MIDAZOLAM IN TERMINAL CARE

67

intermittent bowel and urinary incontinence. He had multiple tattoos on his arms, back, and chest. Routine laboratory studies were normal excpt for a T4/T8 quotient of 0-8. He was HIV antibody positive. A spinal myelogram and magnetic resonance imaging of the head and spinal cord were normal. Cerebrospinal fluid (CSF) protein was 66 mg/dl, glucose 56 mg/dl, with 0 white blood cells/1. Bacterial, viral, and fungal CSF cultures revealed no growth. HIV-associated myelopathy was diagnosed and zidovudine was started. The patient denied homosexual activity, intravenous drug use, and blood transfusions. He had had sex with prostitutes before his incarceration. 7 months before the onset of his illness he had been given multiple tattoos from a fellow prisoner. The same "dirty" needles had been used to tattoo other inmates.

Tattooing is not uncommon in certain segments of the population, one being male prisoners. Lately, self-tattooing, even schoolchildren, has been noted.l Both patients had been tattooed in prison with unsterilised needles and this is a potential source of transmission of HIV; in case 2 prostitutes may have been a risk factor. Clinicians should be alert to amateur tattooing in prison as a possible source of HIV infection. among

Section of Hematology/oncology,

Harry S. Truman Memorial Veterans Hospital, University of Missouri, Columbia, Missoun 65201, USA McDonald

1. Thompson W,

DONALD C. DOLL

JCH. Self-tattooing by school children. Lancet 1983;

ii

1243-44

AIDS AND MEDICAL ETHICS

SIR,-We do

not

need

to

reinvent the wheel

or

"reintroduce"

AIDS-plague doctors, as suggested by Dr Rubenstein (Dec 12, p 1079). Infection specialists already exist and are unlikely to fail to face up to the challenge of AIDS any more than to the dangers of haemorrhagic fevers or other dangerous infections with which they are accustomed to dealt No doubt, however, their depleted ranks could usefully be reinforced. Incidentally, both Samuel Pepys and his own doctor were among those who did not flee London in the Great Plague. Pepys states that the plague began in the city on about June 10, 1665, in the house of his own doctor where the manservant died from bubonic plague. After some weeks of self-imposed quarantine, Dr Burnett returned to activity but eventually fell "victim to his own zeal", probably as a result of participating in a post-mortem examination, on Aug 25, 1665 .2 CDS Unit, Ruchill Hospital, Glasgow G20 9NB

NORMAN R. GRIST

Department of Infectious Diseases, Ruchill Hospital

DERMOT H. KENNEDY

1. Grist NR. Infections a new awakening? J Infect 1985, 11: 1-3. 2. Pepys S. In. Braybrooke R, ed Diary and correspondence of Samuel Pepys, FRS, 4th ed London: Hurst & Blackett, for Henry Colbum, 1854.

ATENOLOL IN IRRITABLE BOWEL SYNDROME

SIR,-Dr Marzuk (Nov 14, p 1143) reports a single case in which atenolol might have been an effective treatment for irritable bowel syndrome (IBS). Thyrotoxicosis could have accounted for the case features and was not specifically mentioned as having been excluded. Single case studies are amenable to statistical analysis, to exclude a placebo effect, and this case would have been ideal for such an approach.l Our studies with atenolol in IBS are less optimistic. Our rationale for starting a pilot study of atenolol was that upper

gastrointestinal function in man (which is disturbed in IBS2) is controlled by a &bgr;-adrenergic mechanism under both non-stressful’ and stressful’ conditions. Fielding and Regans have suggested that patients with IBS show a marked cardiovascular response to stress, although Fielding** found no symptomatic benefit with timolol. We used atenolol (100 mg daily) for 2 weeks in eight patients with typical symptoms of IBS and negative investigations (four diarrhoea predominant, four abdominal pain and bloating), and assessed symptomatic response. We also measured oro-caecal transit off and on the drug. Only one patient reported symptomatic

improvement with a reduction in post-prandial bloating. All patients’ transit times (30-105 min) were within the range expected from our normal data (30-165 min). The reduction in transit time induced by atenolol (0-60 min) was also within the normal range (0-80 min). Because atenolol had little

or no

effect

on

symptoms in these

patients, despite a measurable effect on gut function, we felt it inappropriate to proceed to a larger trial until the pathophysiology of IBS and the role of the adrenergic system in IBS are better However, p-blockers, selective or not, are useful in inhibiting some somatic manifestations of stress and may be helpful in certain anxious patients with IBS.

understood.

Department of Gastroenterology, Oldchurch Hospital, Romford, Essex RM7 0BE Department of Medicine, Hope Hospital, Salford 1.

