The 'Milwaukee protocol' (MP) for rabies victims

Q: Can rabies victims be saved?

Krishna: The 'Milwaukee protocol' (MP) can sometimes save such  a person: The only treatment that will save them is an experimental procedure called the Milwaukee Protocol, in which the person is put into an artificial coma and kept on life support, in an attempt to keep them alive while the body fights the disease. There is still no cure; it just gives the person a fighting chance. 

Rabies is caused by the rabies virus, an RNA-based virus in the genus Lyssavirus. Transmission typically occurs when virus-laden saliva from a rabid animal enters a wound or mucous membrane. The Milwaukee protocol, a novel procedure (1) in which the patient was placed in a drug-induced coma and given an antiviral cocktail composed of ketamine, ribavirin, and amantadine. Considering the theory that rabies pathology stems from central nervous system neurotransmitter dysfunction, doctors hypothesized suppressed brain activity would minimize damage while the patient's immune system developed an adequate response.

But the survivors can suffer serious brain damage!

When you are bitten by a rabid animal, the pathogen travels up your nerve pathways to your brain. Once it gets to your brain, that is the end game. That is also when symptoms appear. There is no cure after that.

Unless you are one of the VERY few people for whom the above protocol works.

The Milwaukee protocol, a procedure reported to prevent death after the onset of rabies symptoms, has been performed over 26 times since its inception in 2004 but has only saved one life. Overwhelming failure has lead health officials to label the protocol a red herring.

Q: Can rabies occur after several years?

Krishna: The incubation period of rabies in humans is generally 20–60 days. However, fulminant disease can become symptomatic within 5–6 days; more worrisome, in 1%–3% of cases the incubation period is >6 months. Confirmed rabies has occurred as long as 7 years after exposure, but the reasons for this long latency are unknown.

Q: Explain MP in detail.

Krishna: 

Milwaukee Protocol, version 6 (updated November 2018) (2)
Protocol
1. DO NOT administer rabies vaccine or immunoglobulin to a patient with rabies. This practice
has never worked and may cause adverse outcomes.
• RIG delays development of rabies antibodies in CSF, essential for survival.
• Preliminary evidence favors detrimental survival times after rabies vaccine in bat rabies.
• We have administered beta-interferon to a few rabies patients with poor prognostic
epidemiology, with evidence for a beneficial peripheral effect on viral load. This can be
considered in particular for dog rabies, where CSF responses are often poor. It appears to
stabilize peripheral rabies disease and “buy” an additional week for serological response to
develop.
2. Maintain patient in isolation.
• There has never been a laboratory-documented case of human-human transmission of
rabies (other than by transplantation of corneas or solid organs).
• Patients can be removed from isolation when saliva is negative by RT-PCR on 3 occasions in
the presence of serum neutralizing antibodies > 0.5 IU/ml by RFFIT, FAVN or other test for
neutralizing antibodies.
3. Transfer patients with laboratory-confirmed rabies to a tertiary care facility capable of critical
care including intracranial pressure monitoring.
• Institutions in developing countries can handle rabies if they treat head trauma and/or
tetanus within critical care units.
4. Treatment requires access to a rabies reference lab
• Transport needs to be prioritized. There can be delays in transporting samples to rabies
reference laboratories and in their analysis and reporting that compromise patient care.
Reporting should be done by telephone or email as quickly as possible in addition to
through standard reporting channels.
• Depending on logistics of transport, treatment with the Milwaukee Protocol may need
to begin if patient is approaching day 5 without a diagnosis. Sedation for 7 days is less
dangerous than untreated rabies.
• Consider use of Bio-Rad Platelia Rabies II Kit (human) #355-1180 for rabies antiglycoprotein antibody, that is ELISA based and for which comparative studies and
precedent for use in humans exist. This can be done locally with fast turnaround and
reference laboratory backup confirmation.
• Consider use of ADTEC Corporation RAPINA lateral flow assay, a single use bedside test
for determining rabies anti-glycoprotein antibody. See Vaccine (2012) 30: 3891-96
• Reporting of results needs to be rapid to be useful in a rapidly progressive encephalitis.
Arrange for results to be reported by phone, email or text to a designated member of
the treatment team in addition to standard reporting practices that take longer.
• By the same token, send permission to the rabies reference lab to quickly share results
with us when they are reported to the local treatment team. [In particular, CDC Atlanta
has recently required this permission before communicating results.]
5. Treatment also requires access to a rehabilitation facility

6. Involve us early and daily. There is a lot to learn and to interpret. Treatment generally requires
2 lines of communication:
Milwaukee Protocol, version 6 (updated November 2018)
• A small group of physicians, lab officials and outside consultants with confidential
communications. This has been done by email and by text-messaging applications such
as WhatsApp.
• A larger group of public health and laboratory authorities charged with epidemiology,
public health response, logistics and drug procurement, and public relations. This has
been done by conference calls and email.

Footnotes:

1. https://www.mjdrdypu.org/article.asp?issn=0975-2870;year=2017;volum...

2. https://www.mcw.edu/-/media/MCW/Departments/Pediatrics/Infectious-D...