2
383 hypogonadism,I3,14 and the initiation of puberty.ls,16 One interesting feature of the induction of ovulation with GnRH, analogous to the earlier findings in the rhesus monkey, is that the massive preovulatory surge of LH secretion occurs despite an unchanging GnRH pulse frequency or amplitude, , though this does not necessarily mean that the same is true physiologically. Supraphysiological GnRH stimulation, whether through increased frequency or amplitude or use of the "superactive" agonist analogues, produces a seemingly paradoxical inhibition of gonadotropin secretion.17,18 Although a post- receptor effect has been proposed 19 the mechanism appears to be a "down-regulation" of the GnRH receptors. 1,18,20. Normally, the gaps between the physiological pulses allow time for receptor recycling or regeneration. This inhibitory effect has led to an expanding range of applications for the GnRH agonists.in situations where a specific (and temporary, if required) reduction or abolition of gonadotropin secretion is beneficial. 17,18 These applications include contraception (both male and female) and the management of endometriosis, precocious puberty, and sex-hormone- dependent cancers (such as those of breast and prostate). For the gonads, too, pulsatile stimulation may be important. In the testis, a pulsatile pattern of LH initiates and maintains LH receptors and steroidogenesis whereas single large doses lead to end-organ desensitisation with loss of LH receptors,21 a down-regulation phenomenon similar to that concerning GnRH and the pituitary. For the gonads, however, pulsatile therapy is not necessary since large doses and infrequent administration (eg, human chorionic gonadotropin in hypogonadal men or follicle-stimulating hormone in anovulatory women) is effective. This is an aspect that may be re-evaluated now that smaller, more convenient, and more robust pumps have been developed. Further down the line, the pulses initially generated in the hypothalamus become blunter but they can be detected in ovarian oestradiol secretion in the follicular phase4 and progesterone secretion in the luteal phase.4,22 With progesterone secretion in the rhesus monkey the pulses are not always coincident with those of LH:22 they may be caused by changes in ovarian blood flow, or there may be an "ovarian oscillator". The reproductive end-organs may also release hormones in a pulsatile manner. Recent work in domestic animals has shown that the uterus releases prostaglandins in a 13 Valk TW, Corley KP, Kelch RP, Marshall JC. Hypogonadotrophic hypogonadism: Normal responses to low dose pulsatile administration of gonadotropin- releasing hormone. J Clin Endocrinol Metab 1980; 51: 730-38. 14. Donald RA, Wheeler MJ, Sonksen PH, Lowy C. Hypogonadotrophic hypogonadism resistant to hCG and responsive to LHRH: Report of a case. Clin Endocrinol 1982; 18: 385-89. 15. Marshall JC, Kelch RP. Low dose pulsatile gonadotrophin-releasing hormone in anorexia nervosa: a model of human pubertal development. J Clin Endocrinol Merab 1979; 49: 712-18 16. Hoffman AR, Crowley WR. Induction of puberty in women by long-term pulsatile administration of low-dose gonadotrophin-releasing hormone. N Engl J Med 1982; 307: 1237-41. 17. Sandow J, Clayton RN, Kuhl H. Pharmacology of LHRH and its analogues. In. Crosignani P, Rubin BL, eds. Endocrinology of human infertility: New aspects. London: Academic Press, 1981: 221-46. 18 Sandow J Clinical applications of LHRH and its analogues. Clin Endocrinol 1983; 18: 571-92. 19. Smith MA, Perrin MH, Vale WW. Densitisation of cultured pituitary cells to gonadotrophin-releasing hormone. evidence for a post-receptor mechanism. Mol Cell Endocrinol 1983; 30: 85-96 20 Clayton RN, Catt KJ. Gonadotropin-releasing hormone receptors: Characterization, physiological regulation and relationship to reproductive function Endocr Rev 1981; 2: 186-209 21. Catt KJ, Harwood JP, Clayton RN, et al. Regulation of peptide hormone receptors and gonadal steroidogenesis. Recent Progr Hormone Res 1980; 36: 557-622. 