1234

may itself be responsible for the central depression whichmay recover completely under proper oxygen therapy.This work supports the view that these patients, whohave become severely anoxic without time for acclimatisa-tion, are in urgent need of oxygen, and that every effortshould be made to restore them to a reasonable colour.Patients with chronic anoxia present a different problemsince their need for oxygen is less urgent and their centraldepression less labile.

Of the various components into which respiratoryinsufficiency may be analysed,6 g central depression,although a common and occasionally the leading abnor-mality,’ is perhaps the least understood. As even thechronic form has no manifest structural basis, there is atleast the hope of reversing it, and two drugs have recentlybeen studied to this end. The first is the carbonic-anhy-drase inhibitor, acetazolamide, whose continued adminis-tration for periods of several months has recently beenreported.8 Doses of 500 mg. a day were partially successful

, in sabotaging the kidney’s attempts at compensating therespiratory acidosis ; consequently the plasma-bicarbon-ate fell, the acidosis increased and, presumably throughincreased ventilation, arterial pC02 fell and p02 roseslightly. There was no restoration of central sensitivityto carbon dioxide, nor in a complementary study 9 wasthere increased tolerance to oxygen. It is not certainthat this purchase of a modest reduction of hypercapniaat the cost of further acidosis is a good biochemicalbargain, and we are not told what the patients felt aboutit. Prolonged administration of acetazolamide entails ahazard of potassium depletion," and few physicians willfeel tempted on present evidence to use it in this way.The second drug to be considered is salicylic acid. The

hyperpnaea produced by large doses is familiar, and isnow known to be due to a direct stimulation of the

respiratory centre.11 The result is normally a hypocapniaand respiratory alkalosis mitigated by a decrease in

plasma-bicarbonate brought about by the kidney. Thesechanges are the reverse of those found in central respira-tory depression in which it is to be expected that sali-cylates would tend to restore normal values ; and thishas been found to be so in a few patients given 3-7 g.a day of aspirin.12 This dosage is not prohibitively high,but is likely’ to produce side-effects, and the patientsbecame irritable and some developed tremor. Tenney andMillerp in recent work on the pharmacology of salicylates,draw attention to a property previously reported butusually overlooked-namely, the stimulation of oxygenconsumption. An infusion of sodium salicylate maydouble oxygen consumption ; oral dosage may producea sustained increase of about 20%. This may well limitits use in patients with respiratory insufficiency who arevery sensitive to changes in metabolic needs.For patients with chronic respiratory insufficiency

with prominent central depression, evidenced by hyper-capnia with little respiratory distress, stimulation withaspirin may be worth trying. Acetazolamide may be ofvalue as a short-term adjuvant in running down plasma-bicarbonate. There seems a fair prospect of objectiveimprovement in blood gas-tensions and pH. Whether thepatients will be grateful is doubtful, since, as Dornhorst 6pointed out, successful reversal of central depressionmay prolong life but will almost certainly increase

dyspncea.5. Lancet, 1953, i, 380.6. Dornhorst, A. C. Ibid, 1955, i, 1185.7. Auchincloss, J. H., Cook, E., Renzetti, A. J. clin. Invest. 1955,

34, 1537.8. Fishman, A. P., Samet, P., Cournand, A. Amer. J. Med. 1955,

19, 533.9. Galdston, M. Ibid, p. 516.

10. Counihan, T. B., Evans, E. M., Milne, M. D. Clin. Sci. 1954,13, 583.

11. Rapoport, S., Guest, G. M. J. clin. Invest. 1945, 24, 759.12. Wégria, R., Capeci, N., Kiss, G., Glaviano, V., Keating, J.,

Hilton, J. Amer. J. Med. 1955, 19, 509.13. Tenney, S. M., Miller, R. M. Ibid, p. 495.

TREATMENT OF HYPERTROPHIC PYLORIC

STENOSIS

IT has been estimated that hypertrophic pyloricstenosis appears in 3 or 4 out of every 1000 newborninfants. The mortality of the condition has fallen

strikingly in the past thirty years, partly because of thegeneral reduction in infant mortality but mainly becauseof better diagnosis and treatment. Surgical treatment isnow more or less confined to Rammstedt’s operation ofpylorotomy, which has superseded earlier proceduressuch as gastro-enterostomy or forcible dilatation of thepylorus. Medical treatment consists of stomach wash.outs, careful graduated feeding, and the administrationof a spasmolytic drug of the atropine series. Atropineitself has been largely replaced by methyl atropinenitrate, which has a greater cholinergic effect, andthis drug, either in watery or alcoholic solution, or in theform of lamellae given sublingually, has been the standarddrug. A new spasmolytic derived from scopolamine hasnow been used in a clinical trial described by Corner,2following favourable reports from Scandinavia.3 Methylscopolamine nitrate is said to have five times the spasmo-lytic effect of atropine on guineapig intestine and twoto three times that of methyl atropine nitrate. Further,in ordinary doses, it less often has such side-effectsas dryness of the mouth and mydriasis.

