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Details of published rabies cases treated with the Milwaukee Protocol (ketamine, midazolam, phenobarbitol, ribavirin and amantadine)*
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Rabies encephalitis is a fulminant, almost universally fatal infection involving the central nervous system. A unique treatment protocol, including anti-exicitotoxic therapy and induced coma was credited with the survival of a vaccinated teenager with bat rabies encephalitis in 2005. However, multiple efforts to replicate this expensive and intense...
Citations
... The baseline eye exam showed normal anterior and posterior segments, with a cup-to-disc ratio of 0.3 and no sign of disc edema in both eyes. He was intubated on day four and placed on the Milwaukee protocol, which consisted of sedation using midazolam, haloperidol, and ketamine to reduce neuronal hyperexcitation while awaiting viral clearance by the immune system [3]. ...
Rabies is a rare but rapidly progressive and almost universally fatal disease. A previously healthy 59-year-old male presented with rabies encephalitis. We measured his optic nerve sheath diameter (ONSD) daily in both eyes using ultrasonography to indirectly monitor for elevated intracranial pressure (ICP). We performed CT and MRI brain on days when his ONSD changed significantly. An increase in ONSD temporally correlated with radiologic findings of cerebral edema and acute subarachnoid hemorrhage (SAH). ONSD measurement is a fast, inexpensive, and widely-available imaging modality that may serve as a surrogate marker for elevated ICP. It may be especially useful in patients who are difficult to be transported to radiology due to the unstable nature of their disease.
... The Milwaukee Protocol has undergone several modifications from the first version to the current version (6.0), but the literature shows that further adjustment is needed 30,32,40,41 . In addition to supportive therapy in an intensive care unit, the use of effective antivirals seems to be a key point in treating rabies. ...
INTRODUCTION:
Rabies is a major and seriously neglected public health problem worldwide. A treatment consisting of supportive therapy with the use of drugs that show antiviral activity is called the Milwaukee Protocol. In Brazil, this protocol was adapted to the national reality and called the Recife Protocol. In this study, we compared the Milwaukee Protocol with the Recife Protocol, assessing the differences and how these differences may change the course of clinical management.
METHODS
We searched electronic databases for the use of anti-rabies treatments. A total of 65 articles were published between 2004 and 2019.
RESULTS:
The protocols have similarities in care related to rabies patients and are important for the treatment of patients in intensive care units. Both protocols indicate deep sedation, antiviral use, constant concern with electrolyte balance, and vasoconstriction related to the condition. Many differences were observed in this study. For the Milwaukee Protocol, sedation should be gradually removed after the eighth day, and on the twelfth day, the patient should be without sedation. In the Recife Protocol, in order to avoid immunomodulation, it is recommended to remove sedation according to the titers of neutralizing antibodies to the rabies virus in the cerebral spinal fluid.
CONCLUSIONS:
In addition to the differences and similarities raised, our findings indicate that these protocols require a large center for rabies treatment, but the disease most often occurs in places where resources and hospital infrastructure are scarce.
... The patient evolved to an almost complete recovery, including extensive physical and neurological rehabilitation [9]. However, several attempts to reproduce this treatment failed [37][38][39]. ...
Background:
Between 40,000-70,000 people die yearly of rabies, an incurable disease. Besides post-bite vaccination, no treatment is available for it.
Methods:
First, virus dilution for antiviral effects in mice was determined. Then, animals were treated as follows: control (NaCl 250 µL/animal/day); bufotenine (0.63, 1.05 and 2.1 mg in 250 µL of NaCl/animal/day); rabies (10-6,82CVS dilution); and test (10-6,82 CVS dilution and bufotenine, in the above-mentioned doses). Animals were observed daily for 21 days or until the 3rd stage of rabies infection. Twitch-tension and liposome studies were applied to understand the possible interaction of bufotenine with receptors, particularly acetylcholine.
Results:
Bufotenine was able to increase the survival rate of intracerebrally virus-infected mice from 15 to 40%. Bufotenine did not seem to interfere with the acetylcholine response in the skeletal muscle, indicating that its mechanism of action is not blocking the virus entrance due to nAChR antagonism. By analyzing liposomes, we could observe that bufotenine did not passively penetrates cell membranes, indicating the necessity of complementary structures to cell penetration.
Conclusions:
Bufotenine is a promising candidate for drug development. After further chemical modification, it might be possible to dissociate minor side effects, increase efficiency, efficacy and pharmacokinetics, yielding a true anti-rabies drug.
... Meanwhile, the induction of the therapeutic coma aims to offer enough time for the immune system to produce anti rabies antibodies. However, as the viral phosphoprotein antagonizes the production of any intra-cerebral immune response, this approach for treatment failed to help patients to survive [26,32,[76][77][78][79]. The use of Milkwaukee protocol could save the life of only 5 out of 44 patients. ...
Rabies is a vaccine-preventable fatal disease in man and most mammals. Although rabies is recorded in 150 territories and is responsible for at least 60,000 human deaths every year worldwide, it is a neglected tropical problem. Most of the rabies free countries are considered to be fragile free as the disease may re-emerge easily through wild mammals. For the performance of effective rabies eradication programs, a complex set of strategies and activities is required. At the time, a joint project of WHO-OIE-FAO which was announced in 2015, plans to control animal-human-ecosystems rabies interface. For effective rabies control, prophylactic policies must be applied. These include various educational outreaches for farmers and people living in endemic areas, enforced legislation for responsible dog ownership, control programs for the free-ranging stray dog and cat populations, field large-scale vaccination campaigns, and the development of new vaccine delivery strategies for both humans and animals. The present work presents the advances in the development of new safe, effective and economic vaccines for domestic dogs, and oral vaccines for the control of the disease in wild animals. It presents also some therapeutic protocols used for the treatment of patients.