A. S. MCINTYRE W. R. BURNHAM D. G. THOMPSON

Guyatt G, Sackett D, Taylor DW, Chong J, Roberts R, Pugsley S Determining optimal therapy: Randomized trials in individual patients. N Engl Med 1986; 314: J

889-92. 2. Cann PA, Read NW A disease of the whole gut? In. Read NW, ed. Irritable bowel syndrome. London: Grune & Stratton, 1985. 53-63 3. Mclntyre AS, Thompson DG, Burnham WR, Walker E. Sympathetic modulation of human intestinal transit. Gastroenterology 1987; 92: 1527 4. O’Brien JD. Studies of the effects of experimental stress on upper gastrointestinal function. London: University of London, 1987. MD thesis. 5. Fielding JF, Regan R. Excessive cold pressor responses in the irritable bowel syndrome. Irish. J Med Sci 1984; 153: 348-50. 6. Fielding JF. Timolol treatment in the irritable bowel syndrome. Digestion 1981; 22: 155-58.

MIDAZOLAM IN TERMINAL CARE

SIR,-In terminal cancer we often use continuous subcutaneous infusions of diamorphine. Of 151 patients who died at this hospice between July and October, 1987,99 (65-6%) received subcutaneous infusions of diamorphine in the terminal phase of their disease. Patients with respiratory distress due to secretions in the upper airways were also given hyoscine, usually in the last few hours. Several such patients require sedation, and we normally use methotrimeprazine, which has antiemetic, antihistamine, and sedative properties.’ It is analgesic in its own right and is stable in solution with diamorphine.12 42 of the patients on subcutaneous diamorphine also received methotrimeprazine; in 7 methotrimeprazine was replaced by midazolam. We have faced two clinical problems with methotrimeprazine. First, parkinsonian symptoms may arise (or be worsened in patients with pre-existing parkinsonism). Secondly, in very agitated or distressed patients, and especially those with prominent dyspnoea, this drug has not provided adequate sedation. We have used rectal diazepam for additional sedation but this approach has drawbacks in patients with rectal tumours or rectal leakage. Midazolam is used as an intravenous anaesthetic induction agent and for intravenous sedation for minor procedures. 8 male and 3 female patients aged 20-81 years (mean age 66 [SD 16] years) received midazolam in combination with diamorphine; 7 patients were given hyoscine as well. All drugs were combined in the same syringe. 7 of the 11 patients had had parkinsonian symptoms while on methotrimeprazine; 1 had Parkinson’s disease; and 3 patients had severe dyspnoea secondary to intrathoracic tumour. The initial dose of midazolam was 1-51 (SD 0-96) rising to 2-54 (1-91) mg/h. The initial dose of diamorphine (which had in all cases been used for at least 48 h before midazolam was given) was 16.06 (31 29) rising to 30-16 (61 99) mg/h. The combination was administered for 21-25 (12-88) h. If patients switched from methotrimeprazine to midazolam are excluded, the combination was given for 34 19 (14-83) h. The 35 patients given methotrimeprazine as an adjunctive sedative, without changing to midazolam, received the drug for 38-62 (22-86) h. We found midazolam in combination with diamorphine (and, when necessary, hyoscine) to be an effective sedative for continuous subcutaneous administration. It was stable in the syringe for up to 24 h; we observed no local skin reactions and no other adverse effects. In view of midazolam’s potential for respiratory depression, in combination with opioids, patients were observed closely, but no unusual changes in respiratory patterns were observed. More

68 invasive assessment of respiratory function was not justified. The chief disadvantage is the large volume required to deliver the drug at high doses; the syringe driver used (Graseby MS16A, Graseby Medical, Watford) is designed for a 10 ml syringe. We feel that midazolam has a part to play in symptomatic relief in terminal disease when other sedatives for subcutaneous infusion are ineffective or contraindicated. St Catherine’s Hospice, Crawley, West Sussex RH10 6BH 1.

Twycross RG. In. Saunders CM The management Edward Arnold, 1978. 65-92

EMILE DE SOUSA BRIDGET A. JEPSON of terminal disease London:

2. Baines M. In: Saunders CM. The management of terminal disease. London: Edward Arnold, 1978 99-118.

Conference ’

Developments in Toxicology: Retrospect and Prospect

AT a symposium at Guy’s Hospital, London, on Nov 20-21, held in honour of Dr Roy Goulding, founder of the National Poisons Information Service and first director of the Poisons Unit, Guy’s Hospital, Sir Robert Kilpatrick (University of Leicester) commented on the change of emphasis in toxicology over the past thirty years from a view of the expected benefits of novel compounds to a widespread concern over potential risks. This tendency could distort the scientific approach, as it had with the herbicide aldicarb, which had recently been banned in the USA because of an inverse dose-response curve.

