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100 mg. per 100 ml., sugar 78 mg. per 100 ml., culture ofcerebrospinal fluid sterile; serum-cholesterol 260 mg. per 100ml.; serum-lipalbumin 26-5% (normal range 17-30%),P-lipoprotein fraction 30-3% (range 29-53%), j3-Iipoprotein/lipalbumin ratio 1-14 (range 1-1-2-8) and P-lipoprotein/lipalbumin-plus-OI.-lipoprotein ratio 0.73 (range 0-6-1-8). Urineanalysis was normal, as were chest and skull X-rays.The patient was given no treatment and her condition

remained unchanged for twenty hours, after which she rapidlydeteriorated, with signs of increasing intracranial pressure, andshe died twenty-four hours after admission.At necropsy (Lieut.-Colonel W. E. Clifford) there was a

cerebral infarct of the left hemisphere in the area of supply ofthe left middle-cerebral artery which was occluded by a

thrombus, 1 cm. (0-39 in.) long, at its origin. There was slightatheroma of the aorta and arteries of the neck, but no otherabnormality was found.

In the absence of other predisposing causes it is felt thatintravascular thrombosis in this case could be attributed to theoral contraceptive.

British Military Hospital,Dhekelia, Cyprus,

British Forces Post Office 53. D. E. BRADFORD.

BARBITURATE POISONING

SIR,-As your leading article (Jan. 28, p. 200) states, it isalmost impossible to compare results in different series of casesof barbiturate poisoning " because of varying standards andmethods of assessment ". A frequently used classification forclinical purposes is that of Reed et al./ who divided patientsinto four groups, the most severe being those with " respiratorydepression ... or circulatory failure ... or both". Some yearsago, in collaboration with Dr. A. Chiesa and Dr. A. A. E.Massoud, we studied a selected group of twenty-two suchpatients who were referred to us by admitting medical officersbecause they seemed to fit into this category. Full details ofour study will be reported elsewhere but we give here, insummary, our main findings and conclusions.

Hypoventilation, which we defined as being present underthese circumstances if the arterial PC02 was greater than 50 mm.Hg, was found in only three patients; a fourth was apnaeic onadmission and intermittent positive-pressure ventilation wasbegun immediately, so we were unaware of the initial Pco,.The level of 50 mm. Hg was chosen as the upper limit ofnormal because such a Paco2 is known to occur in physiologicalsleep.2 8

Although ventilation was normal, as defined by the PaCO2,in eighteen subjects, the ventilatory response to carbon dioxidewas impaired in several. The accompanying figure shows theventilatory response to carbon dioxide on three different occa-sions in one of these subjects: (a) soon after admission; (b) 12hours later, while still unconscious; and (c) shortly after

recovery of consciousness. (This was done by a rebreathingtechnique, recording end-tidal carbon dioxide and ventilatoryvolume simultaneously; we were careful to ensure an un-

obstructed airway at all times.) It can be seen that there wasan increase in both carbon dioxide sensitivity (increase inventilation for each mm. Hg rise in PC02) and threshold (Pco,intercept at zero ventilation, calculated by extrapolation of theresponse line) in the 12 hours between the first two recordings;there was a further insignificant rise in sensitivity to carbondioxide on regaining consciousness.

In half the patients (all with normal PaC02) ventilation volumewas measured and ranged from 8-08 to 3-26 (mean 6-50:1-48)litres per minute (body temperature and pressure, saturatedwith water vapour). Mean alveolar ventilation was 3-04:0-72(range 4-18—1-70) litres per minute. This confirms the doubt

expressed in your leader whether a minute-volume of less than4 litres is a sufficient criterion on which to base the need for

1. Reed, C. E., Driggs, M. F., Foote, C. C. Ann. intern. Med. 1952, 37, 290.2. Mills, J. N. J. Physiol., Lond. 1953, 122, 66.3. Robin, E. D., Whaley, R. D., Crump, C. H., Travis, D. M. J. clin.

Invest. 1958, 37, 981.

artificial ventila-tion. Conversely,in one boy who hadaspirated gastriccontents, and whodied 17 hours afteradmission, theminute - volumewas as high as 15

litres, yet his Paco2was 80 mm. Hg.His high minute-volume initially ledto a false impres-sion that he was

hyperventilating,but at a Paco2 ofthis level the pul-monary ventilationshould have beenabout five times

greater, so that forthis PaC02 he wasunderventilating.The case stresses

the importance of

blood-gas measure-ments and under-lines the fallacy inrelying even on a

measured minute-volume.

Ventilatory response to carbon dioxide inpatient with barbiturate poisoning whileunconscious (a, on admission, and b, 12hours later) and after recovery (c, 40hours after admission).

