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raised strong suspicions of an ectopic pregnancy. A scanfour days later revealed an enlarged uterus, identifiableplacenta and fetal parts, but neither fetal head nor fetalmovements (fig. 2c); the uterus was smaller thanexpected at twelve weeks of normal pregnancy. Levels ofH.C.G. began to decline, and pregnancy tests became

negative (fig. 1). Pelvic pain continued through this

period.Laparoscopy thirteen weeks after the last menstrual

period, or eleven and a half weeks after oocyte recovery,revealed a small amount of blood in the pelvis and aright tubal ectopic pregnancy with oozing from a smallperforation site about 3 cm from the right uterine cornu.The ampulla was enlarged, distorted, and occluded, andthere was no escape of blood at the distal end. The righttube was excised together with the diseased left tube.

Histological examination showed decidual tissue withinthe fallopian tube with degenerated chorionic tissue andother necrotic, haemorrhagic material, the appearancebeing typical of a tubal pregnancy. Attempts to cultureembryonic cells were not successful. The patient made arapid recovery and was discharged from hospital a weeklater; suppression of lactation was necessary, and men-struation was subsequently re-established.

Discussion

There can be no doubt that pregnancy was estab-lished in this patient following the reimplantation of anembryo into her uterus. The course of early pregnancyappeared to be normal, but the fetus evidently died

through its location in the oviduct.The patient had not ovulated before oocyte collection,

oocytes were recovered from all but one follicle, hertubes had become progressively occluded, and sheabstained from intercourse during the entire course oftreatment. Pregnancy thus arose after the embryo wasreimplanted, but it was carried into the oviduct ratherthan the uterine cavity perhaps through being placed atthe fundus. Eight weeks later a small bleed occured intothe occluded right tube forming a small haemato-salpinx,although the embryo survived. Two weeks later morepersistent bleeding caused death of the embryo.

Physiological conditions in the uterus of patients withoccluded oviducts could differ from those with patentoviducts. The free movement of fluids through the ovi-ducts would be prevented, and an embryo might becomelocated in the oviducal lumen (fig. 3). Fluids move

through the oviduct towards the uterus after ovulation,although the amount is much less than at ovulation.9

Perhaps the embryo was able to implant in the oviductmore easily than in the uterus, for studies in animalshave shown that implantation occurs in ectopic siteswithout the intricate endocrine conditions needed foruterine implantation.3 Tubal implantation might there-fore be possible when uterine implantation is not. Tro-phoblast is more invasive in ectopic sites in animals,which could explain the early rise in levels of urinaryH.C.G. in our patient; a similar situation can also be in-ferred from some other data. 10

Our observations provide the first documented evi-dence that human embryos cultured for four and a

quarter days are capable of implantation. The low rateof implantation in earlier work may have been due toadverse uterine conditions or the techniques of reim-plantation. Treatment with exogenous steroids could

depress endogenous luteal activity, and may have causedthe gradual decline of cestrogens in our patient duringearly pregnancy, for progestogens can impair luteal acti. ,

vity." Some endocrine support of the uterus may never.theless be needed in the luteal phase after the use ofH.M.G. and H.C.G. since luteinisation is sometimesdelayed or weak.12 I

Cornual conditions should be assessed in patientsbefore embryos are reintroduced into the uterus. Thereis obviously no risk of an ectopic pregnancy if the ovi.ducts are completely absent, but careful monitoring ofthe early pregnancy is essential if the oviducts are dis.eased.

We thank the North Western Regional Health Authority and theOldham Area Health Authority, Miss L. Howells, Miss J. Purdy, Prof.C. R. Austin, and many others for their encouragement in this work.

REFERENCES

1. Greenhill, J. P. Obstetrics; chapter 32. Philadelphia, 1965.2. Scott, J. S. in Integrated Obstetrics and Gynaecology for Postgraduates (edited

by C. J. Dewhurst); chap. 14 Oxford, 1972.3 Kirby, D. R S. Adv. Biosci. 1970, 4, 256.4. Wynn, R. M. Am. J Obstet. Gynec. 1974, 103, 723.5. Beier, H. M. J. Reprod. Fert. 1974, 37, 221.6. Steptoe, P. C., Edwards, R. G. Lancet, 1970, i, 683.7. Steptoe, P. C., Edwards, R. G., Schulman, J. Purdy, J. M. Int. Cong. Fertil.

Buenos Aires, 1974.8. Steptoe, P. C., Edwards, R. G., Purdy, J. M. Nature, 1971, 229, 132.9. Lippes, J. Obstet Gynec. A. 1975, 4, 119.

10. Saxena, B. B., Landesman, R. Fert. Steril. 1975, 26, 397.11 Johansson, E. D. B. Acta obstet. gynec. scand. 1973, 52, 37.12. Edwards, R G., Steptoe, P C. J. Reprod. Fert. 1975, suppl. 22, p. 121.

