539

dormant throughout foetal life. Unfortunately evidenceas to the dynamics of bilirubin metabolism in foetal life ishard to obtain.

Summary12 cases of severe haemolytic disease of the newborn

with associated obstructive jaundice detectable at birthare described.

‘

Early, adequate exchange transfusion is the most im-portant factor in management. Biliary obstruction doesnot contribute toward kernicterus but may lead to

hypoprothrombinaEmia, which should be prevented.Failure to recognise this clinical entity may result inunnecessary repetition of exchange transfusion.These cases represent a definite clinical entity within the

spectrum of disease caused by rhesus incompatibility.Ve are grateful to the obstetricians and paediatricians at South-

mead Hospital for their cooperation and interest. Our thanks are dueto Dr. G. H. Tovey, in whose department the serological andhæmatological determinations were performed, and who gavevalued advice during the work and in the preparation of the manu-script. Dr. F. J. W. Lewis supported us throughout by his interestand the provision of consistently reliable biochemical estimations.

REFERENCES

Billing, B. H., Lathe, G. H. (1958) Amer. J. Med. 24, 111.Brown, A. K., Zuelzer, W. W. (1958) J. clin. Invest. 37, 332.Cornblath, M., Kramer, I., Kelly, A. B. (1955) Amer. J. Dis. Child. 90, 628.Harris, R. C., Andetsen, D. H., Day, R. L. (1954) Pediatrics, 13, 293.Hawksley, J. C., Lightwood, R. C. (1934) Quart. J. Med. 27, 155.Hsia, D. Y. Y., Patterson, P., Allen, F. H., Diamond, L. K., Gellis, S. S.

1952) Pediatrics, 10, 243.Lathe, G. H. (1955) Brit. med. J. i, 192.Lightwood, R. C., Bodian, M. (1946) Arch. Dis. Childh. 21, 209.Stempfel, R., Broman, B., Escardó, F. E., Zetterstrom, R. (1956) Pediatrics,

17, 471Still, G F. (1927) 5th ed. Common Disorders and Diseases of Childhood;

p 375. London.

ASPIRIN AND GASTRIC HÆMORRHAGE

A. MUIRM.R.C.P.

CONSULTANT PHYSICIAN, SOUTH LANARKSHIRE GROUP

ISABEL A. COSSARM.B. Edin., D.C.H.

JUNIOR HOSPITAL MEDICAL OFFICER,LAW HOSPITAL, CARLUKE, LANARKSHIRE

IT has been known for twenty years that salicylates andallied compounds may produce gastric hæmorrhage.Douthwaite (1938), Douthwaite and Lintott (1938), andHurst and Lintott (1939) all reported this fact. In four

years Hurst (1943) saw 51 patients whose gastric bleedinghad no evident cause, and in about half of them heattributed it to aspirin.Dodd et al. (1937), Honigberger (1943), Caravati and

Cosgrove (1946), Gross and Greenberg (1948), and Ivyct al. (1950) thought that the form of salicylate takenmade little difference to its gastric effect, because thedrug acted through the blood-stream, after its absorption.This was generally accepted until our own investigationswere published in 1955. We came to the conclusion thatof every eight episodes of gastroduodenal haemorrhage,one was caused by local aspirin irritation, usually produc-ing an acute erosive gastritis.

Paul ’1943), Wolf and Wolff (1943), Waterson (1955), andAihbone and Flint (1958a) did not agree. But the conclusionsof Aihbone and Flint have been firmly criticised by Acheson1958 ; and they themselves have recently admitted that some

of their contentions were wrong (Allibone and Flint 1958b).Brown and Mitchell (1956) found that 72% of a series of

with gastroduodenal haemorrhage had just takenStubbe (1958) showed a 70% incidence of occult

bleeding in 180 patients receiving aspirin. Lange (1957)rtpantd that in patients with gastroduodenal haomofrhage,

the proportion who had taken aspirin before the bleeding was37% in those with peptic ulcer and 56% in those with negativeradiological findings. He regarded aspirin as particularlydangerous in elderly patients with a long history of addictionto it. Schneider (1957), in six out of ten persons studied,found gross bloodstaining in every specimen of an aspirintest-meal.

Alvarez and Summerskill (1958) incriminated salicylates inover 40% of 103 consecutive patients admitted to hospitalwith gastroduodenal haemorrhage attributed to peptic ulcer(chronic or acute). They found too that half the patients whotook salicylates lost blood in their stools-these patientsincluding cases of peptic ulcer and X-ray-negative dyspepsiaand controls. They found no evidence that soluble calciumaspirin is any less irritant than insoluble aspirin.