22. Healy DL, Schenken RS, Lynch A, Williams RF, Hodgen GD. Pulsatile progesterone secretion its relevance to clinical evaluation of the corpus luteum Fertil Steril 1984; 41: 114-21. pulsatile manner which is controlled by pulses of oxytocin presumed to be from the brain.23 This is related to episodic regeneration of oxytocin receptors which is in turn oestrogen- dependent. Pulsatile hormone production thus has its origins in the brain but the effects are seen throughout the reproductive system. The unravelling of this neuroendocrine axis has been exciting and it has lately been turned on its head by the unexpected finding of substantial amounts of "brain hormones" (such as oxytocin and GnRH-like peptides) as well as receptors for them in the gonads,24,25 though their significance remains to be established. COTSIDES—PROTECTING WHOM AGAINST WHAT? IN the hagiology of British geriatric medicine those who first proscribed the routine use of cotsides for elderly patients in hospital rank with the liberal spirits of the 18th century who struck off the fetters from patients in lunatic asylums. It is therefore with an element of shock that we learn, 30 years later, that in the United States of America use of cotsides is still routine practice for hospital patients aged more than 65 or 70. Rubenstein et al,’ writing from the University Health Services at Harvard, present a stimulating review of some of the medical, legal, and ethical issues. As with so much that is absurd or distasteful about North American medical practice, the blame lies more with the abuse of litigation than with the callousness of doctors. If an elderly patient in the USA falls out of bed when cotsides have not been in position subsequent litigation can be expected to conclude that care has been negligent. The use of cotsides is taken by lawyers to indicate that the hospital has made an effort to protect the patient. Ironically, although the effort may prevent successful litigation it is unlikely to benefit the patient. When used with a confused or restless patient, cotsides probably do not diminish his risk of falling, may increase his confusion and distress, and certainly ensure, whether he is confused or lucid, that if he does fall it will be from a greater height. Rubenstein et al record that in 14 out of 16 falls associated with getting out of bed the patient was climbing over the cotsides, and, where the information was available, his purpose was a visit to the toilet or some other legitimate errand. In Britain, where cotsides are rarely and selectively used, hospital fall-fracture rates are lower than in the United States. American physicians face the task of persuading lawyers and insurance commissioners to conceive it possible that a measure assumed to improve safety might actually increase hazards. It is suggested that a randomised controlled trial of cotsides might achieve this. This proposal raises interesting ethical and legal issues. One difficulty is that, once lawyers have been allowed to define what is good medical practice, re- evaluation becomes practically impossible since a doctor cannot, without fear of litigation, allocate patients to a treatment which the courts have decreed to be inferior-even if there is no scientific evidence to support that view. Can it even be assumed that courts would necessarily respect 23 Schramm W, Bovaird L, Glew ME, Schramm G, McCracken JA. Corpus luteum repression induced by ultra-low pulses of prostaglandins F2 alpha. Prostaglandins 1983; 26: 347-61 24. Wathes DC, Swann RW, Birkett SD, Porter DG, Pickering BT. Characterization of oxytocin, vasopressin and neurophysin from the bovine corpus luteum. Endocrinology 1983; 113: 693-98. 25. Sharpe RM. The hormonal regulation of the Leydig cell In: Finn CA, ed. Oxford reviews of reproductive biology: Vol IV. Oxford: Clarendon Press, 1982. 241-317. 1. Rubenstein HS, Miller FH, Postel S, Evans HB Standards of medical care based on consensus rather than evidence the case of routine bedrail use for the elderly Law Med Health Care 1983; 11: 271-76