Corner treated 117 babies with the new drug, combinedwith a strict feeding plan and the administration of

parenteral fluids when necessary. The diagnosis wasestablished by two criteria-visible gastric peristalsis anda palpable pyloric tumour-and confirmed by two

experienced observers. All cases were treated in hospitaland the earlier ones were kept in hospital for the wholeperiod of treatment. The drug was generally given bymouth in doses of 0.1 mg. six times daily, fifteen minutesbefore feeds. If vomiting recurred, or the child was

severely dehydrated at the start of treatment, the drugwas given subcutaneously in doses of 0.05 mg. six timesdaily. At the beginning of the trial supplies of the drugwere scarce and treatment had to be stopped after a fewweeks, and this sometimes led to relapse. Later on,however, it was possible to continue treatment for atleast ten weeks and relapses no longer occurred. The

response to treatment was usually very rapid, vomitingceasing immediately in 75 cases and within forty-eighthours in a further 19. A few infants continued tovomit slightly even after five days, but their conditionwas otherwise satisfactory and treatment was continued.Gain -in weight was at first rather slow in many babies.but this could be partly attributed to the low calorieintake at the start of treatment. One child died duringthe course of treatment : he was severely infected andalthough vomiting was controlled he had persistent anor-exia and died after four weeks’ treatment. Anotherchild responded inadequately to treatment, and Ramm-stedt’s operation was performed on the nineteenth day.

This trial confirms previous reports of the effectivenessof the drug in hypertrophic pyloric stenosis. It does not.however, decisively settle the argument in favour ofmedical treatment on the one hand or surgery on theother. In the best circumstances, the mortality fromsurgery is now very low 4 5 ; and the big advantage ofoperation is that the infant can be sent home after afew days on a normal feed and no further supervision isusually needed once the sutures are removed. Recurrenceafter operation is exceptional. Medical treatment, on theother hand, requires a long period of supervision, withfrequent visits to hospital. Drug treatment must becontinued for many weeks, and if for some reason the

1. Davison, G. Arch. Dis. Childh. 1946, 21, 113.2. Corner, B. D. Ibid, 1955, 30, 377.3. Malmberg, N. Acta pœdiatr., Stockh. 1949, 38, 472.4. Wood, E. C., Smellie, J. M. Lancet, 1951, ii, 3.5. Browne, D. Proc. R. Soc. Med. 1951, 44, 1057.

1235

mother stops treatment the symptoms are liable to recur.Further, the lengthy treatment may lead to an over-protective attitude by the mother and breed difficultiesin later life. Surgical success depends on the skill andexperience of the surgeon and the’ quality of the nursingcare. Rammstedt’s operation seems deceptively simplein expert hands, but requires constant practice for goodresults. Todd suggested that the indications for opera-tion were failure of medical treatment after a trial ofseven days, gross dehydration, and a birth-weightbelow 7 lb. But if an experienced surgeon is available,operation is probably the best treatment unless there issevere infection.

CHEMOTHERAPY OF TUBERCULOSISA REPORT of the 14th conference on tuberculosis

chemotherapy of the Veterans Administration andNational Tuberculosis Association of the U.S.A. has latelyappeared.’ It is nine years since the 1st conference washeld, when the early results of treatment with strepto-mycin at nine Veterans Administration hospitals weredescribed. The list of transactions at the 14th conferenceclearly reflects the great advance in our knowledge ofantituberculous drugs, as well as the value of continuouscooperation in studying them. Streptomycin, p-amino-salicylic acid, and isoniazid in various combinations

occupy much of the story ; but there is also news ofpyrazinamide, cycloserine, tetracycline, viomycin, s-ethyl-I-cysteine, streptohydrazide, calcium benzoyl p-amino-salicylate, corticotrophin, and D-glucuronolactone iso-

nicotinyl hydrazide. The experimental design of theAmerican organisations’ large-scale trials may not alwaysbe perfect ; -but a machine has been constructed andmaintained capable of giving valuable information in ashort time and flexible enough to adapt itself rapidly tochanging ideas. The Medical Research Council’s trialsin this country are more rigorous and precise : they askfewer questions, and the answers are correspondinglymore definite. The two types of cooperative clinicalresearch are complementary -to each other.The future programme of the Veterans Administration

includes a study of the surgical removal of lesionsremaining after antibacterial treatment. As we observedrecently, only a controlled trial will finally decide whetherit is necessary to remove such lesions. Such a trial wasstarted in a Veterans Administration hospital in June,1953.9 By the end of 1954, 59 patients had been allocatedat random to resection and non-resection groups. So far 2of the 33 who had a resection and 2 of the 26 who did nothave shown bacteriological or radiographic evidence ofrelapse. But it is much too early to draw conclusions.The clinical trials of the U.S. Public Health Service alsoinclude examination of another important problem.A random group of children with uncomplicated primarytuberculosis is being treated for a year with isoniazidwhile a similar group receives inert tablets. The childrenwill be followed for two years and it is hoped, if sufficientnumbers can be included in the trial, to find out whetherisoniazid does indeed reduce the incidence of complica-tions.1o 0 Bentley 11 has lately expressed concern lest

