156
could the generalist usefully do for a severe bums contracture, osteomyelitis of the tibia, or a rectovaginal fistula? If the front-line doctor is not an orthopaedic surgeon, how should he treat all the fractures? If with less-than-perfect skills and much-less-than-perfect asepsis and equipment, he attempts the fashionable open methods of osteosynthesis of the AO school (Arbeitgemeinschaft fiir Osteosynthesenfragen), it will too often earn its sobriquet "always osteomyelitis". So, he needs the closed methods that will give his patients the best chances of a painless useful limb. Similar appropriate methods have now been assembled for twenty specialties of surgery and anaesthesia by a physician who, instead of soliciting chapters from his surgical colleagues, put himself into the position of the front-line doctor, wrote the chapters himself, and then asked the surgeons for their comments.4,5 The Declaration of Alma Ata listed health education among the eight essential activities of primary health care. It is hard to imagine a programme for the control of AIDS or diarrhoea without it. It is also part of the general process of development that enables people to take control of their lives by learning how to prevent or control disease. Health education should therefore be one of the front-line doctor’s skills, and he should be expert enough to know how to make it work. Remarkably, there is little firm evidence about whether it works, and under what conditions, or how it is best done. A review6 of the scientific quality of sixty-seven attempts to evaluate health education programmes found that only three met all four of the following criteria: (a) they were sufficiently well described to be replicable (47%); (b) they described the educational level of the target group (40%); (c) they were controlled studies of more than 60 people or two clusters (21 %); (d) they used observable changes in health status (33%) or behaviour (33%) as an endpoint. Within these severe limitations, the results in the articles confirm the commonly accepted view that successful health education depends on the use of a few messages, of proven benefit, repeatedly, in many ways. The surgeon superintendent of a well-known district hospital in Africa gave as his priorities the administration, the staff, the plant, and only then the patients, on the grounds that patients, especially in quantity, cannot be cared for satisfactorily until the first three priorities have been met. The role of the front-line doctor as manager has been described in valuable detail by Pearson,8 who covers such matters as provision of supplies ("beware of fraud"), accounting ("don’t keep public and private money together"), and even how to keep the roof on the hospital in a high wind. In many such hospitals the staff, even the doctor, may have to grow their own food. As one of them lately wrote from Ghana: "The maize farm in the backyard is as green as ever, the rabbits, sheep, goats and chickens are doing well, and that is survival, even for the doctor!"
1. Silver GA. The uses of adversity. Lancet 1991; 337: 1404-05. 2. WHO and UNICEF. Declaration of Alma Ata. Lancet 1978; ii: 1040-41. 3. WHO. Hospitals and health for all. WHO Tech Rep Ser 1980; 774. 4. King MH. Primary surgery. 2 vols. Oxford: Oxford University Press, 1990. 5. King MH. Primary anaesthesia. Oxford: Oxford University Press, 1986. 6. Levinsohn BP. Health education interventions in developing countries: a
methodological review of published articles. Int J Epidemiol 1990; 19: 788-94. 7.
King MH, Hall R. Zambia: commitment triumphs over adversity. Lancet
1991; 337: 166. 8. Pearson CA. Medical administration for front line doctors. FSG Communications, 57/59 Whitechapel Road, London E1 1DU, UK. 1990. ISBN 1-87118016.
