December 1997
NAPA VALLEY, Calif. - Recent data suggests that the timing of dexamethasone in meningitis treatment is important if the adjunctive therapy is going to prevent hearing loss and other sequela.
"Whether you use dexamethasone or not is not why I'm here," said George H. McCracken Jr., MD, at the recent Pediatric Infectious Diseases Society annual meeting. "It is not my argument. My argument is this: when you decide to use it, it's the timing that counts."
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Dexamethasone inhibits the inflammatory response in the central nervous system (CNS) caused by the antibiotic. Therefore, it should be given before or with the antibiotic. "Now, when exactly it should be given is very difficult to say - other than preferably before or at the same time [as the first dose of antibiotic]," said McCracken. "How long after [the antibiotic] is it effective or no longer effective is very, very difficult to determine."
The natural history of Haemophilus meningitis in the rabbit model has been followed. Inflammation rises slowly - over a 20-hour period, tumor necrosis factor (TNF) rises to about 10 ng/mL, and the white cell count rises to about 2,000 white blood cells (WBC). A similar rise is seen in children with meningitis.
If a dose of ceftriaxone (Rocephin, Roche) is given within six hours, that inflammatory response is changed. TNF concentrations skyrocket to 25 ng two hours after the dose. The WBC count rises to about 30,000.
If a dose of dexamethasone is given before the dose of ceftriaxone, the dexamethasone modulates the TNF response and the WBC count starts to rise, but then falls back, decreasing inflammation. That modulation is not seen if ceftriaxone is given first.
"If you give dexamethasone one hour after the ceftriaxone - so ceftriaxone is given at six hours, the dexamethasone at seven hours - the TNF goes way up. And then the white cells keep rising," explained McCracken, who is professor of pediatrics, the Sarah M. and Charles E. Seay chair in pediatric infectious diseases at the University of Texas Southwestern Medical Center in Dallas.
The dexamethasone effect is only on the secondary inflammatory response; it has no effect on what happens up to the time of diagnosis and administration of therapy, he added.
There are many factors that influence this type of response. These include the antibiotic used, the timing of dexamethasone, the bacterial cause and how many bacteria are present when therapy is initiated.
A recent study in the Journal of the American Medical Association looked at dexamethasone therapy in pneumococcal meningitis. The results showed severe hearing loss was less likely if dexamethasone was given before or with the first parenteral antibiotic dose vs. giving it after the antibiotic.
"Give it for two days," McCracken said. "I think that's the optimal way of administration. When is it too late to give it? I have no idea, but I suggest to you that one hour or longer is probably too late."
This presents a problem in using dexamethasone in the United States - most children receive a dose of antibiotic in the emergency room before being sent to the ward, which probably precludes the effectiveness of dexamethasone, he said.
Currently, most physicians feel they should give the child a "shot of something" before they are admitted. "Perhaps, they should give them a shot of dexamethasone and antibiotic before they leave the emergency room," he suggested.
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