507

exposed to ASA, 14 (11 cases and 3 controls) had taken it for gastric discomfort, 4 for insomnia, and 44 for other reasons (eg, tiredness and malaise). Among the Icases who had taken ASA for gastric discomfort before the episode of gastrointestinal bleeding, 7 had taken ’Alka-Seltzer’, an effervescent preparation of ASA 320 mg, calcium phosphate 200 mg, sodium bicarbonate 1900 mg, and citric acid 1050 mg. In Spain a television advertisement shows a couple arriving home from a party. One complains of headache, the other of gastric discomfort; both take alka-seltzer. In Spain, the box for this preparation claims "effervescent, analgesic, antacid". During a visit to a Latin-American Ministry of Health, one of us saw an application from a drug manufacturer to register an effervescent preparation of ASA as a "digestive". In many countries-at least in Latin America, Africa, and Asia-effervescent preparations of ASA are promoted as digestives and for abdominal discomfort. We found that among the 11 patients with gastrointestinal bleeding who had taken a preparation containing ASA before they bled, 7 had a history of peptic ulcer (4) or epigastric pain (3). In other countries the picture may be even worse. For example, in the USA, ’Alka-seltzer’ preparations are labelled as "pain reliever and antacid" and "for acid indigestion or heartburn with headache or minor pains. Also upset stomach with headache from overindulgence". We think it is time to stop the promotion, either open or subliminal, of ASA preparations for the treatment of abdominal discomfort. Drug manufacturers and health authorities have a heavy responsibility in this respect. ALBERT FIGUERAS

JOAN JUAN Pharmacology Unit, Universitat Autònoma de Barcelona, Ciutat Sanitària de la Vall d’Hebron, 08035 Barcelona, Spain

ELENA BALLARÍN LOURDES VENDRELL XAVIER CARNÉ JOAN-RAMON LAPORTE

1. Laporte J-R, Carné X, Vidal X, Moreno V, Juan J. Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Lancet 1991; 337: 85-89.

Fenoterol and its bromide SIR,-Mr Green (June 29, p 1613) postulates that the bromide delivered with fenoterol by metered dose inhaler (MDI) might damage both the lung and heart by increasing the oxidant properties of eosinophils. Under physiological blood concentrations of bromide and chloride, activated eosinophils secrete nearly maximum hypohalous products in addition to other cytotoxic compounds, largely

There is, therefore, no reason to believe that the bromide delivered by fenoterol inhalation substantially alters the bromide concentration in the lung or in blood. It is obvious that the slight changes in bromide concentration produced by one or more puffs of fenoterol hydrobromide will not have much effect on eosinophil oxidant properties. Emerging epidemiological evidence, including careful examination of the New Zealand epidemiology studies, does not support the premise of a unique hazard for fenoterol alone.8 Further evidence (your Aug 3 note, p 307) is emerging that the association of bronchodilator drugs and increased risk of asthma death is not restricted to fenoterol, which happens to be a hydrobromide. When properly used, fenoterol is a very effective and safe betamimetic for asthma treatment. Proper use, however, requires careful clinical monitoring. If regular use of betamimetics is required, concomitant treatment of the underlying inflammation is essential.9 Department of Research and Development, and Corporate Department Medicine, Boehringer Ingelheim KG, 6507 Ingelheim, Germany

R. HAMMER H.-M. JENNEWEIN E. KUTTER M. T. LOPEZ-VIDRIERO

Mayeno AN, Curran AJ, Roberts RL, et al. Eosinophils preferentially use bromide to generate halogenating agents. J Biol Chem 1989; 264: 5660-68. 2. Brune D, Samsahl K, Wester PO. A comparison between the amounts of As, Au, Br, Cu, Fe, Mo, Se and Zn in normal and uraemic human whole blood by means of neutron activation analysis. Clin Chim Acta 1966; 13: 285-91. 3. Cretius K, Beyermann K. Die röntgenfluorimetrische Analyse der organischen Bestandteile biologischen Materials. Klin Wschr 1962; 40: 89-97. 4. Gonda I. Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract. Grit Rev Ther Drug Carrier Syst 1990; 6: 273-313. 5. Van As A. Pulmonary airway clearance mechanisms: a reappraisal. Am Rev Respir Dis 1.

1977; 115: 721-26. Kelly CA, Fenwick JD, Corris PA, et al. Fluid dynamics during bronchoalveolar lavage. Am Rev Respir Dis 1988; 138: 81-84. 7. Cheek DB. Extracellular volume; its structure and measurement and the influence of age and disease. J Pediatr 1961; 58: 103-25. 8. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-87: a further case-control study. Thorax 1991; 46: 105-11. 9. Barnes PJ. Our changing understanding of asthma. Resp Med 1989; 83: 17-23.