The brain in fulminant failure
hepatic
When accompanied by coma, fulminant hepatic failure carries a high mortality. Important causes of coma are cerebral oedema and intracranial hypertension, in which death is caused by cerebral herniation. The typical signs and symptoms of raised intracranial pressure such as headache, bradycardia, and papilloedema are usually absent. Computed tomographic scanning is a poor and unreliable method of detection1 although it may be valuable in displaying the focal intracranial lesions that sometimes accompany acute hepatic failure.2 Since there is still no reliable non-invasive method, intracranial pressure has to be measured via an extradural or epidural device. The cause of cerebral oedema in fulminant hepatic failure remains uncertain. Current thinking suggests two major pathophysiological mechanismsvasogenic and cytotoxic. In the former, the bloodbrain barrier breaks down and allows serum protein to leak through the normally selectively permeable capillary endothelium into the brain parenchyma; in cytotoxic oedema, intracellular uptake of water leads to brain cell swelling. At a molecular level these two processes have much in common and cannot be readily separated.3 Inhibition of Na/K-ATPase, toxin-induced disturbance of blood-brain barrier permeability, osmotic effects of glutamine, and primary injury to astrocytes have all been proposed as contributors to the brain damage.4Although there is little doubt about the importance of raised intracranial pressure in the production of cerebral oedema, correlation between the two is poor.5,6 Cerebral perfusion pressure-the difference between mean arterial pressure and intracranial pressure-is a useful prognostic indicator, mean values of less than 40 mm Hg being associated with ischaemic brain injury. In fulminant hepatic failure, unlike many other conditions associated with raised intracranial pressure, cerebral blood flow is usually subnormal.’ What can be done to reduce intracranial pressure and prevent the lethal sequelae of cerebral oedema? Intravenous mannitol is effective, but repeated use tends to be harmful since it results in hyperosmolarity and cell dehydration. Hyperventilation relieves intracranial hypertension8 but the reduction in cerebral blood flow caused by lowering of PCO2 may
157
provoke
further brain
damage. Thiopentone9
and
dexamethasone also reduce intracranial pressure in most types of cerebral oedema but dexamethasone has
proved disappointing in hepatic failure. None of these than a transient effect and it is doubtful whether any of them has any impact on survival unless the underlying cause of the intracranial hypertension is dealt with. Emergency liver transplantation alone offers this possibility, 10 and highly encouraging reports have emerged from some units." There are, however, many disappointing instances of patients not regaining consciousness after apparently successful grafting.ll,12 Such failures may be attributable to irreversible brain damage, either present at the time of transplantation or possibly precipitated by the surgical procedure itself. A paper from King’s College Hospital, London, provides information in this regard. Keays and co-workers13 report their experience of monitoring intracranial pressure and cerebral perfusion pressure continuously before, during, and after liver transplantation in six patients with fulminant hepatic failure. Intracranial pressure rose from the induction of anaesthesia to the pre-clamp phase of the operation, fell slightly during the anhepatic phase, and rose further during reperfusion. Cerebral perfusion pressure fell during induction and remained low throughout the operation. Although intracranial hypertension and critically low cerebral perfusion pressure was noted in most patients, only two of the six failed to regain consciousness and careful examination of the pressure indices does not reveal any striking differences between those who died and those who recovered. The number of patients was small (the authors have done well even to produce these limited data) but the results raise important questions concerning the value of intracranial pressure measurement. The notion that life or death is determined by pressure measurements is likely to be too simple; perhaps we need to look at the brain cells and their chemical constituents for the critical changes that affect the brain in fulminant hepatic failure. Existing techniques have precluded such investigation, but nuclear magnetic resonance, with its potential for analysing intracellular metabolites, may offer scope for future research.14 treatments has
more
1. Munoz SJ, Robinson M, Northrup B, et al. Elevated intracranial pressure and tomography of the brain in fulminant hepatic failure. Hepatology
1991; 13: 209-12. 2. O’Brien CJ, Wise RJS, O’Grady JG, Williams R. Neurological sequelae in patients recovered from fulminant hepatic failure. Gut 1987; 28: 93-95. 3. Klatzo I. Pathophysiological aspects of brain oedema. Acta Neuropathol
1987; 72: 236-39. 4. Blei AT. Cerebral edema and intracranial hypertension in acute liver failure: distinct aspects of the same problem. Hepatology 1991; 13: 376-79. 5. Nora LM, Bleck TP. Increased intracranial pressure complicating hepatic failure. J Crit Illness 1989; 4: 87-89. 6. Ede RJ, Williams R. Hepatic encephalopathy and cerebral oedema. Semin Liver Dis 1986; 6: 107-18. 7. Almdal T, Schroeder T, Ranek L. Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases. Scand J Gastroenterol 1989; 24: 299-303.
8. Ede RJ, Gimson AES, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. J Hepatol 1986; 2: 43-51. 9. Forbes A, Alexander GJM, O’Grady J, et al. Thiopental infusion in the treatment of intracranial pressure complicating fulminant hepatic failure. Hepatology 1989; 10: 306-10. 10. Editorial. Transplantation for liver failure. Lancet 1987; ii: 1248-49. 11. Bismuth H, Samuel D, Gugenheim J, et al. Emergency liver transplantation for fulminant hepatitis. Ann Intern Med 1987; 107: 337-41. 12. Emond JC, Aran PP, Whitington PF, Broelsch CE, Baker AC. Liver transplantation in the management of fulminant hepatic failure. Gastroenterology 1989; 96: 1583-88. 13. Keays R, Potter D, O’Grady J, et al. Intracranial and cerebral perfusion changes before, during and immediately after orthotopic liver transplantation for fulminant hepatic failure. Q J Med 1991; 79: 423-33. 14. Bosmann DK, Deutz NE, De Graaf AA, et al. Changes in brain metabolism during hyperammonaemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatology 1990; 12: 281-90.