Experimental Toxicology Dr Tom Connors (MRC Toxicology Unit, Carshalton) defined the purpose of toxicology as the reduction of morbidity and mortality due to exposure to toxic substances and, possibly, ionising radiation. He was concerned that the present emphasis on "strategic" research diverted funds to a search for answers to specific questions-to the detriment of basic research. Short-term cancer tests had been ossified since the late 1950s and were now of little use in reducing the incidence of cancer. Fundamental work by the Millers, Ames, Parke, and others, however, had led to greater understanding of the mechanism of chemical carcinogenesis and work by Farmer et al on haemoglobin alkylation meant that it was now possible to monitor and even quantify carcinogen exposure. The apparent paradox that activation and deactivation of carcinogens were both mediated by cytochrome P 450 was discussed by Prof Dennis Parke (University of Surrey). In 1961 Remmer proposed the existence of two forms of this enzyme with different specificities. It is now known that there are up to 90 cytochromes P 450 in four major groups. Thus cytochrome P 4501 (cytochrome P 448) inserts oxygen at hindered positions on compounds such as polynuclear aromatic hydrocarbons, many of which also induce this enzyme. Cytochrome P,;oI, which appears in the fetus before cytochrome P4so itself (cytochrome P450III), may have evolved to fulfil a role in steroid metabolism but it is now probably redundant. Cytochrome P450II1 is found in all phylogenetic groups from amphibia onwards and is concerned with the detoxification of xenobiotics. Active intermediates may be involved in the development of atherosclerosis, rheumatoid arthritis, and cataracts, as well as in carcinogenesis. Dr Francis Roe (Wimbledon) emphasised the difference between essential compounds, such as many drugs and pesticides for which "safety margins" were needed, and "non-essential" substances, such as cosmetics, which should be used at a "no-effect" level. In both cases rigorous control of experimental design and of the interpretation of results was required to ensure consistency in toxicity testing. A hitherto neglected factor was that food and water were allowed ad libitum in many experiments, contrary to the lifestyle of animals such as rodents in the wild. Recent work by Salmon et al has shown that restricted feeding decreases organ weight, enzyme induction, and the incidence of neoplastic changes, with obvious implications for toxicity assessment. Discussing the basis for carcinogenicity testing, Dr Richard

Carter (Royal Marsden Hospital, London) felt that epidemiological data were most useful when there was a large risk and a clear dose/response and when changes in exposure led to changes in incidence. It was, however, emphasised that there were no data for most environmental/occupational chemicals. With long-term bioassays the concept of the maximum tolerated dose was questionable and the interpretation of results was difficult if there was no clear dose/response. Knowledge of spontaneous tumour incidence in animals was inadequate, so it was nearly impossible to use such studies to provide quantitative assessment of human risk. Mr Frank Sullivan (United Medical Schools of Guy’s and St Thomas’) discussed the reproductive toxicology tests employed in the UK and USA in relation to the segmented tests used in Japan; and he concluded that the Japanese system was perhaps better. In the future there would be less emphasis on dose and more on pharmacokinetics. Caffeine was teratogenic at a single dose of 100 mg/day but not at 4 x 25 mg/day, the peak concentration being important. In contrast, cyclophosphamide had an effect at a sustained low dose because the area under the curve was important. Behavioural teratology was a further major area of concern. The fetal alcohol syndrome was now the second or third most frequent cause of mental retardation in children in the UK. The contributions of methyl mercury, inorganic mercury, lead, phenytoin, and smoking to behavioural abnormalities remained uncertain. The problem of extrapolating metabolic and data from animals to man was addressed by Dr Bruce (Servier). Man metabolised most compounds relatively slowly and, although normalisation for life span and body weight could produce comparable data for some extensively metabolised compounds, the value of this approach was not yet clear. Kinetic measurements in man must be related to dynamic observations if they were to have any value, but at present most published papers did not fulfill this

epidemiological

kinetic

Campbell

criterion. Prof Andre McLean (University College London) emphasised that epidemiology could give some useful information on drug with phenobarbitone which, although causing hepatic in animals, did not have this effect in man because there seemed to be a threshold level. Postmarketing surveillance would continue to be important in assessing the safety of new products. He also discussed the role of intestinal enzymes in metabolism/toxicity studies. These enzymes were inducible and could respond rapidly to individual compounds while the liver enzymes responded more slowly to the diet as a whole. In neither case was there evidence that induction was harmful rather than adaptive. Mr Les Ness (Proctor & Gamble) reviewed the toxicity testing performed by the cosmetics industry. Some members of the symposium felt that much unnecessary animal work was performed, possibly because of a preponderance of experimental toxicologists on the various committees concerned. All that was often needed were answers to the simple questions "is it caustic?" and "does it sensitise?" Concern was also expressed that little attention was paid to percutaneous uptake and the consequent risk of systemic toxicity.

safety,

as

tumours

Applied Toxicology Discussing occupational toxicology, Dr Tim Carter (Health and Safety Executive) noted that legislation introduced in the last century to control heavy chemical usage was the earliest example of toxicological regulation. Subsequently many problems had been controlled, ranging from the elements lead and mercury to particulates responsible for pneumoconiosis. For many substances there was a long delay between exposure and the first manifestations of toxicity. Thus, although the carcinogenicity of blue asbestos was recognised by 1968, the number of documented cases continued to increase; and, with vinyl chloride, it was expected that new patients would present up to at least the year 2000. A further major problem was the difficulty in assessing adverse behavioural effects in the absence of reliable tests, while the possibility of alcohol or drug abuse must not be neglected in investigating individual cases. Prof Colin Berry (London Hospital Medical College) emphasised that pesticides, unlike many of the other compounds