# Caring for patients with rabies in developing countries - the neglected importance of palliative care.

Arnaud Tarantola, Yoann Cabrol, Bangalore Jayakrishnappa Mahendra, Sotheary In, Hubert Barennes, Hervé Bourhy, Yiksing Peng, Sowath Ly, Philippe Buchy

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## To cite this version:

Arnaud Tarantola, Yoann Cabrol, Bangalore Jayakrishnappa Mahendra, Sotheary In, Hubert Barennes, et al.. Caring for patients with rabies in developing countries - the neglected importance of palliative care.. Tropical Medicine and International Health, 2016, 21 (4), pp.564-7.
10.1111/tmi.12670 . pasteur-01429841

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1 Caring for rabies patients in developing countries - the

2 neglected importance of palliative care

3 Arnaud Tarantola¹,²; Yoann Crabol¹; Bangalore Jayakrishnappa Mahendra³; Sotheary In¹,²; Hubert

4 Barennes¹; Hervé Bourhy⁴; Yiksing Peng¹,²; Sowath Ly¹; Philippe Buchy⁵

5 1. Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia

6 2. Rabies Prevention Center, Institut Pasteur du Cambodge, Phnom Penh, Cambodia

7 3. Kodagu Institute of Medical Sciences, Madikeri, India

8 4. WHO Collaborating Centre for Reference and Research on Rabies, Institut Pasteur, Paris, France

9 5. Virology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia

10 6. GlaxoSmithKline, Vaccines Value & Health Sciences, 150 Beach Road, Singapore

11

12

13

14

15 Contact:

16 Arnaud Tarantola, MD, Msc

17 Head, Epidemiology and Public Health Unit

18 Institut Pasteur du Cambodge

19 5, Bvd. Monivong

20 BP 983 - Phnom Penh

21 Royaume du Cambodge

22 Mobile: +855 (0) 12 333 650
23 Fax: +855 (0) 23 725 606

24 Email: atarantola@pasteur-kh.org
25
# Ten years after “Management of rabies in humans” – a
developing country perspective

27
## Key points

28
Human rabies cases occur in rural developing settings where clinicians lack training and

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medication. Even in resource-poor settings and using essential drugs, there is much

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healthcare workers can do to help patients and families at no risk to themselves.

31
## Key words

32 Rabies; treatment; palliative care; diazepam; midazolam; hydrophobia; developing countries

33
## Abstract

34
Although limited publications address clinical management of symptomatic rabies patients in

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intensive care units, the overwhelming majority of human rabies cases occur in the rural

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setting of developing countries where healthcare workers are few, lack training and drugs.

37
Based on our experience, we suggest how clinicians in resource-limited settings can make

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best use of essential drugs to provide assistance to rabies patients and their families, at no risk

39
to themselves. Comprehensive and compassionate patient management of furious rabies

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should aim to alleviate thirst, anxiety and epileptic fits using infusions, diazepam or

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midazolam and antipyretic drugs via intravenous or intrarectal routes. Although the patient is

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dying, respiratory failure must be avoided especially if the family, after being informed, wish

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to take the patient home alive for funereal rites to be observed. Healthcare staff should be

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trained and clinical guidelines should be updated to include palliative care for rabies in

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endemic countries.
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In 2003, Jackson AC. et al.¹ wrote a comprehensive and well-cited article on the management of human rabies, duly reminding us of its dismal outcome, even in intensive care units of resource-rich countries. As the authors then clearly stated, most human rabies cases notified worldwide occur in developing countries where rabies remains a major and probably underestimated public health issue ²⁻⁴, even emerging in some heretofore unaffected territories.⁵,⁶ Over a decade later, little has changed in terms of clinical management of human rabies.

Not all persons who are bitten by a rabid animal become infected with rabies and human patients have – in extremely rare instances – survived rabies, mostly in the New World.¹,⁷⁻¹⁵ This is not the case with confirmed cases of human rabies acquired from dogs in the Old World, which overwhelmingly have a lethal outcome: only two reported cases have survived rabies in India, the country with the highest burden, but both had gross neurological sequelae.⁴,¹⁴,¹⁵

Rabies cases occur mostly in rural settings of developing countries.⁴ Few of the many dog bite victims in countries such as Cambodia have access to timely and appropriate post-exposure prophylaxis (PEP).⁹,¹⁶ Worldwide, there are an estimated 59,000 human rabies cases (and deaths) attributed to rabies each year.⁴

To date, there is no effective and validated etiological treatment available for rabies once the symptoms have set in and clinicians remain seemingly powerless.⁸,¹⁷ This is particularly the case in the rural developing setting where little or no intensive care is available or remains beyond geographical or financial reach. What then can we do to aid rabies patients – especially in rural areas - of developing countries?
69 Health care workers (HCW) in developing countries confronted with human cases of
70 suspected or confirmed rabies are not entirely helpless and their role remains essential. We
71 wish to remind readers of the specificities of managing rabies cases in the developing setting.