COTSIDES—PROTECTING WHOM AGAINST WHAT?

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Page 1: COTSIDES—PROTECTING WHOM AGAINST WHAT?

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hypogonadism,I3,14 and the initiation of puberty.ls,16 Oneinteresting feature of the induction of ovulation with GnRH,analogous to the earlier findings in the rhesus monkey, is thatthe massive preovulatory surge of LH secretion occursdespite an unchanging GnRH pulse frequency or amplitude,

, though this does not necessarily mean that the same is truephysiologically.

Supraphysiological GnRH stimulation, whether throughincreased frequency or amplitude or use of the "superactive"agonist analogues, produces a seemingly paradoxicalinhibition of gonadotropin secretion.17,18 Although a post-receptor effect has been proposed 19 the mechanism appears tobe a "down-regulation" of the GnRH receptors. 1,18,20.Normally, the gaps between the physiological pulses allowtime for receptor recycling or regeneration. This inhibitoryeffect has led to an expanding range of applications for theGnRH agonists.in situations where a specific (and temporary,if required) reduction or abolition of gonadotropin secretionis beneficial. 17,18 These applications include contraception(both male and female) and the management of

endometriosis, precocious puberty, and sex-hormone-

dependent cancers (such as those of breast and prostate).For the gonads, too, pulsatile stimulation may be

important. In the testis, a pulsatile pattern of LH initiates andmaintains LH receptors and steroidogenesis whereas singlelarge doses lead to end-organ desensitisation with loss of LHreceptors,21 a down-regulation phenomenon similar to thatconcerning GnRH and the pituitary. For the gonads,however, pulsatile therapy is not necessary since large dosesand infrequent administration (eg, human chorionic

gonadotropin in hypogonadal men or follicle-stimulatinghormone in anovulatory women) is effective. This is an aspectthat may be re-evaluated now that smaller, more convenient,and more robust pumps have been developed.Further down the line, the pulses initially generated in the

hypothalamus become blunter but they can be detected inovarian oestradiol secretion in the follicular phase4 andprogesterone secretion in the luteal phase.4,22 With

progesterone secretion in the rhesus monkey the pulses arenot always coincident with those of LH:22 they may be causedby changes in ovarian blood flow, or there may be an "ovarianoscillator". The reproductive end-organs may also releasehormones in a pulsatile manner. Recent work in domesticanimals has shown that the uterus releases prostaglandins in a

13 Valk TW, Corley KP, Kelch RP, Marshall JC. Hypogonadotrophic hypogonadism:Normal responses to low dose pulsatile administration of gonadotropin- releasinghormone. J Clin Endocrinol Metab 1980; 51: 730-38.

14. Donald RA, Wheeler MJ, Sonksen PH, Lowy C. Hypogonadotrophic hypogonadismresistant to hCG and responsive to LHRH: Report of a case. Clin Endocrinol 1982;18: 385-89.

15. Marshall JC, Kelch RP. Low dose pulsatile gonadotrophin-releasing hormone inanorexia nervosa: a model of human pubertal development. J Clin Endocrinol Merab1979; 49: 712-18

16. Hoffman AR, Crowley WR. Induction of puberty in women by long-term pulsatileadministration of low-dose gonadotrophin-releasing hormone. N Engl J Med 1982;307: 1237-41.

17. Sandow J, Clayton RN, Kuhl H. Pharmacology of LHRH and its analogues. In.Crosignani P, Rubin BL, eds. Endocrinology of human infertility: New aspects.London: Academic Press, 1981: 221-46.

