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activation-induced cell death in patients with, than in those without, HIV-1 infection.10 The HIV-1 viral proteins Tat and gp120 have been shown to sensitise CD4-positive cells to Fas/Fas ligand-mediated, activationinduced apoptosis.11 HCV might alter either production or apoptosis of T cells, thus blunting the expected increase in CD4-positive cells. Although the primary site of HCV replication is hepatocytes, HCV also replicates in peripheral blood mononuclear cells12 and has been found in lymphoid tissue of patients coinfected with HIV-1.13 Although patients with HCV infection alone do not generally have alterations in mononuclear cell populations until there is advanced liver disease, perhaps HCV interferes with the ability of stem cells to proliferate during immune reconstitution. Another possible explanation is that HCV sensitises cells to apoptosis. HCV may bind to other molecules related to Fas, members of the tumour necrosis factor receptor superfamily, which in some circumstances may sensitise the cells to apoptotic signals.14 Intriguingly, Taya et al15 have reported that patients with HCV infection express a large amount of cell-surface Fas on peripheral blood mononuclear cells and that HCV RNA was preferentially detected from these Fas-positive cells. Thus, HIV-1 and HCV may act synergistically to increase apoptosis of CD4-positive cells. If HCV does have deleterious effects on CD4-cell responses with HAART, the implication is that patients with HCV/HIV-1 coinfection may benefit from anti-HCV therapy, both to decrease incidence of HCV-related advanced liver disease and to increase the effectiveness of HAART. The current best therapy for HCV infection, which is interferon plus ribavirin, may be difficult in HIV1-positive patients because of severe toxicity, especially in individuals on HAART. Moreover, there is evidence of antagonism in vitro between ribavirin and nucleoside analogues16, which has led to some concern about the use of ribavirin and HAART. Several prospective controlled treatment trials of HCV in the setting of HIV-1 infection are in progress, and it will be interesting to observe whether increases in CD4-cell count are a benefit of HCV treatment. A better outcome of HAART may depend ultimately on better therapeutic options for HCV in HIV1-infected individuals. Camilla S Graham, *Margaret James Koziel Infectious Disease Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA 1 2

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Alter MJ, Mast EE, Moyer LA, Margolis HS. Hepatitis C. Infect Dis Clin North Am 1998; 12: 13–26. Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology 1999; 30: 1054–58. Zylberberg H, Pol S. Reciprocal interactions between human immunodeficiency virus and hepatitis C virus infections. Clin Infect Dis 1996; 23: 1117–25. Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta VA (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis 1999; 29: 150–54. Jenny-Avital ER. Does hepatitis C virus really have no effect on survival in cases of infection with human immunodeficiency virus? Clin Infect Dis 2000; 30: 409–10. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000; 356: 1800–05. Pezzotti P, Galai N, Vlahov D, Rezza G, Lyles CM, Astemborski J. Direct comparison of time to AIDS and infectious disease death between HIV seroconverter injection drug users in Italy and the United States: results from the ALIVE and ISS studies. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 275–82.

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Donahoe RM, Vlahov D. Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 1998; 83: 77–87. Hellerstein M, Hanley MB, Cesar D, et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 1999; 5: 83–89. Gougeon ML, Montagnier L. Programmed cell death as a mechanism of CD4 and CD8 T cell deletion in AIDS. Molecular control and effect of highly active anti-retroviral therapy. Ann N Y Acad Sci 1999; 887: 199–212. Westendorp MO, Frank R, Ochsenbauer C, et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 1995; 375: 497–500. Lerat H, Berby F, Trabaud MA, et al. Specific detection of hepatitis C virus minus strand RNA in hematopoietic cells. J Clin Invest 1996; 97: 845–51. Laskus T, Radkowski M, Piasek A, et al. Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes. J Infect Dis 2000; 181: 442–48. Lai MM. Hepatitis viruses and signal transduction: true to the core? Hepatology 2000; 32: 427–29. Taya N, Torimoto Y, Shindo M, Hirai K, Hasebe C, Kohgo Y. Fasmediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C. Br J Haematol 2000; 110: 89–97. Vogt MW, Hartshorn KL, Furman PA, et al. Ribavirin antagonizes the effect of azidothymidine on HIV replication. Science 1987; 235: 1376–79.