PERCEPTION OF ASTHMA

A. R. RUBINFELD M. C. F. PAIN

Respiratory Unit, Royal Melbourne Hospital, Parkville,Victoria 3050, Australia

Summary Subjective assessment and objectivemeasurements of airways obstruction

were compared in 82 patients during methacholine-in-duced asthma. 15% of the patients were unable to sensethe presence of marked airways obstruction (forcedexpired volume in 1 s less than 50% of the predicted nor-mal value). These subjects could not be characterised asa distinct group on the basis of their sex, age, or

duration of their asthma. This reinforces the need for

objective measurement of lung function in the manage-ment of asthma.

Introduction

TREATMENT of asthma, whether by the physician orthe patient, is usually guided by the presence or absenceof chest tightness, wheeze, or dyspnoea. However, thispractice could lead to inadequate treatment if fluctua-tions in airways calibre are not always readily perceivedby the patient. In this case therapy could be delayeduntil quite late in an attack of asthma.

It has been recognised for over twenty years thatfunctional abnormalities may be found in symptom-freeasthmatic patients and recently these abnormalities andtheir incidence have been defined in greater detail’The purpose of this study was to extend these observa-tions to the acute situation. Symptoms and spirometric

883

measurements were compared in asthmatic patients inwhom a controlled attack of asthma was induced withmethacholine aerosol. An attempt was made to definecharacteristics which could be used to predict those pa-tients with poor perception of their asthma.

Materials and Methods

82 patients were studied, of whom 61 were asthmatics orformer asthmatics, attending as hospital outpatients. Theremaining 21 had occupational asthma. Medication was notrestricted prior to the provocation tests. Informed verbal con-sent was obtained from each patient.

Fig. 1-Distribution of baseline F.E.V.1 amongst the symptom groups.Group means are indicated.

Fig. 2-Relationship between subjective and objective assessment of air-ways obstruction at height of attack of asthma.

Group means are indicated.

A= poor perceiver because of inability to sense marked baseline air-ways obstruction (F.E.V., -, 50% predicted normal).

= poor perceiver because of inability to sense marked final airwaysobstruction (F.E.v.; < 50% predicted normal).

Methacholine solution was prepared in sterile isotonic salinein concentrations of 1.25, 2.5, 5, 10, and 25 mg/ml. The aero-sol was produced from ’Vaponephrin’ (Bennet) nebulisers,driven with an oxygen flow of 5 1/min. Spirometry was carriedout using a water-filled ’Pulmotest’ (Godart) spirometer.

After measurement of baseline vital capacity and forcedvital capacity (F.v.c.) twice, the first dose of aerosol was givenas a single vital capacity inhalation, the nebuliser being heldat the open mouth. After 5 s’ breath holding, normal breathingwas continued, and a duplicate F.v.c. manoeuvre was carriedout 3 min later. This procedure was repeated using increasingmethacholine concentrations until either F.v.c. or forcedexpired volume in 1 s (F.E.V.l) fell by more than 15%, or thepatient complained of severe tightness in the chest. The bestF.E.V.1 of any duplicate was used for calculations.

All patients were initially symptom-free. At the height of theinduced attack they were asked to classify their degree of tight-ness as zero, mild, moderate, or severe, and were groupedaccording to this response. The attack was reversed by inhala-tion for 30 s of 1% isoprenaline from a Wright nebuliser.

Statistical analyses were calculated using either a linearregression technique for the group means, or a x2 test with acontinuity correction to allow for small numbers.4 The F.E.V.1is reported as a percentage of the predicted normal value usingthe tables of Goldman and Becklake.5

Results

The 21 patients with occupational asthma were ana-lysed separately because of possible misrepresentation oftheir symptoms as a result of claims for compensation.The following results relate to the 61 hospital-basedpatients.

Initial F.E.V.1When initial F.E.V.1 was examined, there was no tend-

ency for those patients with more severe final symptomsto have greater initial airways obstruction (fig. 1). De-spite the lack of symptoms in all patients at this stage,6 subjects (5 male, 1 female) (10%) had an F.E,V’l lessthan 50% of that predicted; they were considered to be"poor perceivers" of airways obstruction.

F.EY’l at Height of Attack

At the height of the attack, subjects with more severesymptoms tended to have the lowest F.E.V’l values

Fig. 3-Relationship between subjective assessment of airways obstruc-tion and precipitancy of induced attack.

Group means are indicated.

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PATIENT’S ASSESSMENT OF AIRWAYS OBSTRUCTION

N.s.=Not significant

(r=097) (fig. 2). Among the 13 patients remainingsymptom-free at the height of the attack, 4 had anF.E.V.1 less than 50% of that predicted. 1 had been cate-

gorised as a poor perceiver prior to the attack. Thus, 9patients (15%) were asymptomatic, despite marked air-ways obstruction, 6 in their basal state and 3 at theheight of an attack.

