Rabies: the disease and the value of intensive care treatment

Intmrwc core Nurrmg (1991) 7.55-60 @ Longman Group UK Ltd 1991

R : the di care treatment Richard

P. Hatchett

Rabies remains an incurable disease which is endemic in many parts of the world, particularly the Indian sub-continent. Strict muzzling orders in the latter part of the 19th century and today’s modern quarantine laws have ensured the disease has remained eradicated from Britain. Isolated imported cases of human rabies do still occur and present a variety of problems for both nursing and medical staff. This article looks at the clinical features of the disease, the success in developing a potent yet safe vaccine and questions the value and justification in using an intensive care environment for rabid patients who are essentially suffering from a terminal illness.

INTRODUCTION The majority of British nursing and medical staff have not encountered a case of human rabies. Only 21 cases have been recorded in Britain since 1902, all of which were fatal. This paucity of British cases has led to several patients being misdiagnosed in the early stages as suffering from psychiatric disorders (Kaplan et al, 1986; Redfern, 1989). The disease is still endemic in many parts of the world, being particularly prevalent in the Indian sub-continent. In these poorer areas, nervous tissues vaccines, which have not improved greatly since the days of Pasteur, are still being used with their concomitant risk of serious adverse reactions and questionable potency. Once the clinical signs of rabies have developed the prognosis is virtually hopeless. RkhHd P. H&&&t, RGN ENB 100 Lewisham Intensive Therapy Unit, Lewisham Hospital, London. (Requests for offprints to RPH) Manuscript

accepted 18 January

1991

Yet this undermines the great success and importance of adequate human immunisation with modern vaccines, and the widespread vaccination of wildlife to halt the progress of rabies (Wilhelm & Schneider, 1990).

Clinical features The incubation period for rabies can vary from between less than 1 week to, rarely, over a year. The prodromal period which lasts for several days includes non-specific features such as a sore throat, malaise, headache and nausea. Commonly there is intense itching around the healing animal bite, if this has been the contact with rabies. The disease presents in two clear clinical forms. Furious rabies, which is the commoner manifestation in man, occurs when the disease predominantly affects the brain stem and cranial nerves, whereas in paralytic (dumb) rabies the spinal cord and spinal nerves are predominantly involved. 53

Furious rabies This form of the disease has a more hectic onset of symptoms, and without the intervention of intensive care death usually occurs within a few days of the onset of symptoms. Hydrophobia (a fear of water) is the most characteristic feature of the disease. There is both a terror and convulsions in response to attempts to drink. This will worsen until even the mention of water can induce a convulsion. Drafts of air will excite a reaction, (aerophobia) and the patient will frequently die during one of these convulsions due to cardiac or respiratory arrest. Other features include acute agitation and hallucinations alternating with periods of lucidity. Hyperactivity of the autonomic nervous system occurs resulting in tachycardia, hypersalivation, sweating and priapism (painful and persistent erection of the penis). Meningism and alternations in body poikilothermia (large temperature due to changes in the environment) may be manifest due to hypothalamic involvement.

Paralytic (dumb) rabies This is a rarer form, although more common in animals. It is seen in approximately 20% of human cases (Warrell 8c Warrell 1988). The clinical course is sometimes called ‘dumb because the patient’s laryngeal muscles can become paralysed. Paralysis begins in the bitten limb and ascends to the muscles of respiration. Fasciculation (isolated fine muscle twitching) and sensory disturbances commonly occur. The term ‘dumb’ rabies also refers to the far quieter course of the disease, with patients rarely suffering with hydrophobic convulsions. The patient thus tends to survive for a longer period than those with furious rabies, perhaps up to 30 days, but will eventually succumb to paralysis of the respiratory muscles (Kaplan et al, 1986). In 1975 a patient who had developed rabies from a dog bite in the Gambia was transferred to the National Hospital, Queens Square, London, for intensive care management. On arrival on the sixth day of the illness he was described as being; ‘. . .lucid

and

orientated

and

gave

a clear

account of the circumstances of the bite, but he was agitated, apprehensive, and continuously spitting saliva. He was gripped at intervals by powerful step-like inspiratory spasms of an apneustic type which interfered with respirations and speech’ (Manton et al, 1976).

