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CHEEK-POUCHES

Do unsupervised patients take their treatment asinstructed ? To know the existence and extent of anydefaulting is important, not only for the effectivetreatment of the individual but also for assessing theefficacy of drugs in clinical trials. It was only quiterecently that doctors became really concerned aboutpatients not taking their drugs, though as long ago as1736 the County Hospital at Winchester dischargedan unfortunate patient for " irregularity in taking hismedicine ".1 The problem emerged with the comingof prophylaxis against rheumatic fever and effectivetreatment for tuberculosis. Chest physicians reportedthat the P.A.S. they prescribed often never appeared inthe patient’s urine. Usually such defaulting carries atherapeutic penalty; but not always, and on occasionsrecalcitrant patients do just as well as the conscientiousones 2-4-presumably because the dosage of manydrugs is not critical. What sort of circumstances pre-dispose to defaulting ? Patients may stop taking theirdrugs for many reasons, including poor motivation,social isolation, occasional and desultory supervision,low social class, unpleasant side-effects, and divi-ded rather than once-daily dosage. A patient with apainful inflammation will take an antibiotic for certain,particularly if he is seen each day. He will equallycertainly stop taking it soon after his symptoms arerelieved. 5,6 s

How can the organisers of clinical trials demonstratethat their patients have, in fact, complied with instruc-tions and taken their tablets ? Few will wish toemulate the petty-officer of the German Navy on theSouth African Station who, after the parade to swallowquinine, was detailed to examine the mouths of thesailors, " especially the cheek pouches ".’ 7 The first

attempt to modify the design of a trial to meet thedifficulty was made in 1962 with the use of tablet-counting and phenol-red as a tablet marker 8 (detect-able in the urine). Later workers have used sodiumbromide 9 and riboflavine 4,10 as tablet markers; ribo-flavine fluoresces strongly in urine and probably con-forms most closely to the ideal.The testing of urine for markers or metabolites can

only be done occasionally, and by itself does not sufficeto provide conclusive evidence about the conformity ofthe patient. Some method of tablet-counting shouldalso be used. Patients may bring back their box oftablets so that the residue may be counted. This is

simple but not very subtle, and it is difficult to becertain whether the tablets have gone down the

patient or down the water closet. A better method isthe " discrepancy estimate ".4 4 A critical number oftablets is prescribed so that, by design, they are

exhausted at or near the time of the next consultation.

1. Clarke, A. A Sermon Preached in the Cathedral Church of Win-chester before the Governors of the County Hospital. London,1736.

2. Tuberculosis Chemotherapy Centre, Madras. Bull. Wld Hlth Org.1959, 21, 101.

3. Stradling, P., Poole, G. Tubercle, 1963, 44, 71.4. Porter, A. M. W. Br. med. J. 1969, i, 218.5. Bergman, A. B., Werner, R. J. New Engl. J. Med. 1963, 268, 1334.6. Charney, E., et al. Pediatrics, Springfield, 1967, 40, 188.7. Muhlens, P. Arch. schiffs. Tropenhyg. 1906, 10, 370.8. Joyce, C. R. B. J. chron. Dis. 1962, 15, 1025.9. Roth, H. P., Caron, H. S., Hsi, B. P. Clin. Pharm. Ther. 1970, 11,

228.10. Jones, I. H., Letemendia, F. J. J. Br. med. J. 1966, ii, 948.

A casual question " have you got enough tablets leftuntil I see you again ? " and discreet probing will soonreveal the extent of compliance of the patient, butleaves him ignorant of the challenging nature of thequestions.There is widespread assumption that inpatients

receive and take their medication as prescribed. When-ever this assumption is examined objectively the resultsare disquieting. 1-13 While it is wrong for the organisersof inpatient trials to overlook the possibility of ns-takes and omissions, it is even more unjustifiable toundertake trials on outpatients or in general practicewithout providing evidence about conformity to treat-ment schedules. Means to determine complianceshould now be incorporated in the protocol of anydrug trial undertaken on unsupervised patients.