chemotherapy should actually increase the incidence ofsegmental lesions in the lungs of these children. In this

country the M.R.C. are planning a trial of long-continuedantibacterial treatment of chronic infectious patients 12-another important aspect of modern therapy.There remains the question of using isoniazid alone in

pulmonary tuberculosis, Here again, the Veterans

6. Todd, R. McL. Arch. Dis. Childh. 1947, 22, 75.7. Transactions of 14th Conference on the Chemotherapy of

Tuberculosis. Veterans Administration. Washington, U.S.A.February, 1955.

8. Lancet, Aug. 13, 1955, p. 330.9. Raleigh, J. W., Decker, A. M., Bell, J. W. Trans. 14th Conf.

Chemotherapy of Tuberculosis, 1955, p. 199.10. Ferebee, S. H. Ibid, p. 123.11. Bentley, F. J. Brit. med. J. Oct. 29, 1955, p. 1084.12. D’Arcy Hart, P. Lancet, Sept. 3, 1955, p. 509.13. Ibid, 1955, i, 238.

Administration are carrying out a pilot study. Unfor-tunately, no doubt for ethical reasons, only patientswithout lung cavities will be treated, and the trial is

unlikely to give a clear-cut answer to the main problem.In this country too such a trial would hardly be accept-able 11 ; but it could perhaps be carried out in countries-where the social conditions justify taking a known riskfor the sake of providing the only feasible treatment forlarge numbers of tuberculous patients.

ANOTHER NEW BLOOD-GROUP

MANY new blood-groups have been discovered becausean antibody has appeared in the blood of a patient whohas been repeatedly transfused. Recently a hithertounidentified antibody was detected in the serum of aMr. V when his blood was being cross-matched for his27th transfusion ; and details of this antibody, namedafter him, have been reported from New York andLondon by DeNatale, Cahan, Jack, Race, and Sanger.14,-Mr. V was in St. Luke’s Hospital, New York City, andthe prospective donor was a Negro. Inquiry showed that6 previous donors had been Negroes, and tests with a setof 20 standard test cells showed that the only positivereactions with Mr. V’s antibody were obtained with 2 ofthe 6 specimens of Negro blood that happened to be-included in the standard set. Attention was thus directedto Negro blood, and samples from 168 New York Negroes-were tested ; 45 (27%) reacted positively with the Vantibody. The blood of 444 white blood-donors was.tested and only 2 (0.5%) positive samples were found ;both were natives of Puerto Rico. Investigations wereextended to London and to West Africa. In London 407’

samples of blood were tested and only 2 (0-5%) V-positivereactors were found ; but a group’of 150 West Africansliving in Lagos or Accra included 60 (40%) V-positive.reactors. When the rest of the blood-groups of the tested-bloods were worked out, it was seen that V-positive is.particularly associated with the Rh types cde and cDe.-For this reason it is thought that the V antigen is some-how connected with the Rh blood-group system, but at,present the precise connection is unknown.

Racial differences in the distribution of blood-groups.are well known, and Mourant 15 has shown how much-information has been accumulated. There are other

examples of gross racial differences. Thus only 3% ofChinese are Rh (cde) negative, and the cde chromosomeis rare or entirely absent in the Siamese and in CentralAmerican natives. The North American Indians showonly groups 0 and A, with a remarkable preponderance,of group 0 ; the distribution in the Chippewa Indians.is 87.5% group 0 and 12.5% group A, with none ingroups B or AB. It is already known that African Negroes(south of the Sahara) show a high frequency of cDe ;various races show from 48 to 90%, with an average of60%, and the mutation cDue is almost limited to thesepeoples.From a practical point of view we need to know whether

the V antigen is likely to lead to the formation of anti-bodies, and whether consequently Negro donors shouldbe avoided when taking blood for transfusion into whiterecipients. Fortunately, V is apparently not a powerfulimmuniser. As DeNatale et al. point out, " tens ofthousands of white people must have received bloodtransfused from Negro donors, yet only Mr. V has

responded by making anti-V." The antibody will befound, and any possible reaction will occur, only aftera second transfusion of Negro blood. Blood from the twoV-positive English donors was found to be still survivingin their V-negative recipients two or three weeks aftertransfusion. Nor is it thought that the V antigen is likelyto cause haemolytic disease in newborn Negro infants,14. DeNatale, A., Cahan, A., Jack, J. A., Race, R. R., Sanger, R.

J. Amer. med. Ass. 1955, 159, 247.15. Mourant, A. E. The Distribution of the Human Blood Groups

Oxford, 1954.