Modes of transmission By far the most usual mode of transmission of the rabies virus to man is through the bite of an infected animal (Warrell & Warrell, 1988). This is commonly from a dog or cat, but in recent years in the United States a large number of rabid contacts have been wild carnivores and bats (Anderson et al, 1984). Transmission from rabid bats is not uncommon in that country and usually induces the paralytic form of the disease. (Warrell 8c Warrell, 1988). Human to human infection is theoretically bodily secretions, possible due to infected although the virus has never been isolated in blood (Helmick et al, 1987). The only clearly documented cases of one human infecting another were through cornea1 transplants from infected donors (Gode & Bhide, 1988). Transmission from aerosol inhalation is extremely rare but has been reported in two unrelated incidents of two laboratory staff who were working with a strain of the virus (MMWR 1972, MMWR 1977). The inhalation route has also been suspected in two United States patients who died after visiting caves infested with millions of bats, many of whom were rabid (Warrell & Warrell, 1988). In a retrospective study in the United States of human rabies cases reported over a period of 19 years, 6 out of 38 cases had exposure of unknown origin (Anderson et al, 1984). This is important because it emphasises that a break in the skin is not always evident in rabies, the virus can also be transmitted through intact mucous membranes.

Epidemiology The number of human rabies cases world-wide is very difficult to establish. This is because the countries where the disease is endemic are often

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underdeveloped, and reporting of the disease appears to be performed inaccurately. In Britain, as previously mentioned, there have been 21 cases this century and in the United States 38 cases of human rabies have been reported between 1960 and 1979 (Anderson et al, 1984). From 1980-1988 an average of one person per year in the United States acquired rabies. Seventy-three percent of these cases were exposed to rabies by contact outside the country (WHO, 1990). In Mexico 74 people died from rabies in 1988, a 2 1% increase from 1987 - 92% of these cases were contacts with rabid dogs (WHO, 1990). No cases of human rabies were reported in Canada in 1988 (WHO, 1990). Of the poorer countries, Thailand is estimated to have approximately 370 rabid deaths per year, but India is still believed to herald the highest number of rabid deaths worldwide. This is believed to be approximately 20,000 deaths each year (Bogel & Motschwiller, 1986). The difficulty in recording such numbers is complicated by the fact that many families do not take patients to hospital once rabid signs are recognisable, as uncomfortable isolation may be all that can be offered (Warrell & Warrell, 1988). Also, many Indian hospitals frequently encourage families to allow their relatives to die at home in what must be the most terrible way (Warrell 8c Warrell, 1988).

Vaccination In 1885 Louis Pasteur successfully inoculated g-year-old Joseph Meister with a rabies vaccine, after he was repeatedly bitten by a rabid dog. Pasteur used the spinal cords of rabbits infected with rabies virus which had been attenuated by desiccation. Initially a patient was inoculated with a solution of spinal cord dried for 2 weeks, and over successive days the patient would be injected with solutions which had been dried for shorter periods. The rabies virus was thus stronger with each treatment and the patient was able to build up an immunity (Theodorides, 1989). Although the technique proved successful in many cases, Pasteur was using live virus and occasionally rabies was induced in a patient,

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creating what became known as . ‘Pasteur’s Disease’ (Theorides, 1989). In 19 11, Semple, an English doctor, succeeded in inactivating the rabies virus in vaccines (Kaplan et al, 1986). Inoculations of infected spinal cords were used in France as vaccines until the 195Os, but these nervous tissue vaccines (NTV) presented a variety of problems. Their potency was questionable and many injections were required. Frequently as much as 2.5g of NTV had to be injected to achieve successful inoculation (Kaplan et al, 1986). Such a large amount of nervous tissue often led to adverse neuro-paralytic reactions, some of which were fatal. Manifestations of these reactions ranged from headaches, vomiting and varying grades of pyrexia, to changes in mental state, sensory disturbances and convulsions (Appelbaum et al, 1953). Estimates of the frequency of such reactions have varied from 1:2025 (Appelbaum et al, 1953) to as high as 1:220 (Swaddiwudhipong et al, 1987). The physician had to weigh up the risk of the patient developing rabies against the risk of serious reactions to the subsequent vaccine. Such adverse reactions to NTV were attributed to myelin in the nervous tissue. Newborn or immature mammals do not possess myelin, yet the rabies virus grows virulently in their nervous systems (Held et al, 1972). Vaccines developed from young mammals, such as suckling mice and rats, produced a vaccine with a quarter of the reactions that occurred with standard NTV (Kaplan et al, 1986). It was subsequently discovered that when reactions did occur they tended to be severe, and were frequently a Guillain-Barre type syndrome (Held et al, 1972). In a study of 32 patients who had adverse reactions to suckling mouse vaccine, the fatality rate was 2 1.9% (Held et al, 1972). In the 1950s vaccine developed from duck embryos largely superseded inoculations with NTV in the United States and western Europe. Again potency was not high and often as many as 14 painful injections were required. Serious adverse reactions such as anaphylaxis were rare, approximately 5.2 cases per 100,000 vaccinees (Rubin et al, 1973), but localised reactions to the injections, such as pain at the injection site were