6.

Contribution of cortisol deficiency to septic shock

peptides.l Although it is known that eosinophils preferentially use bromide to produce toxic hypohalous acid,l this activity is not likely to be increased in vivo by the doses of bromide delivered with fenoterol.

SiR,—The serum cortisol concentration that is appropriate in septic shock is unknown and Dr Rothwell and colleagues (March 9, p 582) emphasise that cortisol replacement may be of value. This view stimulated debate (May 18, p 1230) about the evidence for adrenal insufficiency in sepsis and its assessment by response to corticotropin. We believe that a haemodynamic improvement after moderate doses of hydrocortisone would detect adrenal insufficiency in septic shock. We treated 14 patients in severe septic shock with supraphysiological doses of hydrocortisone (Hoechst, Germany).

The normal bromide concentration in the blood is 2-3 orders of magnitude higher than the 10 pg/1 figure Green cites. Bromide concentrations are usually reported to be between 20 and 100 gcnol/1, corresponding to 1-6 and 8 mg/1 bromide in blood.2,3 The statement that bromide is delivered via fenoterol MDI in a concentration 20 000-fold higher than that in blood does not indicate what happens in either the lungs or blood. One inhalation of fenoterol MDI of 200 pg delivers 41-6 fig bromide. It is widely accepted that between 10% and 30% of this dose reaches the lung.4 This inhalable fraction is first dissolved in the epithelial lining fluid. The volume of this fluid is estimated to vary between 2-7 m1s and 30 ni 16 and is even higher in airway diseases. This would give a rise in bromide concentration of not more than 5 mg/1, a value that is within the physiological range of blood bromide concentrations. The bromide ion then rapidly diffuses throughout the entire plasma and interstitial fluid space of the body. The ion, in fact, is an indicator for the measurement of the extracellular body fluid volumeEven if one assumes that the total dose of 200 (ig fenoterol hydrobromide would appear in the blood (5 1) this only would amount to less than 10 p.g/1 of bromide, which is well below normal physiological concentrations.

All patients were monitored with arterial and Swan-Ganz catheters. If fluid resuscitation (pulmonary occlusion pressure 15 mm Hg) failed to improve hypotension, vasopressors (dopamine and noradrenalin) were titrated to maintain a mean arterial pressure of 70 mm Hg or more. Doses of dopamine exceeded 12 ug/kg per min in all patients. Since peak cortisol concentrations coincide with maximum haemodynamic instability,l we measured cortisol values and cortisol response to corticotropin (25 IU) at the moment of maximum circulatory collapse. Afterwards a loading dose of hydrocortisone (100 mg) was given, followed by continuous infusion (10 mg/h). Haemodynamic state improved in all patients. The amount of vasopressors infused could be much reduced: after 48 h treatment with catecholamines was discontinued in 6 patients, 3 were infused with a dose of dopamine of less than 5 g/kg per min, and 5 needed doses between 5 and 15 J1g/kg per min. The mean cortisol concentration before hydrocortisone was lower in the 6 patients with short-term vasopressor treatment than in those who still needed high doses of catecholamines (mean cortisol: 20-3 g/dl [SD 11-2] vs 29-4 Ilgjdl [13’2], p=0’19). The response to corticotropin was similar in both groups (7-4 )g/dl, [4.3] vs 6-5 g/dl [2’9]). With

508

respect to 28-day mortality, no patient with maximum response to hydrocortisone and short-term vasopressor therapy died, whereas 4 in the other group did so. Our data support the hypothesis of relative adrenocortical insufficiency in septic shock, which contributes, in part, to circulatory collapse. Low cortisol (ie, < 30 )ig/dl) may be indicative of cortisol deficiency in early septic shock.2 Response to corticotropin, however, did not denote cortisol deficiency. The role of cortisol replacement in the modulation of the immune response remains to be elucidated.3 Intensive Care Unit, Institute of Anaesthesiology, Klinikum Grosshadern, University of Munich, 8000 Munchen 70, Germany

JOSEF BRIEGEL HELMUTH FORST HILDEGARD HELLINGER MATHIAS HALLER

P, Pruzanski W, Stefanski E, et al. Concordance of endogenous cortisol and phospholipase A2 levels in gram-negative septic shock: a prospective study. J Lab

1. Vadas

Clin Med 1988; 111: 584-90. 2. Catalano RD, Parameswaran V, Ramachandran J, Trunkey DD. Mechanisms of adrenocortical depression during Escherichia coli shock. Arch Surg 1984; 119: 145-50. 3. Hermus ARMM, Sweep CGJ. Cytokines and the hypothalamic-pituitary-adrenal axis. J Steroid Biochem Molec Biol 1990; 37: 867-71.

