1476
libraries select what they need instead of receiving donations that may not be relevant to their needs. The demand is very great from requesting libraries and the supply is diminishing from donor libraries. We therefore encourage to seriously consider becoming a member of this The WHO library is also a member of the Exchange, and we find it gratifying that duplicates of our books and periodicals are immediately requested by libraries as soon as the lists are sent out. The Exchange facilitates a constant circulation of information in the health sciences before it has a chance to become outdated.
librarians
exchange.
Office of Library and Health Literature Services, World Health Organization, 1211 Geneva 27, Switzerland
YVONNE GRANDBOIS
ACE inhibitors and LDL-apheresis with dextran sulphate adsorption SIR,-Treatment of patients with severe hypercholesterolaemia extracorporeal removal of low-density lipoproteins (LDLapheresis) with dextran sulphate columns is well tolerated, with
according to our experience in almost 800 treatments in 21 patients in the LDL-apheresis atherosclerosis regression study (LAARS). Professor Olbricht and colleagues (Oct 10, p 908) describe an anaphylactoid reaction in 2 patients during the first treatment with this type of LDL-apheresis, characterised by flushing, dyspnoea, low blood pressure, and bradycardia, which they attribute to the concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. They postulate that this reaction is due to a decreased bradykinin catabolism caused by the drug, together with an increased bradykinin production due to stimulation of blood cells by the negatively charged dextran sulphate. We report a patient who had been treated without adverse events for over 1 year, in whom an atypical reaction during apheresis was noted after treatment with an ACE inhibitor was instituted. The patient was a 44-year-old man with severe primary hypercholesterolaemia (9-1 mmol/1) who had had two myocardial infarctions at age 35 and 42 years. Drug treatment included simvastatin, metoprolol tartrate, and aspirin. From April, 1991, he received biweekly LDL-apheresis, which was uneventful for more than 30 treatments up to July, 1992. Captopril was then added to the regimen for mild congestive heart failure. While he was on 6-25 mg and 12-5 mg twice daily, no adverse events took place during apheresis. After a dose increase to 25 mg twice daily, he had nausea, slight drop in blood pressure, and bradycardia, which resolved spontaneously in the supine position; thereafter the procedure was completed without problems. During the next treatment, while on the same dose of captopril, he had nausea, pounding headache, and flushing of head and neck, without symptoms of dyspnoea, stridor, urticaria, blood pressure drop, or bradycardia. These symptoms started the moment that plasma from the cholesterol-binding column was returned to the patient, and subsided within minutes after the procedure was stopped. Bacterial cultures were all negative. Since the previous 30 treatments had been without adverse effects, it was decided to rechallenge the patient, during which an identical reaction was seen. Clemastine or corticosteroids intravenously had no effect, but symptoms subsided within a few minutes when treatment was stopped. Once it was recognised that this reaction could be related to the use of an ACE inhibitor, captopril was withdrawn 24 h before treatment. No adverse reactions were noted in the two following treatments. These findings indicate that: the (bradykinin-mediated) anaphylactoid reaction to LDL-apheresis with dextran sulphate during the use of captopril can be highly non-specific and does not respond to conventional treatment; that it is dose-dependent; and that, once diagnosed, it can be avoided by withdrawing captopril 24 h before treatment-but this last probably does not apply to ACE inhibitors with longer half-lives, such as enalapril. Department of Medicine, Division of General Internal Medicine, University Hospital Nijmegen, Nijmegen, Netherlands
6500 HB
A. A. KROON M. J. T. M. MOL A. F. H. STALENHOEF