18 Sandow J Clinical applications of LHRH and its analogues. Clin Endocrinol 1983; 18:571-92.

19. Smith MA, Perrin MH, Vale WW. Densitisation of cultured pituitary cells togonadotrophin-releasing hormone. evidence for a post-receptor mechanism. MolCell Endocrinol 1983; 30: 85-96

20 Clayton RN, Catt KJ. Gonadotropin-releasing hormone receptors: Characterization,physiological regulation and relationship to reproductive function Endocr Rev

1981; 2: 186-20921. Catt KJ, Harwood JP, Clayton RN, et al. Regulation of peptide hormone receptors and

gonadal steroidogenesis. Recent Progr Hormone Res 1980; 36: 557-622.22. Healy DL, Schenken RS, Lynch A, Williams RF, Hodgen GD. Pulsatile progesterone

secretion its relevance to clinical evaluation of the corpus luteum Fertil Steril 1984;41: 114-21.

pulsatile manner which is controlled by pulses of oxytocinpresumed to be from the brain.23 This is related to episodicregeneration of oxytocin receptors which is in turn oestrogen-dependent. Pulsatile hormone production thus has its originsin the brain but the effects are seen throughout the

reproductive system. The unravelling of this neuroendocrineaxis has been exciting and it has lately been turned on its headby the unexpected finding of substantial amounts of "brainhormones" (such as oxytocin and GnRH-like peptides) aswell as receptors for them in the gonads,24,25 though theirsignificance remains to be established.

COTSIDES—PROTECTING WHOM AGAINSTWHAT?

IN the hagiology of British geriatric medicine those whofirst proscribed the routine use of cotsides for elderly patientsin hospital rank with the liberal spirits of the 18th centurywho struck off the fetters from patients in lunatic asylums. Itis therefore with an element of shock that we learn, 30 yearslater, that in the United States of America use of cotsides isstill routine practice for hospital patients aged more than 65or 70. Rubenstein et al,’ writing from the University HealthServices at Harvard, present a stimulating review of some ofthe medical, legal, and ethical issues.As with so much that is absurd or distasteful about North

American medical practice, the blame lies more with theabuse of litigation than with the callousness of doctors. If anelderly patient in the USA falls out of bed when cotsides havenot been in position subsequent litigation can be expected toconclude that care has been negligent. The use of cotsides istaken by lawyers to indicate that the hospital has made aneffort to protect the patient. Ironically, although the effortmay prevent successful litigation it is unlikely to benefit thepatient. When used with a confused or restless patient,cotsides probably do not diminish his risk of falling, mayincrease his confusion and distress, and certainly ensure,whether he is confused or lucid, that if he does fall it will befrom a greater height. Rubenstein et al record that in 14 out of16 falls associated with getting out of bed the patient wasclimbing over the cotsides, and, where the information wasavailable, his purpose was a visit to the toilet or some otherlegitimate errand. In Britain, where cotsides are rarely andselectively used, hospital fall-fracture rates are lower than inthe United States.American physicians face the task of persuading lawyers

and insurance commissioners to conceive it possible that ameasure assumed to improve safety might actually increasehazards. It is suggested that a randomised controlled trial ofcotsides might achieve this. This proposal raises interestingethical and legal issues. One difficulty is that, once lawyershave been allowed to define what is good medical practice, re-evaluation becomes practically impossible since a doctorcannot, without fear of litigation, allocate patients to a

treatment which the courts have decreed to be inferior-evenif there is no scientific evidence to support that view. Can iteven be assumed that courts would necessarily respect

23 Schramm W, Bovaird L, Glew ME, Schramm G, McCracken JA. Corpus luteumrepression induced by ultra-low pulses of prostaglandins F2 alpha. Prostaglandins1983; 26: 347-61

24. Wathes DC, Swann RW, Birkett SD, Porter DG, Pickering BT. Characterization ofoxytocin, vasopressin and neurophysin from the bovine corpus luteum.

Endocrinology 1983; 113: 693-98.25. Sharpe RM. The hormonal regulation of the Leydig cell In: Finn CA, ed. Oxford

reviews of reproductive biology: Vol IV. Oxford: Clarendon Press, 1982. 241-317.1. Rubenstein HS, Miller FH, Postel S, Evans HB Standards of medical care based on

consensus rather than evidence the case of routine bedrail use for the elderly LawMed Health Care 1983; 11: 271-76

Page 2: COTSIDES—PROTECTING WHOM AGAINST WHAT?