It is fair to say that most people who have studied thisproblem agree that aspirin causes gastroduodenal bleedingmore often than is generally supposed. The relativelyhigh incidence of aspirin dyspepsia has never been inmuch doubt.

PathologyDo patients with duodenal ulcer commonly have an

erosive gastritis ? The literature on this seemingly simplequestion is chaotic.

In 256 gastrectomy specimens Magnus (1946) found gastritisonly occasionally and it was always mild. The observations ofWalters and Sebening (1932) were similar, but Puhl (1927)found gastritis much more frequently. An ulcerative antralgastritis is regarded as commonplace in patients with duodenalulcer by many European workers (Konjetzny 1930, Christian-sen 1940, Tumen and Lieberthal 1943). Schindler (1950)states that in cases of duodenal ulcer the gastric mucosa usuallyappears normal; but he admits that if the ulcer leads to

obstruction " be it spastic or organic, severe gastritis developsrather regularly. It is often the hypertrophic type but otherforms of gastritis are seen as well. This mixture of all typesof gastritis ... occurs chiefly in the ulcer bearing stomach, and,if it is distinctly visible one may suspect that the patient hasan ulcer."

As a preliminary to our previous studies (Muir andCossar 1955) we examined 20 stomachs removed forduodenal ulcer, and in none did we see acute erosive gas-tritis worthy of the name. We therefore agreed withMagnus that it was, at most, a rarity. But since then wehave examined many more gastrectomy specimens, andhave found acute erosive gastritis in quite a number ofcases of duodenal ulcer in which no aspirin had beentaken. We have therefore modified our views consid-

erably. We no longer accept aspirin as a cause of gastritisunless this is of a relatively specific type: it must prin-cipally affect the lesser curve; it must be erosive or franklyulcerative in type; and, above all, one or more of theerosions must take the shape of, and contain, a firmadherent particle of aspirin (such erosions often beingunder rugae, where they may be invisible to the gastro-scopist). These criteria are almost certainly too strict, butit is better that they should be this than wrong. On thesecriteria, of about 100 gastrectomy specimens which wehave so far seen only 18 have shown gastritis which wecould firmly attribute to aspirin.

This low incidence is not easily reconciled with thebleeding which unquestionably takes place after aspirintest-meals. Looking at gastrectomy specimens, we haveoften been surprised at the normality, or near normality,of the gastric mucosa though the patient had taken aspirinand had had blood in every specimen after an aspirintest-meaL May capillary damage perhaps be caused bysalicylates absorbed into the blood-stream, as was formerlysupposed ?

540

Present InvestigationAll patients with gastroduodenal bleeding admitted to

our unit between February, 1956, and December, 1957,were questioned closely about aspirin-their previousexperience of it, how it affected them, what variety theytook, and how they took it. We investigated 106 patients(39 women and 67 men). The presumptive cause of thebleeding is shown in table i. The patients occupying the

TABLE I—CAUSES OF HÆMORRHAGE

beds to the right of these patients were used as controlsand similarly questioned.

Having come to the tentative conclusion that, if aspirincauses gastroduodenal bleeding, it will probably do sowithin forty-eight hours, we limited our questions to theuse of aspirin in the forty-eight hours before the heemor-rhage (definite melxna or haematemesis).Of the 106 controls, 17 admitted to taking aspirin within

forty-eight hours of admission-a much higher propor-tion than the 5% found in our previous series.Of the 106 patients with gastroduodenal haemorrhage,

57 admitted to taking aspirin within forty-eight hours oftheir haemorrhage (table n). From so small a series it iseasy to draw false conclusions; but it is noteworthy thatof 26 patients (" acute lesion " group) who did not giveany previous history of dyspepsia and showed no X-rayabnormality, no fewer than 19 had taken aspirin.The 57 people who had taken aspirin before their

bleeding were asked some further questions:1. Had they previously noted that aspirin gave them indigestion

or intensified existing indigestion? ?Of the 36 patients. with presumed peptic ulceration 17 were

aware that aspirin made their dyspepsia worse, sometimesactually exacerbating ulcer symptoms if taken in a symptom-free period; 12 had taken aspirin without ill effect; and 7could not or would not give a definite answer.Of the 19 patients in the

" acute’lesion " group, 8 knew from

previous experience that aspirin gave them heartburn; 5 hadtaken it occasionally with impunity; and 6 had never taken anyto their knowledge.