Precipitancy of Attack ,

The time for induction of the attacks varied from 3to 18 min (r=097) (fig. 3). Attacks tended to be morerapid in onset in those patients complaining of severesymptoms.

Age, Sex, and Duration of History of AsthmaThere was no systematic tendency for symptoms at

the height of the attack to be related to the age or sexof the patient (see accompanying table). There was norelationship between the symptoms and the length ofthe history of asthma among the 52 patients for whomthe duration of asthma was known (table).

Patients with Occupational Asthma

These 21 patients (20 male, 1 female) were subse-quently added to the hospital-based group for re-ana-lysis. This introduced a male bias, but the results wereotherwise unchanged. In particular, the proportion ofsubjects unable to sense the presence of marked airwaysobstruction remained as 10% (8/82 patients) in the basalstate, and 5% (4/82 patients) at the height of the attack.

Discussion

There have been few studies relating severity of symp-toms to the degree of airways obstruction present. Thereis little documentation of the proportion of patients un-able to sense the presence of marked airways obstruc-tion, and characterisation of this group. McFadden etal.6 reported that most of 22 asthmatics recovering froman acute attack of asthma became symptom-free despiteairways conductance remaining below 50% of the pre-dicted normal. Our study concentrated on symptoms,either in the basal state or during induced asthma.Of the 82 asthmatic subjects, 10% were asymptomatic

at rest and had marked airways obstruction, and 5 % werestill asymptomatic with marked airways obstruction atthe height of an attack of methacholine-induced asthma.Although most patients could detect the presence of sig-nificant airways obstruction, 15% were found to be poor

perceivers of asthma and could not be characterised asseparate from the remainder on the basis of age, sex, or ithe duration of their prior asthma. Symptom severity inpatients able to sense the development of asthma wasrelated to both the degree of airways obstruction and theprecipitancy of the attack.The fact that a significant number of asthmatics had ’,

unperceived yet marked airways obstruction could beclinically relevant. Whether such patients have a worseprognosis than those able to sense the development oftheir asthma remains unknown. McNicol and Williams’have suggested that much of the childhood chest defor-mity due to asthma, may be due to lack of perception ofthe severity of the disease by the patient or the parents.We found that the poor perceivers of airways obstruc-tion were detected only by measurement of lung func-tion, and could not be predicted by age, sex, or previoushistory of asthma. While a conclusion urging the treat-ment of all symptom-free patients with asthma is unjus-tified, we feel that it is important that objective measure-ments of lung function should be carried out in the

management of asthmatic subjects.This work was supported by grants-m-aid from the National Health

and Medical Research Council of Australia, and the Asthma Founda-tion of Victoria. We thank Dr J. F. Cade and Dr J. D. Mathews forcriticism of the paper and statistical advice; Mrs M. Bickley for techni-cal assistance, and our patients, who were willing to undergo provoca-tion of their asthma.

Requests for reprints should be addressed to M. C. F. P.

REFERENCES

1. Bates, D. V. Clin Sci. 1952, 11, 203.2. Cade, J. F , Pain, M. C. F. Aust. N.Z. Jl Med. 1973, 3, 545.3. Cooper, D M., Bryan, A. C., Levison, H. Am. Rev. resp. Dis. 1974, 109,

703 (abstr.).4. Mathews, J. D., Roger, B. M. J. chron. Dis. (in the press).5. Goldman, H. I., Becklake, H. R. Am. Rev. Tuberc. pulm. Dis. 1959, 79, 457.6. McFadden, Jr, E. R., Kiser, R., de Groot, W. J. New Engl. J. Med 1973,

288, 221.7. McNicol, K. N., Williams, H. B. Br. med. J. 1973, iv, 7.

A FATAL MOTOR-CAR ACCIDENT ANDCANNABIS USE

Investigation by Radioimmunoassay

DERRICK TEALE VINCENT MARKS

Division of Clinical Biochemistry, Department ofBiochemistry, University of Surrey, Guildford, Surrey

GU2 5XH

IMPAIRMENT of driving skills by drugs is an importantcause of traffic accidents. 1 Alcohol is the most impor-tant, though far from the only, drug involved; and of684 fatal accidents investigated by Woodhouse, 321(47%) of the drivers had blood-alcohol levels greaterthan 100 mg/100 ml at the time of death. In 16 itexceeded 400 mg/100 ml.

Unlike alcohol, cannabis has received little attentionas a possible cause of traffic accidents, largely owing tothe difficulty of proving cannabis use objectively.’ Therecent development of a reliable and relatively simplemethod for detecting and measuring cannabis productsin blood and urine3 4 may help to overcome this diffi-culty. As Milner’ has pointed out, the full effect of alco-hol on driving competence was not appreciated until