Postcoital

contraception

SIR,-Dr Silvestre and colleagues (July 6, p 39) from Roussel criticise several recent studies about postcoital contraception and cast some doubt on its efficacy, especially when combined oestrogen-progestagen preparations (CEP) were used. They suggest that a prospective controlled assessment of postcoital contraception with either high-dose oestrogen or CEP is needed, together with studies of emergency insertion of an intrauterine device or late luteal administration of an antiprogesterone. We published such a study in 1985.1 We evaluated Yuzpe’s CEP method and Haspels’ high-dose ethinyloestradiol method. Our prospective double-blind randomised study confirmed the efficacy of both regimens. Van Santen and Haspels were also the first to use mifepristone as an emergency postcoital contraceptive.2 A pregnancy rate of 1-6% was observed. This method provides a good interceptive technique when the time for use of postcoital steroids or for a postcoital intrauterine device has lapsed. It is not a good method to be used every month3 because 600 mg mifepristone in the first cycle may disturb the next cycle and postpone ovulation. Subsequent administration of mifepristone may then be incorrectly timed. University of Utrecht, 3584 CX Utrecht, the Netherlands

ARY A. HASPELS

MR, Haspels AA. A comparison of high-dose oestrogen versus low-dose ethinyl estradiol-norgestrel combination in post-coital interception: a study in 493

1. Van Santen

women. Fertil Steril 1985; 43: 206. 2. Van Santen MR, Haspels AA. Post-coital luteal contragestion by an Contraception 1987; 35: 423. 3. Van Santen MR, Haspels AA. Failure of mifepristone as a monthly Contraception 1987; 35: 433.

antiprogestin. contragestive.

Cerebral abscess associated with dental procedure in hereditary haemorrhagic

telangiectasia SIR,-Brain abscess has been associated with the pulmonary arteriovenous fistulae often seen in patients with hereditary haemorrhagic telangiectasia (HIT)1 but not previously reported to follow dental procedures. A 45-year-old woman presented with a right occipital brain abscess manifested by headache and left homonymous hemianopsia 3 weeks after a dental procedure. Computed tomography (CT) indicated two small lesions in the right lung base consistent with arteriovenous malformations. Magnetic resonance imaging (MRI) revealed a right occipital lesion with a gadolinium-enhancing wall (figure). Aspiration yielded purulent material which grew Bacteroides sp, a microaerophilic streptococcus, and Fusobacterium sp sensitive to penicillin and chloramphenicol. The patient

MRI

Upper

on

scans

of brain.

presentation.

Lower after treatment with intravenous antibiotics and needle aspiration of abscess

responded to intravenous chloramphenicol and repeated aspiration. An MRI scan 4 months after treatment showed resolution of the lesion (figure). A 65-year-old man presented in January, 1991, with right frontal and left frontoparietal brain lesions manifested by broken, nonfluent speech, impaired short-term memory, and right-arm weakness. He had right mandibular pain and X-rays revealed osteomyelitis in the area where a tooth had been extracted 2 months previously. (He had a history of frequent epistaxis, haematemesis, passage of bloody stools, and melaena from telangiectasias in the stomach and small bowel and therapeutic endoscopy and intensive care had often been required. The frequency of his bleeding had been diminished considerably by danazol 200 mg three times daily.) He was treated with intravenous metronidazole, ceftriaxone, and penicillin and neurosurgical drainage. Biopsy findings were consistent with cerebritis but no frankly purulent material was obtained and cultures were negative. His postoperative course was complicated by reaccumulation of multiple areas of brain abscess requiring aspiration. Gram-positive cocci were identified. Since the operation the expressive aphasia and right facial droop have improved. In HHT, an autosomal dominant disease characterised by telangiectasias and arteriovenous malformations, the salient feature is recurrent mucous membrane haemorrhage. Although clinical manifestations of pulmonary arteriovenous malformations are usually present by the third or fourth decades, half the patients may

Contribution of cortisol deficiency to septic shock.

507 exposed to ASA, 14 (11 cases and 3 controls) had taken it for gastric discomfort, 4 for insomnia, and 44 for other reasons (eg, tiredness and mal...
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