REVIEW ARTICLE COPYRIGHT © 2015 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES INC. Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned Frederick A. Zeiler, Alan C. Jackson ABSTRACT: The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol. RÉSUMÉ: Évaluation critique du protocole de Milwaukee pour le traitement de la rage: cette approche inefficace devrait être abandonnée. La survie dans l’encéphalite rabique a été attribuée au protocole de Milwaukee malgré l’absence de données scientifiques à l’appui. Nous avons revu la littérature traitant des recommandations spécifiques de traitement faites dans le cadre de ce protocole. Aucune donnée de la littérature actuelle ne supporte que l’excitotoxicité et le vasospasme cérébral jouent un rôle important dans l’encéphalite rabique. Les traitements suggérés dans le protocole de Milwaukee incluent le coma thérapeutique, l’infusion de kétamine, l’amantadine et le dépistage, la prévention et le traitement du vasospasme cérébral. Il n’existe aucune preuve que de ces traitements soient efficaces contre la rage ou toute autre forme d’encéphalite virale aigüe. Il est donc justifié d’entretenir de graves réserves au sujet des recommandations contenues dans le protocole actuel. Les recommandations contenues dans le protocole de Milwaukee méritent d’être reconsidérées dans leur ensemble avant toute utilisation future du protocole actuel qui s’est avéré inefficace. Keywords: critical care, infectious diseases, infections of the nervous system, intensive care, virology, Milwaukee protocol, neuroprotection, rabies, therapy doi:10.1017/cjn.2015.331 Can J Neurol Sci. 2016; 43: 44-51 Rabies encephalomyelitis remains a difficult therapeutic challenge. To date, numerous therapies have been implemented with all failing to show therapeutic efficacy. 1,2 Few reports of survivors exist in the literature, with the majority of survivors having received post-exposure prophylaxis with one or more doses of rabies vaccine. 3 Documented survivors of rabies may, at least in part, represent advances in cardio-respiratory and other supports within modern critical care units and not be related to specific rabies directed therapies. In 2004 a young patient from Wisconsin survived rabies and her therapy has been dubbed the Milwaukee protocol and relent- lessly promoted. 4 The Milwaukee protocol is a treatment regimen for rabies focused on therapeutic coma and the use of N-methyl D-aspartate (NMDA) receptor antagonist therapy. This protocol has received attention after recovery with mild neurological deficits of one patient who did not receive any rabies vaccine. 4,5 Since the case report was published in 2005, 4 many changes have been made in the protocol to arrive at its current rendition. 6 Critics of the Milwaukee protocol raise concerns of the regimen’s lack of efficacy in human rabies, with at least 31 documented failures reported in the literature to date (Table 1). There are claims that patients from Colombia 19,20 and Peru 12 who died are survivors because they survived the initial phase of acute illness. Another survivor probably did not have rabies, 39 whereas others received doses of rabies vaccine prior to the onset of their disease 40 similar to rabies survivors who did not receive the Milwaukee protocol. Given the concerns with the Milwaukee protocol, we elected to perform a critical appraisal of the suggested critical care directed therapies within the current protocol version, with a focus on NMDA receptor antagonism, therapeutic coma, and cerebral vasospasm. We reviewed the available literature regarding the treatment of human rabies encephalitis over the last decade and have sum- marized all known patients treated with the Milwaukee protocol to date. Furthermore, in order to outline any available evidence to support its use, we reviewed the literature surrounding the Milwaukee protocol for rabies encephalitis. Within the pro- tocol we identified areas of concern for lack of scientific merit. These areas included therapeutic coma, NMDA receptor antagonism, and cerebral vasospasm prophylaxis/detection/ treatment. From the Departments of Surgery (Neurosurgery) (FAZ); Internal Medicine (Neurology) (ACJ), and Medical Microbiology (ACJ), University of Manitoba, Winnipeg, MB, Canada. Correspondence to: Dr. Alan C. Jackson, Health Sciences Centre, GF-543, 820 Sherbrook Street,Winnipeg, MB R3A 1R9 Canada. E-mail: ajackson2@hsc.mb.ca RECEIVED APRIL 27, 2015. FINAL REVISIONS SUBMITTED AUGUST 25, 2015. 44 https://www.cambridge.org/core/terms. https://doi.org/10.1017/cjn.2015.331 Downloaded from https://www.cambridge.org/core. IP address: 18.206.13.133, on 05 Jun 2020 at 21:30:43, subject to the Cambridge Core terms of use, available at