially for malaria, one patient did not have detectable Ebola virus RNA until day 4, and the other two patients were not tested until day 5 or 6. Testing for Ebola virus is often negative early in the course. In addition, the varied course of EVD hinders interpretation of case reports, case series, and uncontrolled studies of new treatments.

"Keeping health care workers and the broader community safe remains a daunting challenge, even in facilities, like those in Hamburg and Atlanta, dedicated to the care of patients with highly communicable diseases," Dr Rubin and Dr Baden write. "But it is important to note that these experiences show that patients with EVD can be cared for safely in properly prepared centers."

They recommend epidemiologic studies to determine the risk for transmission and markers for infectivity, and they highlight the importance of intensive fluid management and care.

"It will be a tremendous challenge to bring to all patients the benefits of routine care, such as intravenous fluid and electrolyte support, as part of the response to this epidemic, but it must be done," Drs Rubin and Baden conclude.

One of the study authors reports a patent related to monoclonal antibodies for Ebola and Marburg viruses (US 8513391 B2), which is licensed to Defyrus Inc. The other authors and the editorialists have disclosed no relevant financial relationships.

N Engl J Med. Published online November 12, 2014. Report full text, Editorial full text


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