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common: all of one group of- 116 vaccinees (Rubin et al, 1973). This vaccine was popular in the United States and Britain until the 1970s and was considered safe enough for pre-exposure prophylaxis. Neurologic reactions were estimated to be approximately 3.1 per 100,000 vaccinees (Rubin et al, 1973). Recent vaccines have included the newer tissue culture vaccines, human diploid cell vaccine (HDCV) (Anderson et al, 1980) and more recently, purified chick embryo vaccine (PCEV) (Wasi et al, 1986). These vaccines have a markedly increased potency with much smaller doses and a greatly reduced incidence of adverse reactions. In the millions of doses of HDCV now administered, only 4 cases of neurological reactions have been reported, none of which were fatal (Tornatore & Richert, 1990). The World Health Organization (WHO) recommend a 3-part treatment for unvaccinated patients having been in contact with rabies (WHO, 1984). This includes adequate cleansing, water flushing and antiseptic treatment of any wounds, the use of immunoglobulin and HDCV. In 1989 WHO re-emphasised the need for immediate and appropriate local wound treatment and the correct simultaneous application of immunoglobulin and vaccine (WHO, 1989). These recommendations followed incidents of rabies in patients who had had post-exposure treatment, but in whom WHO felt such treatment had been inadequately applied, and could have contributed to the development of rabies (WHO, 1988). The following regime is currently recommended in Britain for unvaccinated persons in contact with rabies (HMSO, 1990) and it mirrors WHO’s recommendations.

a) Thorough

cleansing of the wound, by scrubbing with soap and water under a running tap for at least 5 minutes. WHO then recommend the application of alcohol, tincture of iodine (an aqueous solution of povidone iodine) or quarternary ammonium compounds. This is an attempt to kill the virus in the wound (WHO, 1984).

b) Active

and, if indicated, passive immunisation. Human rabies immunoglobulin at a dose of 20 IU/kg. Half the dose is

infiltrated around the wound site, and half is administered intramuscularly.

cl HDCV is administered

at a dose of l.Oml on days 0, 3, 7, 14 and 30.

which is derived from Immunoglobulin, people already vaccinated against rabies, will provide immediate but short-term protection through passive immunisation. It is important to infiltrate half the dose around any wound site, in an attempt to neutralise virus in the wound. The dose of 20 IU/kg is recommended as an adequate dose. If this is exceeded there is the risk that active immunisation will be suppressed due to overzealous passive immunisation. HDCV is administered into the deltoid muscle and not into the gluteal region, as fat deposits may hinder absorption (Grist et al, 1989). It is a sad fact that in many economically underdeveloped countries such as Thailand and India, where rabies is endemic, NTV is still used due to its low cost (Nicholson, 1990). Due to the high production costs of the modern vaccines such as HDCV, (217.50p/ml dose - UK 1990 price) a modified intradermal vaccination regime has been employed in these countries, so that those patients in need of rabies protection can benefit. Thirty percent of the conventional intramuscular regime is administered as a series of intradermal injections with apparent equal efficacy (Warrell et al, 1985). There has also been success in administering PCEV intradermally. This vaccine is cheaper than HDCV and injected intradermally it creates the cheapest post-exposure tissue culture regime widely available (Suntharasamai et al, 1987).

The value and justification of intensive care treatment All of the 2 1 cases of imported rabies in Britain this century have proved fatal, whether intensive therapy had been instigated or not. In deciding whether costly intensive therapy is justifiable for the rabid patient, several important factors have to be considered. Can modern intensive therapy offer the patient any hope of survival and if not, will the patient have a comfortable and dignified death?