Diminished ar-terial oxygen satu-ration was invari-able with a raisedPC02 but occurred even when overall ventilation was normal.In one patient with a P aC02 of 38 mm. Hg, the arterial satura-tion was still only 80% at a stage where it was possible toarouse him by vigorous command; when he was made totake a deep breath his arterial saturation rose promptly tonearly 100%, but then gradually fell to around 80%. Thisbehaviour is consistent with regions of low ventilation-perfusionratio within the lungs which were readily ventilated by a singlelarge breath. In those patients in whom we obtained spiro-graphic records of breathing, occasional deep breaths, so

typical of the normal record, were conspicuously few and farbetween. The rarity or absence of deep breaths in barbituratepoisoning may account for regional hypoventilation and conse-quent hypoxia, even when total ventilation is still appropriatefor carbon-dioxide elimination.Twelve of our patients had a systolic B.P. below 100 mm. Hg.

We confirmed the observation of Barraclough and Sharpey-Schafer 4 that the arterial pressure response to a Valsalvamanoeuvre is abnormal in barbiturate poisoning, there being asteady fall in arterial pressure during the phase of raised intra-thoracic pressure and a gradual return to " control " levelsafter its release instead of the normal overshoot. But this maybe found even in patients whose B.P. remains normal, and weagree with Shubin and Weil 5 that this cannot alone be thecause of hypotension. Moreover, in hypotensive patients wefound that, although it may be possible to raise the B.P. byvasopressor drugs, the abnormality in Valsalva response per-sists. This is consistent with the view that hypotension is dueto ineffective filling of the vascular system, which Shubin andWeil showed may be due to either an absolute decrease inblood-volume or an expanded vascular bed, most probably thevenous capacity vessels.

Four of our patients died. Three were the patients with aPaco2 greater than 50 mm. Hg. The fourth death was fromcardiac arrest in a 60-year-old man (whose Paco2 was 42 mm.Hg). The patient who was apnceic on admission, and in whom

4. Barraclough, M. A., Sharpey-Schafer, E. P. Lancet, 1963, i, 1121.5. Shubin, H., Weil, M. H. Am. J. Med. 1965 38, 853.

681

the initial PC02 was unknown, recovered. The finding of araised Paco2 seems, therefore, to be of grave prognostic signifi-cance. Clearly it is important to know such data as this indifferent patients before allotting them to specific treatmentgroups.

Royal Victoria Infirmary,Newcastle upon Tyne 1.

Manchester Royal Infirmary,Manchester 13.

T. B. STRETTON.

J. B. L. HOWELL.

ASPIRIN FOR YOUNG CHILDREN

SiR,ŃThe recommendations of the Proprietary Associationof Great Britain, described in your Note (March 4, p. 517), thataspirin products made specifically for children should belabelled with dosage instructions, is a useful contributiontowards reducing therapeutic poisoning.The main problem is that of accidental poisoning. Each

year over 2000 children are admitted to hospitals in Englandand Wales with accidental aspirin poisoning. The drug haspractically invariably been taken in the form of flavoured

paediatric aspirin. My study of 170 cases of poisoning withpaediatric aspirin over the past three years has shown thatthese children (90% of whom are in the 2-4 age-group)practically always finish the opened bottle or packet, whichusually contains 50 tablets (a total of 4 g.). A logical andpractical preventive measure which the Proprietary Associationcould recommend to its member companies would be thatpasdiatric aspirin should be sold in packages of not more than12 tablets. Even if the child swallows all of these, the totaldose taken (1 g.) is very unlikely to give rise to toxic effects.Department of Pædiatrics,

Royal Infirmary,Huddersfield. W. P. SWEETNAM.

HAIR-FALL IN BLOOD-DONORS

SIR,-Blood-donors are protected from the danger of iron-deficiency anaemia by haemoglobin estimation or determinationof the specific gravity of the blood before venesection.1I describe here two donors in whom anaemia was not the firstmanifestation of iron deficiency and in whom screening pro-cedures were therefore inadequate. Full details of the caseswill be published elsewhere; the purpose of this letter is todraw attention to a hazard which is easily prevented.The patients were both 21-year-old women who had always

considered they were healthy. They sought advice becausetheir scalp hair had been falling excessively for many monthsand they feared they would go bald. Both were greatly agitatedabout their hair-loss and said their personality had altered.Direct questioning showed they were both blood-donors, andeach had given an average of two units a year for the previousthree years. They had both been bled since the hair-fall beganand had been told that the gravimetric test on their blood wasnormal. They considered their menstrual loss normal, butadmitted to fatigability and brittle nails of increasing severityin the previous few months. They had a fairly minor degree ofthinning of the scalp hair which was uniform over the wholescalp. Neither patient looked pale. Blood-examination showedHb 9-8 g. per 100 ml. and serum-iron level 12 ug. per 100 ml.in one, and Hb 10.5 g. per 100 ml. and serum-iron level 22 fLg.per 100 ml. in the other. Daily samples of hair recovered fromthe comb confirmed that the hair-fall was abnormally profuse.

