918 RITODRINE DOSE AND ECG FINDINGS for which they may persist has not been investigated. A 53-year-old woman presented with a 2 week history of a pi...

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for which they may persist has not been investigated. A 53-year-old woman presented with a 2 week history of a pink vaginal discharge. 14 years previously she had undergone a total abdominal hysterectomy and right salpingo-oophorectomy for a non-malignant condition. 6 weeks before being referred to the gynaecologist she had had what seemed to be a pulmonary embolism and had been prescribed anticoagulants. On speculum examination of the vagina there was obvious granulation tissue at the vault. This was avulsed. Histopathological examination confirmed the presence of granulation tissue only. The vault was then cauterised and was seen to be well healed on subsequent review. This case shows not only that vault granulation tissue can take very much longer to resolve spontaneously than is currently thought but also that symptoms attributable to this may develop after a long quiescence, the trigger here being anticoagulation. It may be important to ensure adequate follow-up for women who have vault granulations cauterised to confirm complete eradication. University Department of Obstetrics and Gynaecology, Leicester Royal Infirmary,


Leicester LE2 7LX

In pregnancy the intravascular volume increases, peripheral vascular resistance falls, and cardiac output rises,3 in combination with relative anaemia and increased oxygen consumption. Thus, the addition of 0 receptor stimulation, further increasing oxygen consumption, may induce myocardial ischaemia. 1,4 Even so myocardial ischaemia is thought of as a rare, albeit potentially serious, complication of (3z sympathomimetic treatment. We found significant ST segment depression in the anteroseptal leads in 73 % of patients receiving ritodrine. This change is highly suggestive of myocardial ischaemia.s Furthermore, in three out of four patients echocardiography revealed septal hypokinesia, an independent indicator of myocardial ischaemia. These findings question the advisability of using &bgr;2-sympathomimetic drugs in the treatment of premature uterine contractions. Although acute myocardial necrosis is rare,’ silent ischaemia could contribute to the cardiomyopathy that has been reported after prolonged ritodrine treatment.6 Hendricks et alreporting similar ECG findings in ritodrine-treated women, suggest that these changes are not likely to represent mycocardial ischaemia, but this view is not supported by the parallel echocardiographic recordings reported here. Departments of Obstetrics and Gynaecology, Rebecca Sieff Government Hospital

Department of Cardiology, Rebecca Sieff Government Hospital, Safed, Safed 13100, Israel



*Faculty of Medicine, Technion, Haifa, Israel. 1. Katz M, Robertson P, Creasy RK. Cardiovascular complications associated with terbutaline treatment for preterm labor. Am J Obstet Gynecol 1981; 139: 605-08. 2. Cohn PF Silent myocardial ischemia in patients with a defective anginal warning system. Am J Cardiol 1980; 45: 697-702. 3. Sullivan JM, Ramanthan KB. Management of medical problems in pregnancy— severe cardiac disease. N Engl J Med 1985; 313: 304-08. 4. Benedetti TJ Maternal complications of parenteral beta-sympathomimetic therapy for premature labor. Am J Obstet Gynecol 1983; 145: 1-6. 5. Rijneke RD, Ascoop CA, Talmon JL. Clinical significance of upsloping S-T segment in exercise ECG. Circulation

1980; 61: 671-78. 6. Dhmaut JF, Boutonnet G, Weber S, et al Responsabilite des betamimetiques presents au cours de la grossesse dans la genese d’une cardiomyopathie du post-partum. Nouv Presse Méd 1978; 7: 4058-62. 7. Hendricks SK, Keroes J, Katz M. Electrocardiographic changes associated with ritodrin-induced maternal tachycardia and hypokalemia Am J Obstet Gynecol 1986; 154: 921-23

1. Greenhalf

JO. Vaginal vault granulation tissue following total abdominal hysterectomy. Br J Clin Pract 1972; 26: 247-49. 2. Howkins J, Williams DK. Vault granulations after total abdominal hysterectomy.J Obstet Gynaecol Br Commonw 1968; 75: 84-86.