Occupational exposure to glutaraldehyde in tropical climates SIR,-The safety and biocidal efficacy of glutaraldehyde’ has led its endorsement by CDC and WHO2,3 as a substitute to formaldehyde in high-level disinfection and cold-sterilisation. In less developed countries, where the supply of sterile disposables and autoclaves are inadequate, the use of glutaraldehyde to control cross-infection in clinical settings that provide invasive services seems reasonable. Since safety considerations with glutaraldehyde largely relate to its volatility, stringent precautions in handling are relevant in warm tropical climates (average ambient temperatures up to 39°C), especially when ventilation may be inadequate. These to
factors increase the risk of vapourised glutaraldehyde exceeding the recommended threshold of 0-2 parts per million.4 Unfortunately, appreciation of these considerations appear to have eluded manufacturers and users. In an outpatient clinic in Nairobi (average annual temperature 23 [SD 4] °C, cetrimide and chlorhexidine were substituted by glutaraldehyde for instrument decontamination and housekeeping about 18 months ago. The glutaraldehyde was left in an open vessel (surface area about 600 cm2 all day in each location of about 11 4m3; ventilation was through 1 44 m2 windows, which remained open for about 10 h daily during a 5-day week. Our concern that there are probably excessive glutaraldehyde fumes prompted us to study individuals who regularly worked in these environments. DETAILS OF AFFECTED RESPONDENTS
Some respondents reported symptoms that mimicked those caused by formaldehyde fumes (table).5-7 We believe that these were adverse reactions to glutaraldehyde fumes. Except in case 2, these adverse reactions probably corresponded to development of hypersensitivity to glutaraldehyde. In addition, in contrast to the familiar smell of formaldehyde,7the smell of glutaraldehyde did not prompt the taking of precautions. As with formaldehyde,* hypersensitisation to glutaraldehyde may not be a function of concentration, especially among those with hypersensitivity to multiple allergens. In this regard, the use of 2% glutaraldehyde in housekeeping in intensive care units, where patients are already likely to have respiratory distress, is of concern. In the manufacturer’s cautions for brands available in Kenya (Cidex, Sporocidin) there is no mention of the volatile nature of
1477
glutaraldehyde and the possible toxicity of its fumes. The lack of precautionary details for glutaraldehyde fumes, especially in warm climates, is inadequate. Manufacturers should provide details of possible side-effects that could arise from glutaraldehyde vapour and the precautions that should be taken to keep the air concentration below the recommended limit. There is an urgent need to develop affordable and effective methods of containing glutaraldehyde fumes. We thank the respondents, Prof J. Kaimenyi for support and interest, and the director, Kenya Medical Research Institute, for permission to report these details.
Kenya Medical Research Institute, Medical Research Centre, PO Box 20752, Nairobi, Kenya, and Division of Oral and Maxillofacial Surgery,
College of Health Sciences, University of Nairobi
D. L. MWANIKI S. W. GUTHUA
-
BL
EM, Gorman SP. Sterilization with glutaraldehyde. In- Block SS, ed. Disinfection, sterilisation and preservation. Philadelphia Lea and Febiger, 1983:
1. Scot
65-88. 2. Guidelines on sterilization and disinfection effective against human immunodeficiency virus (HIV). WHO AIDS series 2. Geneva: WHO, 1989 3. Recommendations for preventing transmission of infection with human Tlymphotropic virus Type III/Lymphadenopamy-associated virus m the workplace. MMWR 1985; 34: 684. 4. Martindale the extra pharmacopoeia. In: Reynolds EF, ed. London: Pharmaceutical Press, 1982: 563-65. 5. Porter JAH. Acute respiratory distress following formalin inhalation. Lancet 1975, ii: 603-04. 6. Hendrick DJ, Lane DJ. Formalin asthma in hospital staff. BMJ 1975, 1: 607-08. 7. Editorial. The hazards of formaldehyde. Lancet 1981; i: 926-27. 8. Osterloh J, Kaysen G, Becker CE. Handling formalin in dialysis units. Dialysis Transplant 1983; 12: 353-61.
Occupational asthma SIR,-We report
two
cases
in
radiographers
of work-related asthma
in
0
5
15 30 602345678910 11 12 13
10 minutes
hours
Time after
challenge
Bronchial provocation testing in 0-0 control, •—• = 11 %
case
1.
