IV Fluids for Dengue Linked to Progression to Severe Disease

Daniel M. Keller, PhD

July 13, 2012

July 13, 2012 (Bangkok, Thailand) — A medical record review of adult patients with dengue but no evidence at baseline of plasma leakage or significant volume depletion suggests that such patients might not benefit from intravenous (IV) fluids if they can absorb oral fluids. In fact, IV fluids might increase the risk for severe disease.

Alex Cook, PhD, assistant professor at the School of Public Health and the Department of Statistics and Applied Probability at the National University of Singapore, told delegates here at the 15th International Congress on Infectious Diseases that IV fluid administration is an unsettled issue.

He explained that dengue virus infection can be asymptomatic, can cause flu-like illness, or can result in dengue hemorrhagic fever (DHF) or severe dengue. When patients in Singapore are admitted to the hospital, they are often badly dehydrated and get IV fluids. We wanted to know whether the IV fluid makes them better or worse, he explained.

In an observational cohort study, Dr. Cook and colleagues found that for dengue patients hospitalized from 2006 to 2008, those receiving more than 1 day of IV fluids were more likely to progress to severe manifestations. Of the patients presenting without DHF, 17% of those who received IV fluids went on to develop DHF, whereas only 8% of those who did not receive IV fluids did. Similarly, of patients presenting without severe dengue, 9% progressed to severe dengue if they received IV fluids, as did 2% of those who did not receive IV fluids.

Dengue and its manifestations are a continuum, and some patients will be more severely affected; "they are more likely to go on to get DHF or severe dengue, and they are also more likely to be given IV fluids," Dr. Cook said.

The researchers used statistical methods to try to "disentangle" the effect of IV fluids from the severity of the disease. They reviewed the medical records of 1529 adults with dengue but without DHF or severe dengue on admission to Tan Tock Seng Hospital in Singapore. Polymerase chain reaction, serologic tests, and other standard criteria were used to diagnose the dengue virus.

Using a statistical technique (penalized regression method), which adjusted for 98 potential demographic, clinical, and laboratory confounders, the researchers assessed the effect of maintenance IV fluids on the development of DHF and severe dengue, and on the length of hospital stay.

Of the 1529 study patients, 1346 were given IV fluids for 2 or more days and 183 were not given IV fluids. The patients getting IV fluids received a median daily volume of 3500 mL (interquartile range, 3050 to 7000 mL) for a median of 3 days. Dr. Cook noted that a weakness of the study is that only about 10% of the patients did not receive IV fluids.

After hospital admission, 248 patients (16%) developed DHF and 122 (8%) developed severe dengue. Patients who did not receive IV fluids had an adjusted odds ratio (OR) of 1.0 for developing severe dengue or DHF; patients who received IV fluids had a 3.6-fold greater risk of developing severe dengue (adjusted OR, 3.6; 95% confidence interval [CI], 1.1 to 12.0; P = .04).

Although the hospital stay for patients who received IV fluids was statistically significantly longer than for patients who did not, it was "about 10%, just a few hours, and we don't care much about that," Dr. Cook said. The patients receiving IV fluids also had a nonsignificant 40% greater risk of developing DHF (OR, 1.4; 95% CI, 0.75 to 2.8; P = .27).

Dr. Cook noted that "it would be valuable to repeat this [analysis] for other cohorts of patients to see whether the effect generalizes beyond Singapore, and to potentially do a clinical trial." He suggested that a 2-year single-center randomized clinical trial with 400 patients in each group (IV fluids or not) would be sufficiently powered "to demonstrate definitively" whether IV fluid administration increases the risk of developing severe dengue.

Thomas Grünewald, MD, PhD, assistant professor of internal medicine and head of the division of infectious diseases and tropical medicine at the Klinikum St. Georg in Leipzig, Germany, told Medscape Medical News that he treats European patients with 1 to 2 L of IV fluid/day for 4 to 6 days without problems.

"Usually patients with dengue fever come to the European clinics in very dry conditions, and because of the fever they have to get fluids.... It could be different in Asian countries or in South American countries," he said. "We try not to give them any antipyretics because of worse outcomes, which we know from malaria and similar diseases. They prolong the disease and sometimes pose more problems; patients have hepatitis, they have renal failure, and the antipyretics can increase these problems." These differences in practice might lead to "bias in the statistics [Dr. Cook] has shown," he explained.

Dr. Grünewald agrees that a randomized controlled clinical trial is a good idea, especially in a country with a large dengue burden. There is "no other way to check whether the fluid overload is really a pathogenic factor, which is iatrogenic, or whether it is just a bystander and not really statistically significant," he said, adding that the study should account for comedications, comorbidities, region of practice, and the population being treated.

Dr. Cook noted that in 2009, before starting the study, he was hospitalized with dengue and received IV fluid. "When you're in the hospital with dengue, IV fluid feels great," he said.

Dr. Cook and Dr. Grünewald have disclosed no relevant financial relationships.

15th International Congress on Infectious Diseases (ICID): Abstract 21.007. Presented June 15, 2012.

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