SIR,--Cough and wheeze have been described as possible undesirable side-effects of angiotensin-converting enzyme (ACE) inhibitors.l°2 The first report of this complication was with captopril. Bronchospasm has also been reported in this context, in patients with or without a history of asthma. 2,3 We describe here a patient who had a chronic cough while taking enalapril. A 61-year-old woman who had never smoked had been taking enalapril 10 mg daily for a year because of hypertension. Soon after the start of treatment she had a severe dry cough, sometimes accompanied by nausea and vomiting. No environmental or predisposing factors could be found. The patient had no personal or family history of atopy. She was in good general condition, with no respiratory symptoms apart from the cough and no sign of left heart failure or oesophageal reflux. Her blood pressure was 130/80 mm Hg. Chest X-ray, lung function tests (no change was observed after 5000 ug acetylcholine), and fibreoptic bronchoscopy were normal. On the assumption that the patient’s cough was due to enalapril, the drug was withdrawn; the symptoms soon disappeared and have not reappeared. The timing of symptoms in relation to treatment and the exclusion of other causes of cough strongly argue that enalapril was responsible. The mechanism is unclear, though kinins3 may be involved: plasma kinin levels rise during ACE inhibition3 and kinins can provoke bronchoconstriction in patients with asthma. However, our patient had no background of bronchial hyperreactivity. Whatever the mechanism, cough should be added to the list of side-effects of enalapril. Department of Lung Diseases, Hôpital Laennec, 75007 Pans, France


1. Sesoko

S, Kaneko Y. Cough associated with the use of captopril. Arch Intern Med 1985; 145: 1524. 2. Semple P, Herd G. Cough and wheeze caused by inhibitors of angiotensin-converting enzyme. N Engl J Med 1986; 314: 61. 3. Gavras H, Brunner H, Turini G, et al. Antihypertensive effect of the oral angiotensinconverting enzyme inhibitors SQ14225 in man. N Engl J Med 1978; 298: 991-95.


SIR,-Vault granulation after total abdominal hysterectomy is a common postoperative finding, having been identified in up to 37 % of hysterectomised patients 8 weeks after surgery.’ Of these, 63% had symptoms attributable to the granulations, and these can vary from postcoital bleeding to vaginal discharge. The prevalence of vault granulation may depend on operative technique, being higher if the vault is left open at the time of surgery.2 Spontaneous resolution is thought to take weeks or months, but the length of time


SIR,-Dr Bumey (Aug 9, p 323) states that asthma mortality rose sharply in several countries, including England and Wales in the 1960s and that asthma mortality may be rising in the United States, which was unaffected by the previous epidemic. May I offer possible explanations. (1) Until the mid-1960s the most widely used method of controlling acute asthma attacks was by an aqueous solution of


adrenaline/atropine delivered to the lung via a hand bulb nebuliser. This method of relief continued to be used widely in the US, where the introduction of selective bronchodilator aerosols was delayed. (2) Selective beta bronchodilators exert little or no alpha stimulation. Is it possible that absence of alpha stimulation removes a valuable protective mechanism? (3) Adrenaline/atropine preparations are delivered to the lung in aqueous solution, propelled by air alone. (4) The somewhat cumbersome method of delivery permits patients to titrate each dose very precisely according to their exact need at that moment. The dose of bronchodilator is drawn in by the patient during normal inspiration, requiring no synchronisation of breathing. This company continues to supply adrenaline/atropine solution (’Rybarvin’) and nebuliser inhalers to the many thousands of older asthmatics who have rejected efforts by family doctors and chest physicians to convert them to selective bronchodilator aerosols. Is it possible that they were right? Rybar Laboratories Ltd, Amersham, Bucks



SIR,-We read with interest the comments by Dr King (Sept 13, 631) on our hypothesis. However, in proposing that all lipid-soluble organic chemicals in sufficient concentration act via their membrane stabilising activity (MSA) on biological membranes in the same way as anaesthetic agents to produce fatal toxicity, we have expressed precisely the same concepts as he does.


