Milwaukee Protocol for Rabies
The Milwaukee protocol is not recommended for the treatment of rabies and should be abandoned, as it has proven ineffective with at least 64 documented failures and no credible evidence of efficacy. 1, 2, 3
Evidence Against the Milwaukee Protocol
Failure Rate and Lack of Efficacy
- The Milwaukee protocol has been aggressively promoted since 2004 after one young patient survived rabies, but over the last two decades there have been at least 64 cases with failure of the protocol with no subsequent detailed reports documenting evidence of efficacy 3
- The protocol, which includes therapeutic coma (midazolam and phenobarbital), ketamine, ribavirin, and amantadine, was likely not directly responsible for the favorable outcome in the original survivor 4
- A documented failure occurred in a 33-year-old Thai patient who received therapeutic coma with burst suppression pattern maintained for 46 hours, plus ketamine and ribavirin, but died on his 8th hospital day 5
Official Guideline Position
- The Advisory Committee on Immunization Practices (ACIP) states that "no proven effective medical treatment is recognized after the development of clinical signs" of rabies 6
- Rabies is associated with the highest case fatality rate of any infectious disease and is not considered curable 6
- Initiation of rabies vaccination after onset of clinical symptoms is not recommended and might be detrimental 6
Recommended Approach to Clinical Rabies
Primary Focus: Comfort Care
- When a definitive diagnosis of rabies is obtained, primary health considerations should focus, at a minimum, on comfort care and adequate sedation of the patient in an appropriate medical facility 6
- Sedation is necessary because patients become extremely agitated in the presence of stimuli such as loud noises, air currents, and the sight or sound of running water during the acute neurologic phase 6
- Patient stress may be compounded by psychological trauma from isolation and hopelessness during fluctuating periods of lucidity 6
Experimental Therapies: Limited Consideration Only
- Medical staff at specialized tertiary care hospitals might consider aggressive experimental therapies only in confirmed cases in young healthy persons at an early stage of clinical disease, after in-depth discussions and informed consent 6
- Families must be aware of the high probability for treatment failure, anticipated expenses, and that rare survivors may have serious neurological sequelae requiring lengthy rehabilitation 6
Survival Data Context
- Survival has been well documented for only six patients total 6
- Five of these six survivors had received rabies vaccination before the onset of disease 6
- Only one patient has recovered from rabies without prior rabies vaccination 6
- Among approximately 33 well-documented survivors (defined as survival at six months), many have had serious neurological sequelae 3
Why the Milwaukee Protocol Fails
Lack of Scientific Rationale
- There is insufficient evidence to support the continued use of ketamine or amantadine for rabies therapy 1
- Ribavirin and interferon-α have proved to be disappointing agents for rabies therapy 1
- The protocol lacks a clear scientific rationale and is associated with high costs and potential complications of therapeutic coma 5
Critical Pitfall to Avoid
- Do not pursue the Milwaukee protocol outside of a clinical trial setting, as it diverts resources from appropriate comfort care and creates false hope for families 5
- The time has come to abandon this failed protocol and consider new approaches based on current knowledge of rabies pathogenesis 3
Prevention Remains the Only Effective Strategy
- Postexposure prophylaxis combining wound treatment, local infiltration of rabies immune globulin, and vaccination is uniformly effective when appropriately administered before symptom onset 6
- New therapeutic approaches for human rabies need to be developed based on better understanding of basic mechanisms involved in rabies pathogenesis 2, 4