72 Diagnosis remains a priority when rabies PEP has been undertaken and failed.² Other people
73 potentially exposed to the same animal and those among the relatives and the healthcare
74 workers who would require PEP must quickly be identified. In approximately 20% of cases, a
75 "paralytic" presentation resembling Guillain-Barré syndrome will require little intervention
76 on the part of the clinical team. In most (80%) of cases, human rabies, febrile or otherwise,
77 will have a "furious" rabies presentation.¹⁸,¹⁹ Although the patient will most likely die,
78 prompt, effective and holistic compassionate clinical management can alleviate suffering for
79 the patients and their families. This can be performed even with extremely limited equipment
80 and drugs. If possible, the patient should be managed in a quiet and darkened room. Patient
81 privacy and dignity must be preserved. Management of furious cases with hydrophobia and
82 several days of fever, however, will require prompt and determined intervention, which must
83 first and foremost alleviate the sensation of thirst, which in our experience can be of mythical
84 proportions.²⁰ This can be done through infusion of 5% glucose solutions to compensate loss
85 of water²¹ or isotonic (0.9% NaCl) saline solution to compensate water and sodium loss,
86 being careful to immobilize the limb with a splint to prevent needle displacement.

87 Subcutaneous or intraperitoneal infusion are a useful alternative. Rather than restraint²²,
88 spastic signs and anxiety can be alleviated with diazepam which will also provide
89 myorelaxant²³, anticonvulsant²⁴ and sedative effects.²⁵ Diazepam is an affordable drug and
90 is widely available as a part of WHO's Model List of Essential Medicines²⁶. It can be
91 administered intravenously (IV) or intramuscularly or intrarectally (IR) (0.1-0.3 mg/kg IV
92 over 3-5 minutes in children or 0.5 mg/kg intrarectally; 10 mg IV or IR in adults).²⁷ This can
93 be repeated every 1-4 hours and can be continued over 24 hours using IV infusion (3-10
94 mg/kg <sup>27)</sup> if needed, guided by symptomatology, taking care to avoid respiratory depression.
95 The intrarectal route can be used at the same doses for maintenance therapy <sup>28</sup> if the infusion
96 cannot be maintained or if the patient is taken home by the informed family. Clinicians - and
97 families - should be aware of the risks of respiratory depression and aspiration. An effective
98 alternative, midazolam is included in WHO's List of Essential Medicine. Following a bolus
99 (depending on required level of sedation), midazolam can be administered at a dose of 1 mg
every 10 minutes by the intravenous route, taking care to reduce doses in
100 dehydrated/hypovolemic patients.<sup>26,29,30</sup> Intramuscular or subcutaneous routes are also
101 possible. Lorazepam is another option, if available, which can also be administered
102 subcutaneously.<sup>30</sup>
103
Treating fever by sponging may not be tolerated by a "furious" rabies patient, but alternating
104 or combined ibuprofen and paracetamol (also called acetaminophen) by non-oral routes
105 (intravenous, injectable or intrarectal) in patients with hydrophobia may provide some relief
106 by somewhat abating fever if it is present.<sup>31</sup> Unfortunately, these drugs are often not available
107 in injectable form in the developing setting <sup>26</sup> and intrarectal paracetamol/acetaminophen
108 does not effectively provide analgesia in the short-term <sup>32-34</sup>.
109
Physical restraint is often used by health care teams who fear that rabid patients may harm
110 them or themselves. It may be useful to prevent infusion displacement or self-harm, but
111 should be used sparingly as it stimulates agitated patients. Restraints may be loosened as soon
112 as patients become sedated/more calm. After prompt albeit limited medical intervention has
113 offered whatever relief it can, local beliefs and economic constraints must be taken into
114 account, in agreement with the patient if possible and the family. In Cambodia, for instance,
115 the patient is usually sent home, preferably alive so that religious rites can be administered
116 and the family not be burdened with the added cost of returning home with a cadaver, which
117 is usually much more costly than with even a moribund patient. Planning for transport may
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119 lead to preferring non-intravenous administration routes.

120 In developing countries - as probably elsewhere - HCW are fearful of contracting rabies
during care. Furthermore, whatever available health care is usually delivered in the first few
121 days or hours by family members potentially exposed to body fluids and without personal
122 protective equipment. Although the risk of transmission from human to human is considered
123 nil<sup>35</sup>, their concerns must be addressed and they must be offered PEP (targeting Category
124 II)<sup>36</sup> following exposure to a human rabies case.<sup>1,10</sup> This will help ensure they continue to
125 provide the best available care to suspected rabies patients.
126

127 The situation of many developing countries is well illustrated by that of Cambodia, a highly
128 enzootic country where only three PEP centers are freely accessible to the public.<sup>16</sup> Much
129 work is needed on the part of the authorities to make PEP accessible after a potentially
130 infective dog bite in developing countries.<sup>9</sup> A network of bite management centers must be
131 developed in rural areas while management of dog populations and systematic immunization
132 of dogs must be promoted countrywide.<sup>37,38</sup> As clinical guidelines<sup>39,40</sup> do not include rabies
133 management, much training and communication is also needed. The place of palliative care
134 in the management of rabies patients must be addressed in national and international
135 guidelines. This would help HCW in developing settings realize that - even if the rabies
136 patient will die - they can dramatically alleviate the suffering of rabies patients and their
137 families, at no risk to themselves.
138

138 Acknowledgements

139 We thank Drs. Cécile Aubron and Olivier Huet for their advice and editorial help.

140 Declaration of competing interests

141 No competing interests. Philippe Buchy is an employee of GSK Vaccines.

142
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