glutaraldehyde BL= baseline
reported but, although it is likely that, under the best conditions, concentrations of glutaraldehyde in radiographic departments are below the occupational exposure standard of 0.7 mg/m3, higher levels may occur during maintenance or where ventilation is inadequate. Concentrations can also vary with the been
brand of developer used since these differ in their degree of glutaraldehyde conjugation. Occupational exposure in endoscopy staff, using 2% solutions of activated glutaraldehyde as a biocide, causes eye and nasal symptoms2 and occasionally wheezing,3 but formal bronchial challenge tests have not been reported. Symptoms have, however, been reported among staff working within the limits.4 Radiographic fixatives contain acetic and hydrochloric acids and ammonium thiosulphate, none of which is a known respiratory sensitiser, and the mechanism of provocation in our second case is unclear. There has been no systematic survey of respiratory symptoms among radiographers but concern about occupational respiratory disease has been expressed within the profession.5 current exposure
radiographers, each case attributable to a different agent. A 25-year-old woman, a radiographer for 5 years, presented with a 12-month history of episodic, work-related breathing difficulties. She had hayfever, but not asthma, since adolescence and had immediate skin-test reactions to inhalant allergens. Her forced expiratory volume in 1 s (FEVl) was 2-8 litres, forced vital capacity (FVC) 3-3 litres, and the dose of histamine that provoked a 20% fall in FEVl by 20% (PC20) was 10 mg/ml. Serial peak flow measurements suggested a relation with work. After single-blind inhalation testing, exposure to an inert control substance provoked no changes in FEVl or bronchial reactivity (figure). Exposure on two separate days for 5 min to 11 % glutaraldehyde (used at her work place) provoked a late asthmatic response associated with a reduction by over 50% in her pretest histamine PC20 at 3 h. The second patient, aged 24, had also been a radiographer for 5 years. She had a history of hayfever and "bronchitis" during childhood. Shortly after starting employment in a specialist radiographic unit with poor ventilation she developed episodic wheezing at work. A severe episode followed exposure to fixative chemicals during repair of a leaking machine. She had immediate skin-test reactions to inhalant allergens; her histamine PC20, was over 16 mg/ml. Single-blind inhalation testing with the two-part radiographic fixative solution provoked a fall in FEV! (maximum 35%) immediately after exposure; her lung function returned to normal after 1 h. There were no changes in her histamine PC20, at 3 h or 24 h. These findings were reproducible and showed a dose-response effect. Challenges with 2% and 1 % glutaraldehyde and a three-part mixture of developing fluid produced no changes in her FEV or in histamine PC20. Glutaraldehyde is used as a hardener during developing, and the one previously reported case of occupational asthma in a radiographer was only tentatively ascribed to this compound.l The patient had been challenged with a mixture of developers and fixatives which had provoked an isolated early fall of 8% in FEV 1 . In our first patient, glutaraldehyde (in a concentration that did not provoke a fall in FEVl in the second patient) reproducibly provoked a late asthmatic response with reduced PC20, confirming this
during pregnancy.’
the cause of asthma, probably because of a hypersensitivity response. Environmental measurements have not
An indirect way to fmd out the relation between oestrogen concentrations during pregnancy and the mammary-gland size of
compound
as
Department of Occupational and Environmental Medicine, National Heart and Lung Institute, London SW3 6NP, UK, Occupational Health Department, St Thomas’ Hospital,
London, and Occupational Health Department, Royal United Hospitals, Bath 1.
P. CULLINAN
J. HAYES J. CANNON I. MADAN D. HEAP A. NEWMAN TAYLOR
Tngg CJ, Heap DC, Herdman MJ, Davies RJ. A radiographer’s asthma. Resp Med
1992; 86: 167-69. 2. Norback D. Skin and respiratory symptoms from exposure to alkaline glutaraldehyde in medical services. Scand J Work Env Health 1988; 14: 366-71. 3. Benson WG. Case report: exposure to glutaraldehyde. J Soc Occup Med 1984; 34: 63-64. 4. Jachuck SJ, Bound GL, Steel J, Blain PG Occupational hazard in hospital staff exposed to 2% glutaraldehyde in an endoscopy unit. J Soc Occ Med 1989; 39: 69-71. 5. Gordon M. Reactions to chemical fumes in radiology departments. Radiography 1987; 53: 85-89.
Prenatal influences and breast
cancer
SIR,-Dr Ekbom and colleagues (Oct 24, p 1015) report evidence of prenatal influences on breast cancer. They correlate indicators of high oestrogen concentration during pregnancy, such as birthweight, birth length, and placental weight, and the incidence of breast cancers in these adults. They suggest that pregnancy oestrogens may well be more strongly related to fetal mammary gland size than to overall fetal size. We have demonstrated great variation in the structural development of the infant breasts and suggested that this reflects the variation in oestrogen concentrations
libraries select what they need instead of receiving donations that may not be relevant to their needs. The demand is very great from requesting libraries and the supply is diminishing from donor libraries. We therefore encourage to seriously consider becoming a member of this The WHO library is also a member of the Exchange, and we find it gratifying that duplicates of our books and periodicals are immediately requested by libraries as soon as the lists are sent out. The Exchange facilitates a constant circulation of information in the health sciences before it has a chance to become outdated.
librarians
exchange.