Immunoglobulin therapy When
unmunoglobulms, injected intramuscularly
(IMIG), were first used for prevention of infection in primary hypogammaglobulinaemia-after some basic technical work on fractionation of plasma proteins during the 1939-45 war1—most donor plasma pools were contaminated with hepatitis B virus. Fortunately the fractionation procedure, which entailed a series of alcohol precipitation steps, substantially reduced infectivity.2 Some IMIGs did transmit hepatitis B in those early days, but for the past 12 years the risk has been virtually eliminated by screening of donors for hepatitis B surface antigen. IMIG has also enjoyed a long record of safety in regard to non-A non-B (NANB) hepatitis. The reasons’ are not clear but lie partly in the route of injection, the small amount of material injected, and the possibility that non-A non-B viruses are inactivated in liquid preparations during storage before being distributed to pharmacies. During the 1970s clinicians treating primary hypogammaglobulinaemia patients realised that IMIG gave less than total protection against infection, and that only a modest rise in serum IgG was possible with the volumes that could be given intramuscularly. Furthermore, at least 10% of patients had severe anaphylactoid reactions after IMIG, possibly due to inadvertent injection of material into a vein. Some clinicians turned to fresh frozen plasma as an alternative, but this carried a substantial risk of transmitting NANB hepatitis. The problem was apparently solved by intravenous immunoglobulin (IVIG) therapy, which soon became established as the treatment of choice for many patients with primary hypogammaglobulinaemia: early trials showed good evidence of improved prophylaxis against infection. Nevertheless, a substantial number of patients do well on IMIG. The decision to use IVIG is largely based on a clinical assessment of the severity and frequency of infections, and not on the serum immunoglobulin levels at diagnosis. Optimism about the safety of IMIGs meant that no-one was prepared for the outbreaks of NANB -
could the generalist usefully do for a severe bums contracture, osteomyelitis of the tibia, or a rectovaginal fistula? If the front-line doctor is not an orthopaedic surgeon, how should he treat all the fractures? If with less-than-perfect skills and much-less-than-perfect asepsis and equipment, he attempts the fashionable open methods of osteosynthesis of the AO school (Arbeitgemeinschaft fiir Osteosynthesenfragen), it will too often earn its sobriquet "always osteomyelitis". So, he needs the closed methods that will give his patients the best chances of a painless useful limb. Similar appropriate methods have now been assembled for twenty specialties of surgery and anaesthesia by a physician who, instead of soliciting chapters from his surgical colleagues, put himself into the position of the front-line doctor, wrote the chapters himself, and then asked the surgeons for their comments.4,5 The Declaration of Alma Ata listed health education among the eight essential activities of primary health care. It is hard to imagine a programme for the control of AIDS or diarrhoea without it. It is also part of the general process of development that enables people to take control of their lives by learning how to prevent or control disease. Health education should therefore be one of the front-line doctor’s skills, and he should be expert enough to know how to make it work. Remarkably, there is little firm evidence about whether it works, and under what conditions, or how it is best done. A review6 of the scientific quality of sixty-seven attempts to evaluate health education programmes found that only three met all four of the following criteria: (a) they were sufficiently well described to be replicable (47%); (b) they described the educational level of the target group (40%); (c) they were controlled studies of more than 60 people or two clusters (21 %); (d) they used observable changes in health status (33%) or behaviour (33%) as an endpoint. Within these severe limitations, the results in the articles confirm the commonly accepted view that successful health education depends on the use of a few messages, of proven benefit, repeatedly, in many ways. The surgeon superintendent of a well-known district hospital in Africa gave as his priorities the administration, the staff, the plant, and only then the patients, on the grounds that patients, especially in quantity, cannot be cared for satisfactorily until the first three priorities have been met. The role of the front-line doctor as manager has been described in valuable detail by Pearson,8 who covers such matters as provision of supplies ("beware of fraud"), accounting ("don’t keep public and private money together"), and even how to keep the roof on the hospital in a high wind. In many such hospitals the staff, even the doctor, may have to grow their own food. As one of them lately wrote from Ghana: "The maize farm in the backyard is as green as ever, the rabbits, sheep, goats and chickens are doing well, and that is survival, even for the doctor!"