Although over 90 % of the agents involved in fatal poisonings may have depressant properties, our suggestion was that over 30 % of all poisoning fatalities are caused by agents which have MSA. We chose beta adrenergic antagonists as being the best series of drugs to study because of the wide range of lipid solubilities and MSA potency in a group of drugs which are otherwise chemically and pharmacologically similar; we did not attempt to make a correlation for other drugs whose MSA is widely accepted. To take two examples, the MSA of the tricyclic antidepressantsl and dextropropoxyphene2 is established as the primary cause of their fatal toxicity. The term membrane stabilisation refers primarily to electrical stabilisation of membrane potential and therefore inhibition of the action potential, and secondarily to preservation of membrane integrity under conditions of stress (osmotic, mechanical, oxidative, thermal, and so on). However, in neither case is it implied that the membrane is rendered physically rigid (although this may occur with divalent cations). The current theory of membrane stabilisation is that lipophilic molecules partition into the membrane lipid bilayer, increasing its fluidity and surface area; this results in disorder of lipoprotein structure, which affects ion channels, enzymes, and receptors; and if the effect is sufficiently strong, cell function becomes deranged. MSA is thus the result of the interaction of lipid soluble chemicals with any biological membrane, not merely in the myocardium but also in the central nervous system (particularly tranquillisers and sedatives such as barbiturates and alcohols). General anaesthesia is thought to follow a similar mode of action to local anaesthesia; the difference between the two being mainly physicochemical (eg, volatility) and pharmacokinetic (distribution to and within the brain) rather than their mode of action, which for both is probably disruption of membrane ion flux. We agree, however, that local anaesthetic agents may have a more specific affinity for the sodium channel, as opposed to general anaesthetics which are believed to affect the sodium channel indirectly by their non-specific interaction with the cell membrane. However, "protein receptor" theories of general anaesthesia are also gaining ground.3,4 The main point we wish to make is that fatal toxicity from MSA occurs when cellular processes are so deranged that vital organ function (the brain via respiratory depression or the heart via circulatory failure) is incapable of supporting life. National Poisons Unit,

Guy’s Hospital, London SE1 9RT

1. Pentel P, Benowitz N. Tricyclic antidepressant poisoning: Management of arrhythmias. Med Toxicol 1986; 1: 101-21. 2. Young RJ. Dextropropoxyphene overdosage, pharmacological and clinical management. Drugs 1983; 26: 70-79. 3. Franks NP, Lieb WR. Mapping of general anaesthetic target sites provides a molecular basis for cut off effects. Nature 1985; 316: 349-51. 4. Smith EB, Bowser-Riley F, Daniels S, Dunbar IT, Harrison CB, Paton WDM. Species variation and the mechanism of pressure anaesthetic interactions. Nature 1984; 311: 56-57.


SIR,-We have tested, in infants not given immunoprophylaxis against hepatitis B, Alexander and Eddleston’s hypothesisl that intrauterine infection with hepatitis B virus (HBV) is modulated by passively transferred maternal antibody to core antigen, resulting in delayed expression of HBV components in the newborn. If anti-HBc IgG suppresses HBV expression in infected infants the peak of HBsAg seroconversion in infants of anti-HBc IgG positive carrier mothers would be expected to be more than 6 months after birth, when serum levels of this antibody drop significantly. In our study2 the seroconversion rate reached its highest point (62%, 21/34) at between 3 and 5 months, at which time 72% of the infants still had high levels of passively transferred maternal ailti-HBc IgG in their serum. Among infants born to mothers who were positive for both HBsAg and HBV e antigen, in whom a transmission rate of 88% was observed between 3 and 7 months agethere was, by the age of 10 months, a significantly larger number of HBsAg positives in those who were seropositive for anti-HBc IgG than in those who were seronegative for this antibody (table i). At age 7-10 months (mean 9 months 4 days) both the infants having anti-HBc IgG had acquired HBV infection, whereas only 1 out of 3 infants who were seronegative, for this antibody had HBsAg. It thus seems that it is the HBV antigen status of the mother rather than her anti-HBc antibodies that determines HBV expression in the infant. Seropositivity for both HBsAg and anti-HBc IgM, with or without e antigen, indicates a recent acute infection or continued virus replication in the presence of active disease.3,4 With this HBV status during the third trimester of pregnancy the chance of intrauterine infection of the fetus would be expected to be high. According to Alexander and Eddleston’s hypothesisl infants born to such mothers should manifest HBV infection frequently and soon after birth if they lack anti-HBc IgG in their serum. Our data, however, show that of the 7 HBV non-infected infants born to HBsAg and anti-HBc IgM positive but e antigen and e antibody negative mothers 6 did not have anti-HBc IgG at 3-7 months (mean TABLE I-RELATION BETWEEN SEROPOSITIVITY FOR HBSAg AND ANTI-HBC






*All +ve for ann-HBc