STEROID ANAESTHESIAPHARMACOLOGISTS have been troubled for a long

time by the rather narrow margin of safety betweenthe anxsthetic dose and the lethal dose of intra-venous barbiturates. The steroid anaesthetic agent,hydroxydione, proved to have a much wider marginof safety, but it had the drawbacks of a long induction-time and a tendency to produce painful venous

thrombosis. 14-16 A new steroid combination was latelydiscussed at a symposium.17 This is known as alpha-dione, or ’ Althesin ’, and is a combination of twosteroids (3 cx.-hydroxy-5 cx.-pregnane-ll ,20-dione and 21-acetoxy-3 <x-hydroxy-5 fx-pregnane-11,20-dione) whichhave structural similarities to progesterone. Thesecond steroid contributes little to the anaesthesia,merely increasing the solubility of the active drug inthe solvent.

In the laboratory animal, alphadione has an ex-ceedingly wide safety margin and a brief duration ofaction. 18 Unlike thiopentone, it has little tendency tocumulate after repeated doses, probably becauseblood-levels are reduced by conjugation of the steroidin the liver rather than by redistribution, as happenswith barbiturates. Radioactive alphadione, labelledwith carbon-14, is distributed initially to the cerebralcortex. A few minutes later the radioactivity is beingconcentrated in the liver, where the steroids are

eliminated in the bile as inactive, highly polar con-jugates. Within 5 days over 95% of the initial radio-active dose may be recovered. Of this, approximately70% appears in faeces and the remainder in urine.The persistence of the radioactivity for a few daysafter a single parenteral dose is evidence for entero-hepatic circulation of the inactive metabolites. Radio-active material is also seen in the placenta and crossesto the fetus, but concentrations in the fetus are verysmall compared with those in adult animals. Animalswith thioacetamide-induced liver damage are six timesmore sensitive to thiopentone than normal animalsbut only twice as sensitive to alphadione. Despite its11. Neve, H. K. J. ment. Sci. 1958, 104, 488.12. Barker, K., McConnell, W. Mod. Hosp. 1962, 99, 95.13. Wallace, W. Lancet, 1965, i, 555.14. Galley, A. H., Rooms, M. ibid. 1956, i, 990.15. Taylor, N., Shearer, W. M. Br. J. An&oelig;sth. 1956, 28, 67.16. Hunter, A. R. An&oelig;sthesia, 1957, 12, 10.17. Postgrad. med. J. (in the press).18. Child, K. J., Currie, J. P., Davis, B., Dodds, M. G., Pearce, D. R.,

Twissell, D. J. Br. J. An&oelig;sth. 1971, 43, 2.

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broad structural similarity to sex hormones, alpha-dione has no noteworthy effect on the reproductivetract in rats. Nor does intramuscular or intravenous

injection produce signs of local irritation in cats. It issaid to protect Landrace pigs against the malignanthyperthermia produced by halothane and suxa-

methonium.19In man, the duration of unconsciousness produced

by a single dose is of the order of 5-10 minutes. Thecirculatory effects are similar to those of thiopentone-the blood-pressure falls slightly and the heart-rateincreases. Diminished myocardial contractility seemsto be part of the explanation, but the fall in blood-pressure may also be linked to a reduction in peri-pheral vascular resistance. After induction of anoes-thesia with alphadione the cardiac output seems to beunchanged.2O In goats it increases pulmonary vascularresistance.

Alphadione’s effect on respiratory exchange seemsto be similar to that of thiopentone, though less pro-longed. Some investigators have recorded a smallrise in P aC02 of the order of 5 mm. Hg. There isusually hyperpnoea immediately after injection, butthis is not so pronounced as that produced by pro-panidid, which has been shown to result from carotid-sinus stimulation.21 The hyperpnoea is often succeededby brief apnoea and then a gradual return of minutevolume by increasing depth of respiration, the res-piratory rate remaining constant. Alphadione in-creases lung compliance, even in asthmatic patients.When the patient is challenged by the irritant effectsof 3% and 4% halothane in the inhaled gases, coughingand laryngospasm are less common than with thio-pentone. Tracheal intubation can be done usingalphadione alone, but only with a large dose. Theremay be excitatory phenomena such as muscle twitchingduring induction of anaathesia. 22, 23 3 On the electro-encephalogram the traces are flatter than those asso-ciated with barbiturate anaesthesia, the proportion ofslower wave frequencies increases as anxsthesiadeepens. Alphadione does not prolong the action ofsuxamethonium nor intensify the action of any of theother myoneural blocking agents currently used.There is no significant interaction with the ordinaryvolatile agents, 24 but there is evidence that when highdoses of atropine (0-02 mg. per kg.) are given for pre-medication the blood-pressure falls more than whenhalf this dose is used. The muscle relaxation affectsjaw muscles and may allow the tongue to obstruct theairway. A herniorrhaphy or a gynaecological examina-tion can be done under alphadione anaesthesia, butfull abdominal-muscle relaxation is not obtained.Where continuous infusions have been used in epi-gastric operations muscle relaxants were also neces-sary. On present evidence, alphadione will be a usefuladdition to the anaathetists’ armamentarium.