TABLE II—CASES IN WHICH ASPIMM HAD BEEN TAKEN BEFORE THE

HÆMORRHAGE

Discussion

About half of a series of patients admitted to hospitalwith gastroduodenal bleeding were found to have takenaspirin within 48 hours of their first haemorrhage as com-pared with 15% of a control series with miscellaneousillnesses. These figures strongly support the contentionthat aspirin is a potent factor in this type of bleeding.Aspirin had been taken by 23 of the 44 patients presumedto have a duodenal ulcer, by 13 of the 24 presumed tohave a gastric ulcer, and by no fewer than 19 of the 26with no previous history of dyspepsia. These figures agreewith our previous ones (Muir and Cossar 1955) if allow-ance is made for the fact that our earlier investigationcovered only the twenty-four hours before the haemorrhage.

Again it was possible to divide the aspirin-hmmtemesisgroup into three categories:

1. In 14 patients the history was so definite that no otherconclusion could reasonably be reached. 9 were in the acute-lesion group, 4 had a duodenal ulcer, and 1 had a gastric ulcer.

2. In 12 patients (6 duodenal ulcer, 3 gastric ulcer, and 3acute lesion) the history, though suggestive, left room for doubt.

3. The remaining 31 patients (14 duodenal ulcer, 9 pstriculcer, 7 no previous dyspepsia, 1 portal hypertension) hadtaken aspirin within forty-eight hours of their initial hæmor-rhage, but their histories gave no clue to whether it was many way responsible for the bleeding. Many of them hadtaken aspirin regularly with impunity; some had stories ofprevious gastric bleeding when no aspirin had been taken tadnone gave the characteristic story of aspirin/hearthurn-and-epigastric-distress/bleeding.Even if we accept only the first category of patients (14)as true examples of aspirin bkeding, we again come to theconclusion that one patient in every eight admitted vA

541

gastroduodenal haemorrhage was directly Suffering from’aspirin intolerance.The source of haemorrhage in these patients must be.

speculative, but we still think that most of the acute-lesion group bled from an acute erosive gastritis.

Further points of interest are:1. Of the people who bled after taking aspirin, fully half

tmew that aspirin gave them indigestion. This applies to boththe acute-lesion group and the presumed-peptic-ulcer group.

2. Aspirin was much more dangerous when taken on anempty stomach. This is in itself evidence that aspirin isharmful to the stomach. Crushing of the tablets apparentlymade little difference to its irritant properties.

3. Only 1 patient had taken soluble calcium aspirin (’Dis-prin’) and he was in the third or doubtful class. This seemsto us significant, because we know that soluble calcium aspirinis prescribed widely in this area. ’

4. Before their bleeding, relatively few of the ulcer patientsnoted any increase in their dyspepsia after taking aspirinwhereas half the acute-lesion patients did so. The formerfinding is at variance with our previous observation that a thirdof our peptic-ulcer patients disliked aspirin because it increasedtheir indigestion.

5. We cannot support Lange’s contention that hæmorrhagefrom aspirin is more likely in older patients.This second series convinces us more than ever that

aspirin is a dangerous drug, particularly for those inwhom it causes indigestion and in those with peptic ulcer.If indeed one gastroduodenal haemorrhage in eight iscaused by aspirin, surely the time has come for a muchfuller investigation into its effect on the stomach.

SummaryOf 106 patients admitted with gastroduodenal hmmor-

rhage, 57 admitted having taken aspirin within forty-eight hours of their initial bleeding. Of 106 patientswithout gastroduodenal haemorrhage, 17% had taken

aspirin in the forty-eight hours before admission.The group of patients who most commonly gave a his-

tory of taking aspirin before the haemorrhage were thosewith acute gastric lesions (no history of dyspepsia).Of the people whose haemorrhage followed ingestion

of aspirin, half knew that aspirin gave them indigestion.Aspirin is more dangerous in this respect if taken on

an empty stomach.REFERENCES

Acheson, R. M. (1958) Lancet, ii, 320.Allibone, A., Flint, F. J. (1958a) ibid. ii, 179.

— — (1958b) ibid. p. 1121.Alvarez, A. S., Summerskill, W. H. J. (1958) ibid. p. 920.British Medical Journal (1955) Editorial, ii, 31.Brown, R. K., Mitchell, N. (1956) Gastroenterology, 31, 198.Caravati, C. M., Cosgrove, E. F. (1946) Ann. intern. Med., 14, 638.Christiansen, T. (1940) Amer. J. med. Sci. 200, 61.Dodd, K, Minot, A. S., Arena, J. M. (1937) Amer. J. Dis. Child. 53, 1435.Douthwaite, A. H. (1938) Brit. med. J. i. 1143.Douthwaite, A., Lintott, G. A. (1938) Lancet, ii, 1222.- 1954; Brit. med. J. ii, 917.Forgie, R. E., Shafer, J. (1958) Lancet, ii, 373.Gross, M., Greenberg, L. A. (1948) A Critical Bibliographic Review.

