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region,’ with data for each diagnosis, operation, and specialty. e

We used an approach that allowed us to distinguish cross- r

boundary flows that occur as a result of specialist practice I

(among other reasons), from those that arise merely because of (

geographical convenience. Levels of inflow for the treatment of !

specific acute conditions, such as appendicitis and acute I

pneumonia, were used to estimate cross-boundary flows due to 1

geographical convenience. Raised levels into the teaching j

district only, or into other districts with acknowledged 1

supradistrict expertise, should identify patients who are :

specifically referred to the specialist care available there.In the teaching district, the proportion of inpatients from

other districts varied by specialty from 3% in geriatrics to 79%in neurosurgery. Overall, 21% of patients admitted in theteaching district and 9-2% admitted in the non-teachingdistricts were residents of other districts. However, for manyconditions (eg, asthma, peritonitis, inguinal hernia) this

proportion was similar in all districts, at about 10% or less.Certain other conditions show much higher levels of cross-boundary flow than this percentage, but into both the teachingdistrict and the non-teaching districts (eg, 20% for fracture ofthe tibia). We recorded flows that were higher into the teachingdistrict than into non-teaching districts for patients likely to betreated by supra-district specialists. These included, for

example, patients with diabetes (15% non-residents in theteaching district vs 8% in the non-teaching districts), Crohn’sdisease (30% vs 8%), arthroplasty (45% vs 14%), andhaemophilia (73% vs 5%).

Supra-district specialist work is not confined to the smallspecialties, a point that you did not bring out. Our results showthat patient flows to teaching hospital experts in the generalspecialties are also substantial (general medicine 22% vs 9%,general surgery 16% vs 8%). The importance of identifyingthis workload lies in the complexity of the care that thesepatients receive and therefore the costs incurred. A patientreferred to a teaching hospital for the management of diabetes,for example, is almost certainly going to be more expensive totreat than the average patient in the same specialty. Theinformation available for monitoring contracts is not generallysophisticated enough to prevent units that provide specialisedcare within general specialties from being financiallydisadvantaged by doing so.We agree, therefore, that there is a need to put in place a

mechanism within the internal market that would take accountof the special position of supra-district specialist care. It is alsotrue that the ramifications of large scale changes in the NH S arevery difficult to predict without quantifying clinical activity.

John Newton, Michael GoldacreUnit of Health-Care Epidemiology, Department of Public Health and Primary Care,University of Oxford, Headington, Oxford OX3 7LF, UK

1 Donaldson LJ. Maintaining excellence: the preservation anddevelopment of specialised services. BMJ 1992; 305: 1280-84.

2 Newton JN, Goldacre MJ. How many patients are admitted in districtsother than their own, and why? J Publ Health Med (in press).

WHO recommendations for IVF

SIR-Stephenson and Wagner (June 26, p 1648) correctly pointout that the clinical and public health approaches to healthpolicy are both necessary and complementary, but go on toattack WHO for holding the scientific group meeting, whichresulted in the WHO technical report on medically assistedconception.The Scientific Group was organised by the Special

Programme of Research, Development, and Research

Training in Human Reproduction, which is co-sponsored byUNDP, UNFPA, WHO, and the World Bank and funded from

xtra-budgetary resources (and not from WHO’s "limited’esources"), to collate and review the state of the art of

nedically-assisted conception. The scientific group was

;onvened as a result of requests from WHO member states for a;ummation of available technical information concerningmedically-assisted conception. These requests were passed onto the special programme. The meeting on health policyFormulation on medically-assisted conception, on the otherhand, was undertaken on the initiative of the WHO EuropeanRegional Office, it was meant to provide clear guidelines forpolicy makers and governments. The two meetings weretherefore complementary, in that the special programme’sco-sponsors felt-in the presence of abuse and confusion-that

indications, limitations, risks, and technical procedures inmedically-assisted conception needed to be clearly defined,specifically to help governments decide on the public healthaspects.The scientific group was not called upon to pronounce upon

public health policy issues; in addition, the technical reportdoes not make any statement that could be construed as astatement of WHO policy. The scientific group and the

meeting organised by the WHO European Office merely dealtwith the two separate and equally important aspects of theproblem. Neither meeting should be interpreted as

formulating WHO’s policy in this area. The report of thescientific group is a part of the WHO Technical Report Serieswhich makes available the findings of various internationalgroups of experts that provide the international communitywith the latest scientific and technical advice on a broad rangeof medical and public health subjects.