384

scientific evidence on the issue? There would surely be noshortage of lawyers ready to defend a profitable falsehood.One benefit of the British system of hospital care is that

patients and their relatives generally assume that hospitaldoctors and nurses practise conscientiously and with goodwill. Standards of good care can therefore be defined andrefined by doctors and nurses purely in relation to the bestinterests of the patients, without thought to protectionagainst alienated relatives anxious to recoup the costs ofhospital care or against lawyers looking for pickings. Withregard to cotsides British good practice2 requires that theseshould not be routinely used and their use should be

continually reviewed. They should be provided, if at all, togive a sense of security to the patient, not to the nursing staff,and should not be employed as a means of restraint-forwhich purpose they are as unethical as ineffective. If cotsidesare used they should not extend the whole length of the bed sothat the patient can get out of bed if he wishes.Although British practice, like American, has no firmer

basis than that of consensus, few British doctors and nursescould be recruited to assist in a trial of the routine use ofcotsides. Rubenstein et al do not make entirely clear whatoutcome measures would be used in the proposed trial but theimplied major criterion would be protection from falls. But isthis the central issue? We can suspect that falls could most

effectively be prevented if all patients were given maximumdoses ofphenothiazines and cotsides were regularly fortifiedwith the pig-nets formerly lashed over the tops of beds ofrestless elderly patients. The objectives of care for the elderlymust include the fostering of rehabilitation and independenceand these objectives are incompatible with the total preventionof falls. What, then, is to be the equation balancing incidenceof falls against the proportion of patients achieving successfulrehabilitation? Would the same equation be appropriate inboth Britain and the USA?- Moreover, many patients, andtheir doctors and nurses, see cotsides as degrading, and theconfused patient may find them frightening. It is true thatthere has never been a controlled trial of the routine use ofcotsides for elderly patients: there has also never been acontrolled trial of the use of fetters in the treatment of

schizophrenia.

DO DETERGENT RESIDUES DAMAGE THE GUT?

IN a study done at the Rayne Institute,1 University CollegeHospital, London, six rats given a 107o detergent solution(’Fairy Liquid’) in their drinking water over several monthsacquired inflammatory and atrophic changes in parts of theiralimentary tract. It was estimated that the rats ingested 35 mgdetergent daily (175 mg/kg). Mercurius-Taylor et al state thateating-utensils washed in detergent solution are often allowedto dry without being rinsed or wiped and that babies’ feeding-bottles are often handled similarly after being washed inextra-strong detergent solutions. Using what were

considered to be typical washing solutions they estimated thata member of such a household might ingest up to 75 mgdetergent each day (about 1 mg/kg); a bottle-fed baby mightreceive up to 250 mg (20-50 mg/kg). The Rayne Instituteworkers were careful to point out that extrapolation from ratto man would not be appropriate on the basis of such a small(and apparently uncontrolled) study; all the same theypostulated that detergent damage could lead to chronic bowel

2 Joint Working Party of the British Geriatrics Society and the Royal College of NursingImproving geriatric care in hospital. London. Royal College of Nursing, 1975 24.

1. Mercurius-Taylor LA, Jayaraj AP, Clark CG Is chronic detergent ingestion harmful tothe gut? Br J Ind Med 1984; 40: 279-81

disease in man. Their modest communication attracted theheadlines- "Washing up liquid ’danger’" (Daily Telegraph),"The hidden danger in washing up-by doctors" (DailyMail), and "Home detergents ’clue to stomach disorders’"(Guardian).The report must have come as an unpleasant surprise to

detergent manufacturers. However, before any conclusionsare drawn from the study it is important to ensure that theassumptions and calculations are valid. There is no published