1. Silver GA. The uses of adversity. Lancet 1991; 337: 1404-05. 2. WHO and UNICEF. Declaration of Alma Ata. Lancet 1978; ii: 1040-41. 3. WHO. Hospitals and health for all. WHO Tech Rep Ser 1980; 774. 4. King MH. Primary surgery. 2 vols. Oxford: Oxford University Press, 1990. 5. King MH. Primary anaesthesia. Oxford: Oxford University Press, 1986. 6. Levinsohn BP. Health education interventions in developing countries: a
methodological review of published articles. Int J Epidemiol 1990; 19: 788-94. 7.
King MH, Hall R. Zambia: commitment triumphs over adversity. Lancet
1991; 337: 166. 8. Pearson CA. Medical administration for front line doctors. FSG Communications, 57/59 Whitechapel Road, London E1 1DU, UK. 1990. ISBN 1-87118016.
The brain in fulminant failure
hepatic
When accompanied by coma, fulminant hepatic failure carries a high mortality. Important causes of coma are cerebral oedema and intracranial hypertension, in which death is caused by cerebral herniation. The typical signs and symptoms of raised intracranial pressure such as headache, bradycardia, and papilloedema are usually absent. Computed tomographic scanning is a poor and unreliable method of detection1 although it may be valuable in displaying the focal intracranial lesions that sometimes accompany acute hepatic failure.2 Since there is still no reliable non-invasive method, intracranial pressure has to be measured via an extradural or epidural device. The cause of cerebral oedema in fulminant hepatic failure remains uncertain. Current thinking suggests two major pathophysiological mechanismsvasogenic and cytotoxic. In the former, the bloodbrain barrier breaks down and allows serum protein to leak through the normally selectively permeable capillary endothelium into the brain parenchyma; in cytotoxic oedema, intracellular uptake of water leads to brain cell swelling. At a molecular level these two processes have much in common and cannot be readily separated.3 Inhibition of Na/K-ATPase, toxin-induced disturbance of blood-brain barrier permeability, osmotic effects of glutamine, and primary injury to astrocytes have all been proposed as contributors to the brain damage.4Although there is little doubt about the importance of raised intracranial pressure in the production of cerebral oedema, correlation between the two is poor.5,6 Cerebral perfusion pressure-the difference between mean arterial pressure and intracranial pressure-is a useful prognostic indicator, mean values of less than 40 mm Hg being associated with ischaemic brain injury. In fulminant hepatic failure, unlike many other conditions associated with raised intracranial pressure, cerebral blood flow is usually subnormal.’ What can be done to reduce intracranial pressure and prevent the lethal sequelae of cerebral oedema? Intravenous mannitol is effective, but repeated use tends to be harmful since it results in hyperosmolarity and cell dehydration. Hyperventilation relieves intracranial hypertension8 but the reduction in cerebral blood flow caused by lowering of PCO2 may
157
provoke
further brain
damage. Thiopentone9
and
dexamethasone also reduce intracranial pressure in most types of cerebral oedema but dexamethasone has
proved disappointing in hepatic failure. None of these than a transient effect and it is doubtful whether any of them has any impact on survival unless the underlying cause of the intracranial hypertension is dealt with. Emergency liver transplantation alone offers this possibility, 10 and highly encouraging reports have emerged from some units." There are, however, many disappointing instances of patients not regaining consciousness after apparently successful grafting.ll,12 Such failures may be attributable to irreversible brain damage, either present at the time of transplantation or possibly precipitated by the surgical procedure itself. A paper from King’s College Hospital, London, provides information in this regard. Keays and co-workers13 report their experience of monitoring intracranial pressure and cerebral perfusion pressure continuously before, during, and after liver transplantation in six patients with fulminant hepatic failure. Intracranial pressure rose from the induction of anaesthesia to the pre-clamp phase of the operation, fell slightly during the anhepatic phase, and rose further during reperfusion. Cerebral perfusion pressure fell during induction and remained low throughout the operation. Although intracranial hypertension and critically low cerebral perfusion pressure was noted in most patients, only two of the six failed to regain consciousness and careful examination of the pressure indices does not reveal any striking differences between those who died and those who recovered. The number of patients was small (the authors have done well even to produce these limited data) but the results raise important questions concerning the value of intracranial pressure measurement. The notion that life or death is determined by pressure measurements is likely to be too simple; perhaps we need to look at the brain cells and their chemical constituents for the critical changes that affect the brain in fulminant hepatic failure. Existing techniques have precluded such investigation, but nuclear magnetic resonance, with its potential for analysing intracellular metabolites, may offer scope for future research.14 treatments has