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Throughout the literature, particularly the older literature, there have been claims of survival from rabies in both animals and man. Hattwick et al. (1972) reviewed 9 purported cases of survival from human rabies. They, however, dismissed 5 cases as probable hysterical rabies and the remaining cases as too poorly documented to be definite affirmations. In recent years there have been 3 documented cases worldwide of survival from purported rabies. The first, a 6-year-old boy from the United States, was bitten by a confirmed rabid bat in 1970 (Hattwick et al, 1972). Despite a 14-day course of duck embryo vaccine, he developed what was believed to be clinical rabies. He suffered a variety of symptoms including a period of unconsciousness, cardiac arrhythmias, respiratory problems, convulsions due to raised intra-cranial pressure, left-sided weakness and a period of aphasia. Aggressive intensive care to treat and further prevent the variety of complications encountered produced a complete recovery after 6 months. The second case in 1972, involved a 45-year-old Argentinian woman who was bitten by a rabid dog (Porras et al, 1976). Again the patient developed what was believed to be clinical rabies, despite a 14-day course of suckling mouse vaccine (symptoms began after the twelfth dose). Recovery was near complete 13 months after the onset symptoms. These two cases are interesting in that the rabies virus was never isolated from either patient. Diagnosis was made on clinical observation, the fact that they were both bitten by rabid animals, and from the extremely high rabies antibody levels in the serum and cerebra spinal fluid (CSF). The levels were considered too high to be caused by vaccination alone. It is important to note that rabies virus can often not be isolated in a patient who has prolonged survival (Manton et al, 1976; Emmons et al, 1973; Bhatt et al, 1974), due to a process of ‘autosterilisation’ (Manton et al, 1976). The third case involved a New York laborawho, despite pre-exposure tory worker immunisation, developed deep coma after it was believed he inhaled an aerosol of fixed rabies virus (MMWR, 1977). Again, extremely high antibody levels were seen in serum and CSF.

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Although intensive therapy was applied and the patient survived, he was subsequently left with severe neurological sequelae. It is clear that in all three cases intensive therapy prolonged life and ultimately allowed survival. The fact that all 3 patients had some form of vaccination prior to the clinical signs may have attenuated the course of the disease. However, the rabies virus was not isolated from any of the patients and the illness may have been severe post-vaccinal encephalomyelitis, despite high rabies antibody levels. Despite the continued application of intensive therapy to rabid patients, with a view to supporting life until the acute disease subsides, no other cases of survival have been reported. Intensive therapy can undoubtedly prolong the life of rabid patients. The longest recorded survival being 133 days (Emmons et al, 1973). Death ultimately results from a refractory problem, usually respiratory or cardiovascular in origin. Careful documentation has allowed the elucidation of a variety of clinical problems which appear to be common to the majority of cases. Certain complications, such as polyuria, seem to manifest once the patient’s life has been prolonged beyond ten days.

A review of common problems associated with intensive care of rabid patients Neurological Neurological manifestations encountered in the rabid patient in the intensive care unit (ICU) follow those already mentioned. Although intensive care can prolong life, for the majority of the time the patient will be unconscious. Unconsciousness usually occurs before the tenth day of illness. For the initial few days heavy sedation, anti-convulsant and paralysing agents plus mechanical ventilation allow the acute distress of terror and convulsions to be more easily managed. This does however, make the assessment of the depth of consciousness difficult. In a study of 7 rabid patients in the KU, pupillary size and reaction and electroencephalogram (EEG) examination were found to be useful guides in this problem (Gode et al, 1976).

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Respiratory complications All the documented cases of rabid patients in ICU reviewed here required mechanical ventilation within the first few days of admission. This facilitated adequate oxygenation which was inhibited by hyperventilation, respiratory spasms and increasing paralysis. Drug induced paralysis with heavy sedation is thus also required to allow adequate mechanical ventilation. In many cases a tracheostomy allowed respiratory and oral secretions to be more easily removed by mechanical suctioning. The comfort of the patient was also improved. Common problems from long-term mechanical ventilation such as consolidation and bronchopneumonia affected many of the patients. This was treated with physiotherapy, mechanical suctioning and broad spectrum antibiotics.

Cardiovascular Initially sinus tachycardia from acute agitation and stimulation of the autonomic nervous system occurs. The documented cases report patients with an extraordianry variety of cardiac arrhythmias appear arrhythmias. Atria1 commonly as do periods of hypotension (Manton et al, 1976; Bhatt et al, 1974; Udwadia et al, 1989; Cohen et al, 1976). As the disease progresses periods of bradycardia may manifest. Rabies myocarditis is a frequent occurrence (Code et al, 1976; Udwadia et al, 1989; Cohen et al, 1976) and is a recognised complication of rabies (Cheetham et al, 1970).

Temperature Primary involvement of the hypothalamus can result in a labile body temperature. This was clearly noted in a review of 7 patients with rabies nursed in the ICU (Gode et al, 1976). Rabid patients will initially present with a pyrexia (Hattwick et al, 1972; Porras et al, 1976; Emmons et al, 1973; Bhatt et al, 1974; Udwadia et al, 1989; Cohen et al, 1976; Rubin et al, 1970), but poikilothermia (Gode et al, 1976) and hypothermia (Bhatt et al, 1974; Udwadia et al, 1989) were all encountered in the cases reviewed here.