Giuseppe BenagianoSpecial Programme of Research, Development and Research Training in HumanReproduction, WHO, 1211, Geneva, Switzerland

Life-sustaining treatment and locked-insyndrome

SIR-Allen’s July 17 commentary on treatment withdrawal forconscious patients with severe neurological disabilityrefreshingly draws attention to the ethical issues clinicians facein the management of such patients. As Allen points out,conscious and legally competent patients have a right to makehealth care decisions about themselves, including whether toaccept or refuse life-sustaining treatment. Few clinicians haveexperience in the management of long-term survivors of thelocked-in syndrome (LIS), and decisions about the use orotherwise of life-sustaining treatments often incorporate somedegree of value judgment about a patient’s present and futurequality of life. The few data1,2 available emphasise prognosis interms of survival and recovery of self-care activities of dailyliving, with little information on the emotional outlook ofpatients, and ignore the effects on care-givers.We examined the quality of life of seven long-term survivors

of LIS (mean age 43 years) identified from our institution andthe nearby Julia Farr Centre, a large chronic care andrehabilitation facility. Five cases had a vascular aetiology, andduration of LIS ranged from 8 to 37 months. Semi-structuredinterviews took place with each patient and their principalcarer, usually a spouse. Only one patient had enough functionto operate a manual or electric wheelchair; all the others wereheavily dependent on others for basic care. Four patients werecontinent, six needed assistance with feeding (gastrostomyin-situ), and four used various types of communication aids.The table summarises the patients’ responses to several

measures of quality of life. According to the Spitzer quality oflife index4 all patients scored 2/2 for the index for support,whereas five patients scored 2/2 for the health index for the

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*General health questionnaire; tSpltzer quality of life index; #Response to the question "If youdeveloped pneumonia tomorrow, would you want antibiotics?"

Table: Quality of life responses

previous week. Six patients had the lowest score (0/2) for bothdaily living and activity categories, and six scored 1/2 for theiremotions, anxiety, and depression. Overall, the mean score forthe Spitzer index was five, indicating these patients with LIShad on average a worse quality of life than cancer patients(mean 7-1), but better than that of terminally ill patients (mean3-3). The general health questionnaire (GHQ-28) could onlybe administered to five patients, three of whom scored 5 ormore within the range for depressive illness. Four patientsadmitted suicidal thoughts. It was important, therefore, toknow whether or not these patients would want life-sustainingtreatment. To our surprise, all patients responsded "yes" to thequestion about antibiotic treatment (table).Our results show that the LIS is a devastating illness, with

long-term survivors remaining heavily dependent on others forcare; they have a poor quality of life, and depressive reactionsare common. However, these patients continue to make smallbut meaningful recovery, and reject the opportunity to endtheir lives, since they would want antibiotic treatment forinfections.

Craig Anderson, Catherine Dillon, Richard BurnsDepartment of Medicine (Neurology), Flinders Medical Centre, Bedford Park,South Australia 5042

1 Patterson JR, Grabois M. Locked-in syndrome: a review of 139 cases.Stroke 1986; 17: 758-64.

2 Katz RT, Haig AJ, Clark BB, Di Paola RJ. Long-term survival,prognosis, and life-care planning for 29 patients with chronic locked-insyndrome. Arch Phys Med Rehabil 1992; 73: 403-08.

3 Spitzer WO, Dobson AJ, Hall J, et al. Measuring the quality of life ofcancer patients. J Chron Dis 1981; 34: 585-97.

4 Goldberg DP, Hillier DF. A scaled version of the General HealthQuestionnaire. Psychol Med 1979; 9: 139-45.

Hyperprolactinaemia during famotidinetherapy

SiR-Cimetidine, and to a lesser extent ranitidine, cause

hyperprolactinaemia and induce gynaecomastia in men andbreast engorgement in women. There is no evidence that

famotidine influences prolactin secretion. 1,2 We describe a casein which hyperprolactinaemia and breast engorgement wererelated to famotidine.A 67-year-old woman with a duodenal ulcer had been treated

with cimetidine and then with ranitidine. Because of

exacerbation of peptic disease famotidine was prescribed.However, as a result of a misunderstanding, she receiveddouble the usual maximum dose of famotidine (80 mg daily) for5 months. In the fourth month of therapy she had breast pain.Her breasts were sensitive and engorged, without evidence ofcysts, masses, or galactorrhoea. Mammography was normal aswere routine blood tests. Prolactin was increased to 130 ng/mL(normal = 5-15) with normal levels of oestradiol (15 pg/mL),luteinising hormone (18-8 mIU/mL), follicle-stimulatinghormone (72-8 mIU/mL) and thyrotropin (1 -5 mU/mL).

