Is mannitol safe for TBI?
|
A recent article in the British
Medical Journal (BMJ) has cast doubt on whether
a trio of studies supporting the use of high-dose mannitol
in the treatment of traumatic brain injury (TBI) ever
actually took place.
Mannitol is an osmotic diuretic
believed to lessen the risk of long-term brain damage
after TBI by reducing intracranial pressure. Although
widely used, the treatment has never been proven effective
in randomized, placebo-controlled trials. "That alone
should have made us a little bit cautious," says Dr
Ian Roberts, coordinating editor of the Cochrane Injuries
Group (CIG) and lead author of the BMJ study.
"As it is, these three papers were the only evidence
of a specific pharmacological treatment being effective
for head injury, and now we believe the results to be
fraudulent. It's extremely disappointing," he adds.
The studies in question, published
between 2001 and 2004 in the peer-reviewed journals
Neuroscience and the Journal of Neuroscience,
claim that administering rapid, high doses of mannitol
(an average of 1.4 g per kilogram body weight) greatly
improved patient outcomes compared to conventional doses.
They were allegedly conducted by neurosurgeon Dr Julio
Cruz at the Federal University of Sïo Paulo —
except the university denies having ever employed him
and there are no hospital records to back up his claims.
PATIENTS
AT RISK
Unfortunately, Dr Cruz is unable to defend himself or
his findings — he committed suicide in 2005. His
three co-authors claim to have had little or no involvement
in his clinical investigations, beyond perhaps allowing
the use of their names. Neither they nor the publishing
journals have shown willingness to look into the matter.
Yet these studies form the only basis of evidence for
the use of high-dose mannitol in treating TBI, potentially
putting patients' lives at risk.
According to Dr Laurent Vanier,
president of the Association of Emergency Physicians
of Quebec and an Er doctor at Charles-LeMoyne Hospital,
in Longueuil, Qc. Mannitol is generally used in severe
cases of TBI, and then only in low doses of 0.5g to
1g per kilogram of body weight.
But owing in part to the fact that
mannitol is such an inexpensive and readily available
substance — it's a sugar alcohol — Dr Roberts
maintains it's used at just about every hospital in
the world. "The fact that doctors use it doesn't mean
it's safe," he insists. "The implications for patients
are serious. They are being treated on the basis of
potentially unreliable evidence," he wrote.
PASSING
THE BUCK
Dr Roberts' involvement in this affair began in May
2006, when he got a call from Dr Jorge Mejia. Dr Mejia
had become concerned about the CIG's inclusion of the
Cruz studies in its influential review after some Brazilian
colleagues told him they believed the late physician's
claims were false.
Since no one had any hard evidence
to back up their suspicions, Dr Roberts contacted the
co-authors: Dr Kazuo Okuchi of Nara Medical University,
Japan; Dr Giulio Minoja, the ICU director of a hospital
in Varese, Italy; and Dr Enrico Facco at the University
of Padua, Italy. None of them could confirm the studies'
legitimacy, so they were removed from the Cochrane database
in 2006, pending investigation.
Dr Roberts also contacted the publishing
journals. At least one editor admitted to suspecting
Dr Cruz had fabricated his data, but said his editorial
board had decided to run the study anyway.
When pressed further, the co-authors
insisted that high-dose mannitol does work and that
Dr Cruz was an honest scientist. However they admit
to not having any knowledge of the dozens of patients
Dr Cruz supposedly treated. "I think they're spineless,
really. They need to accept that they share authorship
of the disputed studies, which means they have a responsibility
to verify whether the findings are true or not," says
Dr Roberts. "If the data are true, defend them, and
if they're false, retract them — but they're doing
neither. They seem to want to keep their heads down
and hope it blows over. It's completely ridiculous,"
he adds, frustrated.
CALL
FOR RESEARCH
Dr Roberts contends that there haven't been big enough
randomized controlled trials comparing mannitol or other
osmotic diuretics like hypertonic saline with placebo
or other TBI treatments.
"If some or all of Cruz's data
on high-dose mannitol are false, then doctors will be
providing their critically ill patients with uncertain
and possibly harmful treatment. In doing so, those doctors
will also deny their patients other treatments that
are based on reliable evidence," Dr Charles Young argued
in an accompanying editorial.
Dr Vanier is just happy the contentious
findings didn't make their way into any major clinical
practice guidelines, "which would have made their removal
from common use extremely difficult," he says. Hopefully,
he adds, the experience will finally lead to new randomized
controlled trials to determine whether there's any basis
for the treatment.
|