. information on how often unrinsed utensils are allowed tostand and dry, but market research data from the two largestBritish detergent makers (Procter and Gamble and LeverBrothers) give figures of 5-10% of households. The resultsthemselves may be questioned on two counts-how reliablewere the calculations for daily inadvertent ingestion in manand how well do the pathological changes reported in the ratsaccord with other studies? On the first issue, several previousestimates2-5 by companies and public health bodies ofmaximum daily intake of detergent from all sources (water,toothpaste, fruit and vegetables, and washed utensils) haveshown values one or two orders lower than those indicated bythe Rayne Institute group. If these figures (0 3 to 15 mg perday) are reliable the six rats tested were exposed to levelsbetween 600 and 40 000 times greater than human exposurelevels, on a weight-for-weight basis. On the second issue, nosimilar adverse effects in the alimentary tract have beenobserved during many toxicity studies of detergents in

current use.6—14 The constituent surfactants of fairy liquid(a linear alkyl benzene sulphonate and an alcoholethoxysulphate) have been fed to rats in 0 5% concentrationsfor 2 years without ill-effects.8,9,11,14 Equivalentconcentrations of all the other major classes of surfactants indomestic and industrial use have likewise been reported asharmless in animal studies. 6—8,10,12,13When sufficiently high concentrations are tested all

surfactants are toxic, with oral LDsos of 1000-3000

mg/kg.6-14 The crucial point, then, even if these recent

toxicity data are substantiated, is whether there is an effectivesafety margin between inadvertent human exposure and thelevel shown to be toxic in the rats. Clearly it is important forthe world to know if washing-up liquids represent a danger tohealth, but the Rayne Institute study cannot be taken asevidence that they do. It would seem sensible, on gastronomicrather than toxicological grounds, to rinse or wipe dry dishes,cups, and cutlery before putting them away.

2 Swisher RD Exposure levels and oral toxicity of surfactants. Arch Envir Health 1968,17: 232-46.

3 Moncrieff RW Oral non-toxicity of surfactants Soap Perfum Cosm 1969, 42: 447-504 Charlesworth FA Studies on the teratogenicity of alkylbenzene sulphonates BIBRA

Bull 1975; 14: 330-33.5 Hiraga K On the safety of detergents, In: Safety problems with detergents Tokvo

Nippon Hair Science Society, 1974. 55-566 Sivak A, Goyer M, Perwak J, Thayer P Environmental and human health aspects of

commercially important surfactants Sol Behav Surfactants 1982, 1: 161-887. Garth Fitzhugh O, Nelson AA. Chronic oral toxicities of surface-active agents J Am

Pharm Assoc 1948, 37: 29-328. Hunter B. Benson HG. Long-term toxicity of the surfactant &agr;-olefin sulphonate(AOS)

in the rat. Toxicology 1976; 5: 359-70.9. Tusing TW, Paynter OE, Opdyke DL, Snyder FH. Toxicologic studies on sodium

lauryl trioxyethylene sulfate Toxicol Appl Pharmacol 1978; 11: 245-50.10 Larson PS, Borzelleca JF, Bowman ER, Crawford EM, Blackwell Smith R Jr.

Hennigar GR Toxicologic studies on a preparation of p-tertiary oxtylphenoxy-polyethoxy ethanols (Triton X-405). Toxicol Appl Pharmacol 1963; 5: 782-89

11 Heywood R, James RW, Sortwell RJ Toxicology studies of linear alkylbenzenesulphonate (LAS) in rhesus monkeys I. Simultaneous oral and subcutaneousadministration for 28 days Toxicology 1978; 11: 245—50.

12 Smyth HF Jr, Calandra JC. Toxicologic studies of alkylphenol polyoxyethylenesufactants. Toxicol Appl Pharmacol 1969, 14: 315-34.

13 Schneider G Detergent materials from petrochemicals. Soap. Chem Specialties 1970(Nov) 56-64

14 Buehler E, Newman FA, WR King. Two year feeding and reproduction study in ratswith linear alkylbenzene sulphonate Toxicol Appl Pharmacol 1971, 18: 83-91