After stopping famotidine the breast changes disappearedwithin about 2 months, with a decrease in prolactin (to 50-8 and

5-5 ng/mL at 2 and 3 months respectively). A macrophagemigration inhibition factor (MIF) assay, done by interactingthe patient’s lymphocytes with macrophages of normal

guineapigs,3 was strongly positive with famotidine in two of thethree assays (migration index 0-66 and 0-63, 0-80 is positive).

Prolactin secretion is stimulated by an intravenous bolus ofcimetidine 200-400 mg, and to a lesser degree by the injectionof 200-300 mg ranitidine.4 By contrast, single intravenousdoses of famotidine 20 mg were associated with significantdecreases in serum prolactin.5 Furthermore, prolactinsecretion was unaffected when famotidine was given orally at40 mg daily for 4 weeks in duodenal ulcer patients. In our case,the oral administration of a large dose of famotidine for a longerperiod was followed by a rise in prolactin and breast changes.Although we did not rechallenge our patient, as did Santucci

et al,6 in a case of omeprazole-associated gynecomastia, webelieve that the adverse effect observed in our case was caused

by the sustained excessive intake of famotidine. Supportingthis view are the disappearance of the hyperprolactinemia afterdiscontinuation of famotidine, the positive MIF assaysuggesting a cellular hypersensitivity mechanism, and theabsence of other therapy.

Georges Delpre, Mordechai Lapidot, Avner Lipchitz, Ella Livni,Uri Kadish

Institutes of Gastroenterology and Adult Endocrinology Beilinson Medical Center,Petah Tikva 49100, Israel; and Sackler Faculty of Medicine, Tel-Aviv University, Israel

1 Giusti M, Savarino V, Bessarione D, Magnolia MR, et al. Prolactinbehaviour during long-term famotidine treatment in man. Clin PharmTher 1986, 14: 3.

2 Langman MJ. The effects of histamine H2 antagonists upon drugmetabolism and upon the endocrine system. In: Mignon M, GalmicheJP, eds. Safe and effective control of acid secretion. Paris: John LibbeyEurotext, 1988: 135-40.

3 Delpre G, Grinblat J, Kadish U, Livni E, Shohat B, Joshua H.Immunological studies in a case of hepatitis following methyldopaadministration. Am J Med Sci 1979; 277: 207-14.

4 Langtry HD, Grant SM, Goa KL. Famotidine: an updated review ofits pharmacodynamic and pharmacokinetic properties, and therapeuticuse in pepetic ulcer disease and other allied diseases. Drugs 1989; 38:551-90.

5 Hayakawa A, Ohe K, Miyoshi A, Marasawa S, Miwa T. Properties offamotidine in relation to safety. Ital J Gastroenterol 1984; 16: 174-76.

6 Santucci L, Farroni F, Fiorucci S, Morelli A. Gynecomastia duringomeprazole therapy. N Engl J Med 1991; 324: 635.

Zolpidem side-effects

SiR-Cavallaro and colleagues (Aug 7, p 374) report tolerancewith withdrawal phenomena in two patients treated with

zolpidem. In fact, we read of chronic overdosing and misuse intwo patients, with serious psychiatric histories. The first

patient was previously a heavy user of triazolam, thioridazine,and, promazine, and had made three suicide attempts (post-marketing surveillance, information on file). She had

experienced two convulsive episodes in the past two years. Weare surprised that no nausea or vomiting was reported.Gastrointestinal disturbances and vomiting were the mostcommon side-effects of zolpidem in several studies and in morethan 280 cases of suicide attempt with zolpidem doses over50-60 mg. We also do not understand how, after two months of"tolerance" or "resistance" to zolpidem, the first patientsuddenly became sensitive again to the drug (poorly oriented,confusion, dysarthric), which corresponds to what is seen in thehypnagogic phases of overdosing. In the second case, thetolerance may have been due to recurrence of depression,which would fit the symptoms.

In our experience of over 30 000 cases, no tolerance orwithdrawal signs to zolpidem have been observed or reportedin normal conditions of use in insomniac patients. Drug