Sedation in terminally ill patients Death from malignant disease is rarely the calm, dignified process so often portrayed on stage and screen. It is commonly heralded by agitation, mental anguish, and general unease and results in a well-recognised state, generally referred to as terminal restlessness.1 This syndrome is complex, with multiple possible causes, including metabolic disturbance, infection, fear, anxiety, uncontrolled symptoms, drug toxicity, confusion, and delirium. It can sometimes be relieved by simple measures, such as repositioning the patient or emptying a full bowel or bladder. In many cases the cause is irreversible and it is usually inappropriate or impossible to determine all contributory factors. A common management approach is sedation. Sedation is also used as a means of relieving specific symptoms (eg, dyspnoea) in patients with advanced disease. Similarly, in the minority of patients in whom pain cannot be fully controlled by standard techniques and analgesics, sedation is occasionally used as the only means of relieving overwhelming distress. The frequency of use of sedation in dying patients varies widely. R L Faisinger and colleagues2 have surveyed the practice of sedation up to the time of death in patients in four hospices in Israel, Spain, and South Africa. Patients were counted as having been sedated if the outcome was to make the patient unresponsive in order to achieve comfort. Delirium and dyspnoea were the commonest problems that had to be managed by sedation. The intent to sedate varied from 15% in Israel, to 36% in Cape Town. The length of time for which sedation was required was consistent across all centres and ranged between 1 and 6 days. The frequency of use of sedation in other published series varies from 20–52%,3 but comparisons are difficult because of differences in terminology and intent. In a retrospective survey at The Royal Marsden, 68 of 100 consecutive patients were receiving some form of sedative at the time of death (unpublished), but were these patients sedated? How does one define sedation? At one end of the spectrum, sedative drugs are used to control symptoms in a dying patient. The aim is not to render the patient unconscious but to use sedation as an adjunct to other symptom-control measures—for

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example, to relieve anxiety or to treat delirium. The drug doses necessary to achieve this effect are generally low. The patient is likely to have some impairment of consciousness already and may regain consciousness or wake through the sedation. At the other end of the spectrum, sedation is used when there is no other means of relieving an unendurable symptom. The classic example is the patient who is fully conscious and not necessarily close to death, but who has severe pain that cannot be controlled by standard means. Here, the intention is different. It is to maintain the patient in a state of unconsciousness so that he or she and does not have to continue to suffer the intolerable symptom. Sedation is maintained until death. This practice is somewhat controversial and attracts such labels as “terminal sedation” and “slow euthanasia”.4 It has been supported by the “double-effect” principle—ie, the concept that it is acceptable to give a medical treatment for the purposes of relieving suffering even though a foreseeable, unintended consequence of the treatment is to hasten death.5 The stated justification is that there is no other means of relieving intractable distress in a dying patient and that it is morally reprehensible to leave a patient to suffer intolerably. Chater and colleagues6 carried out a postal survey to assess the use of terminal sedation by palliative-care experts mainly from the UK and Canada. The majority of respondents agreed that the practice was sometimes necessary and had been used occasionally in the preceding 12 months. In the survey at The Royal Marsden, very few if any of the patients would have been sedated according to Chater’s definition of “the intention of deliberately inducing and maintaining deep sleep”. The concept of sedation causes considerable unease in many palliative-care workers, most of whom are ardently opposed to any form of euthanasia or patient-assisted suicide. Some centres try to avoid the use of sedation altogether by encouraging hydration, infection control, drug rotation, and opioid-dose reduction in dying patients.7 Others advocate the use of antipsychotic agents to sedate delirious and agitated patients in an attempt to improve cognitive function, rather than the use of benzodiazepines, which can only depress cognitive function. There is concern that sedation as the best means of symptom control in the dying patient may be underused because of the fear of employing “terminal sedation”. There are studies confirming that sedation is possible without shortening life. When patients who were sedated were compared with non-sedated patients dying in a hospice and a hospital, Stone et al8 found no significant difference in survival. Similarly, in a case-note review from St Christopher’s Hospice, London, patients receiving no or minimum sedation had a shorter median survival from admission than did those receiving sedatives thoughout.9 The use of sedation in patients with advanced incurable disease is a highly controversial and contentious issue. It points to the importance of palliative care and the experience of people skilled in both symptom control and end-of-life care. The controversy surrounding sedation is more than just a semantic issue. If the aim of good palliation is to avoid a “bad death”, this subject must be addressed openly. Janet Hardy Department of Palliative Medicine, The Royal Marsden, Sutton, Surrey SM2 5PT, UK 1