New Haven.Hongberger, M. (1943) Brit. med. J. ii, 57.Hurst, A. 1943) ibid. i, 768.

— Lintott, G. A. M. (1939) Guy’s Hosp. Rep., 89, 173.Iry, A. C., Grossman, M. I., Bachrach, W. H. (1950) Peptic Ulcer.

Philadelphia.Kotzny, G. E. (1930) Die entzündliche Grundlage der typischen

Geschwursbildung im Magen und Duodenum. Berlin.L, H. P. (1957) Gastroenterology 33, 5.Magnus, H. A. (1937) J. Path. Bact. 44, 389.- 1940 Brit. med. J. i, 415.- 1946 J. Path. Bact. 58, 431.M A., Cossar, I. A. (1955) Brit. med. J. ii, 7.Prol W. D. (1943) J. Iowa St. med. Soc., 33, 155.Prol, H. (1927) Virchows Arch. path Anat. 265, 160.Schandler, R. (1950) Gastroscopy. The Endoscopic Study of Gastric

Pathology; p. 187. Chicago.Schocdet, E. M. (1957) Gastroenterology, 33, 616.Sobbe, L. Th. F. L (1958) Brit. med. J. ii, 1062.H. J., Lieberthal, M. M. (1943) Gastroenterology, 1, 555.W., Sebening, W. A. (1932) Minnesota Med., 15, 579.Wmerson, A. P. (1955) Brit. med. J. ii, 1531.

S., Wolff, H. G. (1943) Human Gastric Function. London.

ALDOSTERONE EXCRETION AND TISSUE

ELECTROLYTES IN NORMAL PREGNANCYAND PRE-ECLAMPSIA

D. KUMARM.B. Lucknow

L. A. W. FELTHAMM.A. Toronto

A. G. GORNALLPh.D. Toronto

From the of Obstetrics and Gynœcology and the Departmentof Pathological Chemistry, University of Toronto, Canada.

THE increase of aldosterone in the urine during latepregnancy (Venning and Dyrenfurth 1956) is a findingof great interest. If it reflects a high level in the plasma,then the immunity of the normal pregnant woman to herhyperaldosteronxmia calls for an explanation. Dieckmannand Pottinger (1956) have reported that the total muscle-sodium is increased in normal pregnancy, but reverts tothe non-pregnant range in pre-eclampsia. Tatum (1956)found no significant difference in the total muscle-sodiumof normal and toxsemic patients.The possibility of defining. a relationship between

aldosterone excretion and tissue-electrolyte metabolismprovided a new approach to the problem, and led to thisreport.

Clinical Factors

Since aldosterone excretion increases considerablywhen the sodium intake decreases (Luetscher andAxelrad 1954), it was necessary to keep the patients inhospital under metabolic-ward conditions. Seventeen

reliable, intelligent, normal pregnant women in their lasttrimester were selected at different times from the pre-natal clinic of the Toronto General Hospital. As a basalintake each patient had for 12 days a low-salt (1 g. sodiumchloride) diet prepared especially for the metabolic ward.Judging from sodium-excretion data, the salt content ofthis diet was generally satisfactory but occasionally it

may have contained up to twice this amount of salt. For6 of the 12 days (sometimes the first 6, sometimes the last6) a normal-salt (8 g.) intake was achieved by supplyingan additional 7 g. of sodium chloride in three portions,either as tablets or as a 20% solution; one portion wastaken by mouth with each meal.

Biopsy specimens of the rectus abdominis muscle wereobtained, after the nerves supplying the area had beenblocked with 2% procaine solution, on the morning ofthe 6th day of the controlled dietary period.About 3 g. of tissue was transferred to a covered weighing

bottle, and taken immediately to the laboratory. There thetissue was placed in a humidified cabinet and blotted free ofsuperficial blood; all visible fat and connective tissue wascarefully removed. The muscle was then cut into small pieceswith scissors, and duplicate representative samples were

weighed on a torsion balance for each of the various analyses.Seven patients with signs of pre-aclampsia and three

’

normal non-pregnant women were investigated in a

similar manner; with one exception they were on thenormal-salt diet during the test.

Analytical Methods. Muscle.—Part of the muscle was used for sodium, potassium,.

and water determinations.

The tissue was placed in tared platinum crucibles, driod at l030Cfor 48 hours, then cooled and weighed. The loss in weight gave ameasure of the water-content of the tissue. The dry tissue was thenashed overnight at 500°C. The ash was diluted appropriately With