B R I E F R E P O R T
Failure of the Milwaukee Protocol in
a Child With Rabies
Angela Aramburo,1Rodney E. Willoughby,5Andrew W. Bollen,6Carol
A. Glaser,7Charlotte J. Hsieh,2Suzanne L. Davis,3Kenneth W. Martin,4and
1Division of Critical Care Medicine, Children's Hospital & Research Center Oakland,
California,2Division of Infectious Diseases, Children's Hospital & Research Center
Oakland, California;3Division of Neurology, Children's Hospital & Research Center
Oakland, California;4Department of Diagnostic Imaging, Children's Hospital &
Research Center Oakland, California;5Division of Infectious Diseases, Children's
Hospital of Wisconsin, Milwaukee, Wisconsin;6Department of Pathology,
Neuropathology Division, University of California San Francisco; and7Encephalitis
and Special Investigation Section, Division of Communicable Disease Control,
California Department of Public Health, Richmond, California
Rabies has the highest case-fatality rate of all infectious dis-
eases, with 50 000 cases occurring annually worldwide. In
2004 an unvaccinated adolescent survived after novel therapy.
We report the management of a child with rabies. Although
the implementation of this same therapeutic protocol was
successful, the child died after 1 month of hospitalization.
Rabies encephalitis was considered universally fatal in humans
until 2004, when an unvaccinated adolescent survived with
novel therapy now dubbed the Milwaukee Protocol (MP) .
This protocol includes therapeutic coma, antiviral therapy, ce-
We report the treatment of a child with rabies, who received the
most timely and complete application of the original MP to
date, and compare this case with other MP attempts, discussing
implications for advancement in the field.
In November 2006, an 11 year-old male from the Philippines
presented to a community emergency department (ED) with
symptoms suggestive of furious rabies. Two years earlier, the
patient had been bitten by a dog in the Philippines and did not
receiverabies vaccine or other post-exposure prophylaxis (PEP);
clinical presentation has been reported elsewhere . Briefly,
sore throat, fever, and fatigue were followed by progressive
shortness of breath, dysphagia, and insomnia. In the ED, he
developed irregular mouth movements, visual hallucinations,
agitation, aerophobia, and hypersalivation.
Upon transfer to our children’s hospital ED, mental status
alternated between extreme agitation and obtundation. Marked
heart rate and blood pressure variability were compatible with
severe dysautonomia. He was intubated for airway protection.
Following thiopental for sedation, he became severely brady-
cardic, requiring brief cardiopulmonary resuscitation (CPR).
Neuromuscular blockade was administered because of pharyn-
geal and diaphragmatic spasms.
On admission to the intensive care unit (ICU), simultaneous
severe variable hypertension and heart rate suggested neurally
mediated catecholamine storm. Echocardiogram revealed severe
secondary left ventricular dysfunction. With a fosphenytoin load
responded to CPR. Inotropic support was required for 4 days.
Coma was induced with ketamine and midazolam infusions, as
recommended in the MP (version 1.1), for presumed rabies.
On hospital day 1 (HD1), direct fluorescent antibody (DFA)
detected rabies virus antigen in corneal impressions; serum and
cerebrospinal fluid (CSF) serologies were negative. From a saliva
sample on HD3, molecular testing performed at the Centers for
Disease Control and Prevention (CDC) detected rabies virus
RNA, corresponding genetically to Philippine dog rabies. Anti-
rabies immunoglobulin G (IgG) was first detected via indirect
immunofluorescence in serum and CSF on HD11 and HD13,
respectively. Initial nuchal biopsy was positive by DFA on HD3
and again on HD19.
On HD1, upon diagnosis of rabies, and after discussion with
the California Department of Public Health, CDC, and authors
of the MP, intravenous ribavirin and enteral amantidine, tet-
rahydrobiopterin (BH4), coenzyme Q10, and ascorbic acid were
initiated. All subsequent titrations and modifications of the MP
were made in direct consultation with the MP primary in-
With therapeutic coma, dysautonomia steadily improved.
Given concerns for development of cerebral electrical silence,
vasospasm, and edema, intense neurologic monitoring was ini-
tiated. This included continuous electroencephalogram (EEG),
continuous cerebral regional oxygen saturation measurement
Received 31 December 2010; accepted 6 June 2011.
Correspondence: Arup Roy-Burman, MD, Division of Critical Care Medicine, Children's
Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609 (arup.roy-
Clinical Infectious Diseases
? The Author 2011. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
d CID 2011:53 (15 September)
d BRIEF REPORT
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