Back IN. Terminal restlessness in patients with advanced malignant disease. Palliat Med 1992; 6: 293–98.

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Fainsinger RL, Waller A, Bercovici M, et al. A multicentre international study of sedation for uncontrolled symptoms in terminally ill patients. Palliat Med 2000; 14: 257–65. 3 Fainsinger RL, Landman W, Hoskings M, Bruera E. Sedation for uncontrolled symptoms in a South African Hospice. J Pain Symptom Manage 1998; 16: 145–52. 4 Billings JA, Block SD. Slow euthanasia. J Palliat Care 1996; 12: 21–30. 5 Quill TE, Dresser R, Brock DW. The rule of double effect: a critique of its role in end of life decision making. N Engl J Med 1997; 337: 1768–71. 6 Chater S, Viola R, Paterson J, Jarvis V. Sedation for intractable distress in the dying: a survey for experts. Palliat Med 1998; 12: 255–69. 7 Bruera E, Franco JJ, Maltoni M, Watanabe S, Suarez-Almazor M. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration and opioid rotation. J Pain Symptom Manage 1995; 10: 287–91. 8 Stone P, Phillips C, Spruyt O, Waight C. A comparison of the use of sedatives in a hospital support team and in a hospice. Palliat Med 1997; 11: 140–44. 9. Sykes N. The management of difficult pain and other symptoms at the end of life. Pain in Europe III, advances in pain research and therapy, Nice, France. September 2000. Abstract ORC/06; 71–72

Challenge of pain in the cognitively impaired See page 1882 Pain is subjective and multidimensional. Responses to pain are expressed by self-report, changes in behaviour, and changes in physiological indices. Several self-report methods, observation scales, and physiological measures have been developed and used to assess pain. Yet the assessment of pain remains difficult. The subjective dimension of pain hampers its measurement. Both the experience of pain and responses to it are mediated by developmental, cognitive, and cultural factors, so they will differ between individuals. Furthermore, selfreporting demands cognitive ability; it does not work in children younger than 3 years of age or in the cognitively impaired. Finally, behavioural and physiological measures, although commonly cited, are not always indicative of pain.1 Cognitive impairment is usually classified on the basis of IQ scores2 as: mild, IQ 50–70; moderate, 35–49; severe, 20–34; and profound, below 20. International systems for classifying disability and disease3,4 categorise cognitive impairment on the basis of mental age. Mild impairment is equivalent to a mental age of 9–12 years, moderate 6–9, severe 3–6, and profound less than 3. Non-numerical classifications include the educable, the trainable, and the severely and profoundly cognitively impaired. The American Association on Mental Retardation definition places emphasis on intellectual functioning, and on psychological, emotional, and environmental factors.5 Very litle has been published on pain in the profoundly impaired and there are very few tools to assess the pain experience of this population.6 An exception is a study by Biersdorff,7 who reported that 25% of a sample of cognitively impaired individuals had a raised pain threshold. The threshold correlated positively with the severity of the impairment. Biersdorff also described impaired response to temperature extremes and self-injurious behaviour in these patients. Sometimes cognitively impaired individuals did distinguish between the sharp and the blunt end of a needle although they did not find the sharp end painful.7 There were even instances of paradoxical pain behaviour7 in which individuals had learned to mimic pain behaviour while not in pain. Other investigators 1867

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