... In contrast to the index patient, efforts to replicate the "Milwaukee protocol" have generally been unsuccessful. [5][6][7][8][9] This has been documented before both in bat-and canine-acquired rabies. Prolonged survival documented in rabies patients on the protocol likely reflects the effect of good intensive care and supportive treatment rather than the protocol itself. ...
Rabies encephalitis is a fulminant, almost universally fatal infection involving the central nervous system. A unique treatment protocol, including anti-exicitotoxic therapy and induced coma was credited with the survival of a vaccinated teenager with bat rabies encephalitis in 2005. However, multiple efforts to replicate this expensive and intense protocol have not been successful. In this article, we report the failure of the protocol in Indian patients with canine-acquired rabies and elucidate the potential explanations for the failure of the protocol in our patients.
... There have been only five cases of human rabies reported in Canada in the past 30 years. [2][3][4][5][6][7] The patient described here died in 2003 and a brief report, focusing on the public health measures, was published shortly thereafter. 4 However, the rarity of this disease in Canada and the unusual clinical and pathological features makes more detailed documentation of this case warranted. ...
... There have been only 25 cases of human rabies reported in Canada since 1925, with most occurring in Quebec (12) and Ontario (7). [2][3][4][5][6][7] The patient reported here is the first and only case contracted in British Columbia, although another individual died of rabies in British Columbia following exposure while hunting in Alberta. 7 Our case demonstrated several unusual clinical and pathological features that are worth emphasizing. ...
... 11 Of the eight cases of human rabies in Canada since 1970 (including this one), seven were due to bats. [2][3][4][5][6] In British Columbia, rabies is endemic only in bats, with an estimate of 1% of all bats infected. 4 In summary, this is the only case of human rabies contracted in British Columbia. ...
Human rabies encephalitis is rare in Canada, with only five cases reported in the past 30 years. The first and only patient who contracted rabies encephalitis in British Columbia died in 2003. Here we provide the first detailed clinical and pathological description of that case, which had several unusual features, including preexisting immunosuppression, paralytic presentation, prolonged survival, focal lesions on neuroimaging and severe neuropathology with focal necrosis, intense inflammation, and abundant viral inclusion bodies.
... However, despite the initial optimism and a few more success stories, several attempts to replicate this have been unsuccessful, leading to skepticism and reservations regarding its scientific rationale for routine use [142][143][144][145][146][147]. Nevertheless, increasing reports of survival/prolonged survival from rabies in the recent past, including those from India, albeit with neurological complications, should provide an impetus to the scientific community to explore newer therapeutic strategies to counter this fatal disease. ...
Rabies viral encephalitis, though one of the oldest recognized infectious disease of humans, remains an incurable, fatal encephalomyelitis, despite advances in understanding of its pathobiology. Advances in science have led us on the trail of the virus in the host, but the sanctuaries in which the virus remains hidden for its survival are unknown. Insights into host–pathogen interactions have facilitated evolving immunologic therapeutic strategies, though we are far from a cure. Most of the present-day knowledge has evolved from in vitro studies using fixed (attenuated) laboratory strains that may not be applicable in the clinical setting. Much remains to be unraveled about this elusive virus. This review attempts to re-examine the current advances in understanding of the pathobiology of the rabies virus that modulate the diagnosis, treatment, and prevention of this fatal disease.
... However, there have been recent reports of survivors of rabies encephalitis through an intensive and prolonged critical care protocol involving sedation, nutritional supplementation, calcium channel blockade, focused neuroprotection, and avoidance of passive or active immunization [62]. However, significant long-term morbidity exists even with stringent adherence to the protocol [63][64][65][66]. The decision whether to implement this protocol for affected patients must take into account a variety of factors such as resource availability and family wishes. ...
Viral infections are major causes of morbidity and mortality among children worldwide. All children, regardless of geographic region, socio-economic status, or age, are vulnerable to severe viral infections. They often require specialized care that ideally necessitates admission to an intensive care unit. This article will review the major viral syndromes and pathogens that affect children, focusing on the current evidence for their acute management in the intensive care unit.
... These findings add to a small body of laboratory studies of human rabies that provide insights into the chronology of rabies virus-host interactions. (3)(4)(5)(6)(7) Materials and Methods ...
Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus. The first human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005. We report a second unvaccinated patient who showed early recovery from rabies and then died accidentally during convalescence, providing an unparalleled opportunity to examine the histopathology as well as immune and virological correlates of early recovery from human rabies.
Case report, rapid fluorescent focus inhibition test, enzyme-linked immunosorbent assay, indirect and direct fluorescent antibody assays, reverse-transcriptase polymerase chain reaction, phylogenetic reconstruction, isolation in tissue culture, pathology and immunohistochemistry.
The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by cat bite. Antibody response in serum and CSF was robust and associated with severe cerebral edema. No rabies virus was cultured at autopsy. Rabies virus antigen was atypical in size and distribution. Rabies virus genome was present in neocortex but absent in brainstem.
Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious rabies virus in the CNS by 76 days, but not clearance of detectable viral subcomponents such as nucleoprotein antigen or RNA in brain.
... It is widely accepted that there is no effective treatment for rabies infection which is almost always fatal once neurological symptoms develop (WHO, 1992;Wilde, 2007). Although 2009; Willoughby et al., 2005), its effectiveness has been questioned (Hemachudha et al., 2006;Jackson, 2013a;McDermid et al., 2008). ...