Fluid and electrolyte balance The patient will frequently present in a dehydrated state, due mainly to the effects of hydrophobia and excessive salivation aggravated by pyrexia. Polyuria (Manton et al, 1976; Bhatt et al, 1974; Udwadia et al, 1989) is a common occurrence late in the course of the disease, manifesting after approximately 10 days of illness: patients pass 200-300mls of urine/h and frequently require the administration of antidiuretic hormone to allow fluid balance to be more effectively maintained. This polyuria, usually diagnosed as diabetes insipidus, appears to reflect increasing damage to the pituitary gland (Bhatt et al, 1974). Electrolyte disturbances occur commonly throughout the illness, and includes hypo’ and hyperkalaemia and hypo’ and hypernatraemia. The rabid patient should be isolated within the ICU area and barrier nursing should be instigated. A team approach is employed in the care of rabid patients, with involvement from the infection control nursing officer and the consultants in neurology, ICU and microbiology. The infection control medical officer and the medical officer for environmental health will all be involved. The infection control policy of the particular health authority should be followed, and usually the senior nurse for ICU will designate a team of nurses to care for the patient. These nurses and other attendants will all have pre-exposure immunisation. Nursing staff will be involved in questioning relatives as to the rabid contact of the patient. Relatives may be immunised if they wish to be in close contact with the patient. Immunisation is not necessary if they have not been in close contact with the rabid source (if known), or in direct contact with the patient’s own secretions. Gloves, gowns and facial visors are used when nursing the patient. Such measures are important due to hypersalivation and the patient’s inability to swallow adequately. All soiled linen and equipment will need to be sterilised or sealed in bags and incinerated. Investigations of infected specimens should be kept to a minimum, to reduce the risk of cross-infection. Diagnostic virology tests are all performed at a specialist laboratory, such as the Central Public

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Health Laboratory at Colindale, London. This laboratory will also provide specialist advice on the care of rabid patients.

CONCLUSION The multi-organ problems associated with rabies are clearly illustrated in this paper and synergistically may add to the ultimate demise of the patient. Survival can clearly be prolonged by intensive therapy. However, with no specific treatment, several cases have illustrated at necropsy that prolonging life may merely have allowed the rabies virus to cause degeneration and destruction to the nervous system, to a degree where the chance of survival is hopeless (Manton et al, 1976; Udwadia et al, 1989). Despite 3 controversial cases of survival from presumed rabies, there have been no other clearly documented cases of survival. WHO believes that modern means of symptomatic treatment may still provide a hope of recovery and should not be withheld (WHO, 1984). Certainly modern intensive therapy has advanced, even beyond the early survival reports of the 197Os, and can be justifiably regarded as a speciality in its own right. It would seem justified in Britain to adopt the more radical approach with the view to supporting life, considering the paucity of rabid cases actually seen in this country. When cases do occur in Britain, such as the &year-old boy with rabies, treated in Birmingham in 1987 (WHO, 1987), it seems totally justified to attempt full intensive therapy in the hope of a fourth recovery. Even if the patient were nursed in the ward environment, there would still be a need for strict isolation, potent analgesics and heavy sedation. The respiratory distress caused by the disease would probably warrant mechanical ventilation for the comfort of the patient and to avoid acute distress to the relatives, whether the ventilation is merely with air or with oxygen support. The role of intensive care in treating rabid patients will be heightened if a new antiviral or therapeutic intervention is ready for use in man.

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Rabies is a very rare disease in Britain and unlike in countries where the disease is endemic, such as India, the British public will have little or no knowledge as to the course or prognosis of the disease. It is important therefore, that if a patient is admitted to the ICU with rabies support is given to the relatives, who may see intensive therapy as a sign of a hopeful prognosis. The grave outcome should be carefully explained. While most intensive care nurses in the United Kingdom will never see a patient with rabies, swift air travel and the opening of the Channel Tunnel increase the possibilities that they may. Prior knowledge of the condition can at least reduce uncertainty if this occurs.

Acknowledgements I am indebted to Professor D.A. Warrell of the Nuffield department of Clinical Medicine, Oxford and to Dr. K.G. Nicholson, senior lecturer in infectious diseases, Groby Road Hospital, Leicester, for their assistance in the preparation of this paper.

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