19 .Hall, L. W., Trim, C. M., Woolf, N. Br. med. J. 1972, ii, 145.20. Savege, T. M., Foley, E. I., Coultas, R. J., Walton, B., Strunin, C.,

Simpson, B. R., Scott, D. F. An&oelig;sthesia, 1971, 26, 402.21. Gordh, T. Proceedings of 10th Scandinavian Congress of An&oelig;s-

thetists, 1971, p. 71.22. Clarke, R. S. J., Montgomery, S. J., Dundee, J. W., Bovill, J. G.

Br. J. An&oelig;sth. 1971, 43, 947.23. Swerdlow, M., Chakraborty, S. K., Zahangir, M. A. H. M. ibid.

p. 1075.24. Bradford, E. M. W., Miller, D. C., Campbell, D., Baird, W. L. M.

ibid. p. 940.

HOW MANY PAEDIATRICIANS ?

A 72% increase in the number of consultant paedia-tricians in Britain over the next ten years-that is oneof the more striking proposals in a lively policydocument issued by the British Paediatric Associationearlier this weeks 1 The increase, which would total261, should, the Association urges, be spread acrossfour areas of work. Priority should be given to pro-viding help for the 83 hard-pressed single-handedpaediatricians, clinical whole-time university staffshould go up by 50 (the report puts the present totalfor Britain’s twenty-three undergraduate medicalschools at 83, and the average for the London schoolsis only 1’2); 84 more consultants would be needed todevelop specialties within paediatrics, and 44 consul-tant posts would be required to take child healthfurther into the community. The main theme of thedocument is the need for more specialisation withinpaediatrics if child-health services in the ’70s are toimprove, but the generalist need not despair-outsidethe university centres, on which much of the extraspecialisation would be based, there would remain animportant demand (e.g., in the two-man teams indistrict general hospitals) for clinicians with no con-suming system interest.

Item by item the B.P.A. presents a convincing case,but how realistic are its suggestions for expansion ?The policy statement embodies the majority view ofthe Association’s members, but on staffing require-ments there seems to have been some disagreement : =" Some of our members, with long experience ofinsufficient staff and limited facilities, regard theseproposals as unreal; others consider them conservativeand subservient to hospital and specialty interests."Some child-health specialists now working in the

local-authority sector might be eligible (or retrained)for consultancies in community paediatrics, but mostof the men and women who would fill the 261 new

posts and the 88 senior registrarships needed to gowith them will be drawn from a medical-school outputfor which plenty of other specialties are competing.The Association is encouraged by the fact that anindependent assessment 2 of career-grade require-ments in the specialty produced a figure remarkablylike its own, but, as Briggs and Opp6 2 pointed out, inthe ’60s paediatrics expanded much more rapidly thanother specialties. Can this differential be maintainedfor another decade ?The Association is anxious to project an attractive

image for pxdiatrics so that newly qualified doctorswill be drawn to the specialty. In its descriptions ofthe challenging roles for paediatricians in preventivemedicine and other community work it succeeds. Buthow appealing to an impatient trainee is the uncertainprospect of a career in a system specialty such aspaediatric gastroenterology if it has to be preceded byan intercalated B.SC. followed by an M.sc. or PH.D. ontop, presumably, of an M.R.C.P. obtained while intraining-posts in paediatrics rather than adult medicine ?

1. P&aelig;diatrics in the Seventies: Developing Child Health Services.Edited by DONALD COURT, M.D., F.R.C.P., chairman, and ANTHONYJACKSON, M.D., F.R.C.P., secretary, Academic Board of the BritishP&aelig;diatric Association. London: Oxford University Press, for theNuffield Provincial Hospitals Trust. 1972. Pp. 107. &pound;1.

2. Briggs, T. W., Opp&eacute;, T. E. Lancet, 1971, i, 1119.