Detailed inquiry showed that both girls had what mostwomen would regard as a rather excessive menstrual loss. Oneof them had given three units of blood in the year in which thehair-fall began. They were thus both likely to be rendered irondeficient. Neither had been advised to take iron after vene-section. They did not connect their hair-loss with the blood-donations and thought it might be due to their abnormalmental state. The response to treatment with 0-9 g. ferrousgluconate daily was excellent. Within two weeks the hair-loss1. Mollison, P. L. Blood Transfusion in Clinical Medicine; p. 2. Oxford,

1967.

decreased to normal, the emotional instability and agitationdisappeared, and they both felt more energetic. Hb concentra-tion became normal in three months and serum-iron level roseto normal in six months in the first patient, and Hb andserum-iron levels became normal in two months in the second.

Gravimetric screening for anaemia is a reliable method

tending to underestimate the haemoglobin concentration ifthere are errors of technique. It is likely, therefore, that boththese girls had a normal haemoglobin level before the lastvenesection, and at this time both of them had been losing hairfor months. The anaemia presumably developed after the lastvenesection, but a state of iron deficiency impairing the hair-growth and possibly causing emotional disturbance precededthe anaemia by months. This is probably an uncommon stateof affairs, but the occurrence of two cases in a routine skinoutpatient clinic within three months of each other suggeststhat it is not rare.

" There is general agreement that those who give bloodregularly should be provided with extra iron: for example,0-4 g. of ferrous sulphate daily for 30 days following eachdonation." 1 questioning of a random group of young womendonors indicates that many of those most at risk are notadvised of the need for iron replacement after venesection.

St. George’s Hospital,London S.W.1. K. V. SANDERSON.

GALLSTONES AND FLATULENT DYSPEPSIA

SIR,-It is a pity that Mr. Capper and his colleagues(Feb. 25, p. 413) should perpetuate the myth that gallstonescommonly cause flatulent dyspepsia. Probably the onlyunbiased observations on this subject are those of Price.2 Theevidence is that flatulent dyspepsia is common in the populationas a whole and that it is not more frequent among subjects withgallstones. Mr. Capper and his colleagues show that regurgita-tion of duodenal contents through the pylorus and gastrichypochlorhydria accompany flatulent dyspepsia. The fact thatall the patients also had gallstones might depend entirely uponthe method of selection of the cases for study.Western General Hospital,

Edinburgh 4. E. B. FRENCH.

DIFFERENTIAL MANTOUX TEST

SIR,-The article by Dr. Keay and Dr. Edmond 3 is aninteresting contribution to the problem of the diagnosticvalue of the intradermal tuberculin test. Although it isgenerally accepted that the use of 5 international tuberculin

FOURFOLD MANTOUX TESTING IN 300 WARD PATIENTS

No. * of reactors to 10 i.T.u. of P.P.D. prepared from:Antigen reaction M. tuberculosis M. avium M. kansasii M. balnei

(human type)

Single.. 3 (1%) 8(2.7%) 1 (0’3%) 0

Multiple.. 5 (1-7%) 3 (1%) 3 (1%) 3 (1%)

Together.. 8 (2-7%) 11 (3-7%) 4 (1-3%) 3

* In parentheses, percentages of all children tested.

units (I.T.U.) of purified protein derivative (P.P.D.) preparationsfrom various mycobacteria gives more specific reactions thanhigher concentrations, it is also known that the frequency ofcross-reactions between different products depends on thelocal prevalence of sensitivity in different geographical areas.42. Price, W. H. Br. med. J. 1963, ii, 138.3. Keay, A. J. Edmond, E. Lancet, 1966, ii, 1425.4. Palmer, E. C., Edwards, L. B., Hopwood, L., Edwards, I. Q. J. Pediat.

1959, 55, 413. Bleiker, M. A. Proc. Tuberc. Res. Counc. Hague, 1959,46, 113. Mellmann, W. J., Barness, L. A. Am. J. Dis. Child. 1962,104, 21. Simon, C. Klin. Wschr. 1962, 40, 631. Cramblett, H. Y.,Siewers, C. M. F., Edmond, E. W., Crews, J. Pediatrics, Springfield,1966, 38, 381.