more
1. Munoz SJ, Robinson M, Northrup B, et al. Elevated intracranial pressure and tomography of the brain in fulminant hepatic failure. Hepatology
1991; 13: 209-12. 2. O’Brien CJ, Wise RJS, O’Grady JG, Williams R. Neurological sequelae in patients recovered from fulminant hepatic failure. Gut 1987; 28: 93-95. 3. Klatzo I. Pathophysiological aspects of brain oedema. Acta Neuropathol
1987; 72: 236-39. 4. Blei AT. Cerebral edema and intracranial hypertension in acute liver failure: distinct aspects of the same problem. Hepatology 1991; 13: 376-79. 5. Nora LM, Bleck TP. Increased intracranial pressure complicating hepatic failure. J Crit Illness 1989; 4: 87-89. 6. Ede RJ, Williams R. Hepatic encephalopathy and cerebral oedema. Semin Liver Dis 1986; 6: 107-18. 7. Almdal T, Schroeder T, Ranek L. Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases. Scand J Gastroenterol 1989; 24: 299-303.
8. Ede RJ, Gimson AES, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. J Hepatol 1986; 2: 43-51. 9. Forbes A, Alexander GJM, O’Grady J, et al. Thiopental infusion in the treatment of intracranial pressure complicating fulminant hepatic failure. Hepatology 1989; 10: 306-10. 10. Editorial. Transplantation for liver failure. Lancet 1987; ii: 1248-49. 11. Bismuth H, Samuel D, Gugenheim J, et al. Emergency liver transplantation for fulminant hepatitis. Ann Intern Med 1987; 107: 337-41. 12. Emond JC, Aran PP, Whitington PF, Broelsch CE, Baker AC. Liver transplantation in the management of fulminant hepatic failure. Gastroenterology 1989; 96: 1583-88. 13. Keays R, Potter D, O’Grady J, et al. Intracranial and cerebral perfusion changes before, during and immediately after orthotopic liver transplantation for fulminant hepatic failure. Q J Med 1991; 79: 423-33. 14. Bosmann DK, Deutz NE, De Graaf AA, et al. Changes in brain metabolism during hyperammonaemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatology 1990; 12: 281-90.
Immunoglobulin therapy When
unmunoglobulms, injected intramuscularly
(IMIG), were first used for prevention of infection in primary hypogammaglobulinaemia-after some basic technical work on fractionation of plasma proteins during the 1939-45 war1—most donor plasma pools were contaminated with hepatitis B virus. Fortunately the fractionation procedure, which entailed a series of alcohol precipitation steps, substantially reduced infectivity.2 Some IMIGs did transmit hepatitis B in those early days, but for the past 12 years the risk has been virtually eliminated by screening of donors for hepatitis B surface antigen. IMIG has also enjoyed a long record of safety in regard to non-A non-B (NANB) hepatitis. The reasons’ are not clear but lie partly in the route of injection, the small amount of material injected, and the possibility that non-A non-B viruses are inactivated in liquid preparations during storage before being distributed to pharmacies. During the 1970s clinicians treating primary hypogammaglobulinaemia patients realised that IMIG gave less than total protection against infection, and that only a modest rise in serum IgG was possible with the volumes that could be given intramuscularly. Furthermore, at least 10% of patients had severe anaphylactoid reactions after IMIG, possibly due to inadvertent injection of material into a vein. Some clinicians turned to fresh frozen plasma as an alternative, but this carried a substantial risk of transmitting NANB hepatitis. The problem was apparently solved by intravenous immunoglobulin (IVIG) therapy, which soon became established as the treatment of choice for many patients with primary hypogammaglobulinaemia: early trials showed good evidence of improved prophylaxis against infection. Nevertheless, a substantial number of patients do well on IMIG. The decision to use IVIG is largely based on a clinical assessment of the severity and frequency of infections, and not on the serum immunoglobulin levels at diagnosis. Optimism about the safety of IMIGs meant that no-one was prepared for the outbreaks of NANB -