Office of Library and Health Literature Services, World Health Organization, 1211 Geneva 27, Switzerland
YVONNE GRANDBOIS
ACE inhibitors and LDL-apheresis with dextran sulphate adsorption SIR,-Treatment of patients with severe hypercholesterolaemia extracorporeal removal of low-density lipoproteins (LDLapheresis) with dextran sulphate columns is well tolerated, with
according to our experience in almost 800 treatments in 21 patients in the LDL-apheresis atherosclerosis regression study (LAARS). Professor Olbricht and colleagues (Oct 10, p 908) describe an anaphylactoid reaction in 2 patients during the first treatment with this type of LDL-apheresis, characterised by flushing, dyspnoea, low blood pressure, and bradycardia, which they attribute to the concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. They postulate that this reaction is due to a decreased bradykinin catabolism caused by the drug, together with an increased bradykinin production due to stimulation of blood cells by the negatively charged dextran sulphate. We report a patient who had been treated without adverse events for over 1 year, in whom an atypical reaction during apheresis was noted after treatment with an ACE inhibitor was instituted. The patient was a 44-year-old man with severe primary hypercholesterolaemia (9-1 mmol/1) who had had two myocardial infarctions at age 35 and 42 years. Drug treatment included simvastatin, metoprolol tartrate, and aspirin. From April, 1991, he received biweekly LDL-apheresis, which was uneventful for more than 30 treatments up to July, 1992. Captopril was then added to the regimen for mild congestive heart failure. While he was on 6-25 mg and 12-5 mg twice daily, no adverse events took place during apheresis. After a dose increase to 25 mg twice daily, he had nausea, slight drop in blood pressure, and bradycardia, which resolved spontaneously in the supine position; thereafter the procedure was completed without problems. During the next treatment, while on the same dose of captopril, he had nausea, pounding headache, and flushing of head and neck, without symptoms of dyspnoea, stridor, urticaria, blood pressure drop, or bradycardia. These symptoms started the moment that plasma from the cholesterol-binding column was returned to the patient, and subsided within minutes after the procedure was stopped. Bacterial cultures were all negative. Since the previous 30 treatments had been without adverse effects, it was decided to rechallenge the patient, during which an identical reaction was seen. Clemastine or corticosteroids intravenously had no effect, but symptoms subsided within a few minutes when treatment was stopped. Once it was recognised that this reaction could be related to the use of an ACE inhibitor, captopril was withdrawn 24 h before treatment. No adverse reactions were noted in the two following treatments. These findings indicate that: the (bradykinin-mediated) anaphylactoid reaction to LDL-apheresis with dextran sulphate during the use of captopril can be highly non-specific and does not respond to conventional treatment; that it is dose-dependent; and that, once diagnosed, it can be avoided by withdrawing captopril 24 h before treatment-but this last probably does not apply to ACE inhibitors with longer half-lives, such as enalapril. Department of Medicine, Division of General Internal Medicine, University Hospital Nijmegen, Nijmegen, Netherlands
6500 HB
A. A. KROON M. J. T. M. MOL A. F. H. STALENHOEF
Occupational exposure to glutaraldehyde in tropical climates SIR,-The safety and biocidal efficacy of glutaraldehyde’ has led its endorsement by CDC and WHO2,3 as a substitute to formaldehyde in high-level disinfection and cold-sterilisation. In less developed countries, where the supply of sterile disposables and autoclaves are inadequate, the use of glutaraldehyde to control cross-infection in clinical settings that provide invasive services seems reasonable. Since safety considerations with glutaraldehyde largely relate to its volatility, stringent precautions in handling are relevant in warm tropical climates (average ambient temperatures up to 39°C), especially when ventilation may be inadequate. These to
factors increase the risk of vapourised glutaraldehyde exceeding the recommended threshold of 0-2 parts per million.4 Unfortunately, appreciation of these considerations appear to have eluded manufacturers and users. In an outpatient clinic in Nairobi (average annual temperature 23 [SD 4] °C, cetrimide and chlorhexidine were substituted by glutaraldehyde for instrument decontamination and housekeeping about 18 months ago. The glutaraldehyde was left in an open vessel (surface area about 600 cm2 all day in each location of about 11 4m3; ventilation was through 1 44 m2 windows, which remained open for about 10 h daily during a 5-day week. Our concern that there are probably excessive glutaraldehyde fumes prompted us to study individuals who regularly worked in these environments. DETAILS OF AFFECTED RESPONDENTS
Some respondents reported symptoms that mimicked those caused by formaldehyde fumes (table).5-7 We believe that these were adverse reactions to glutaraldehyde fumes. Except in case 2, these adverse reactions probably corresponded to development of hypersensitivity to glutaraldehyde. In addition, in contrast to the familiar smell of formaldehyde,7the smell of glutaraldehyde did not prompt the taking of precautions. As with formaldehyde,* hypersensitisation to glutaraldehyde may not be a function of concentration, especially among those with hypersensitivity to multiple allergens. In this regard, the use of 2% glutaraldehyde in housekeeping in intensive care units, where patients are already likely to have respiratory distress, is of concern. In the manufacturer’s cautions for brands available in Kenya (Cidex, Sporocidin) there is no mention of the volatile nature of
1477
glutaraldehyde and the possible toxicity of its fumes. The lack of precautionary details for glutaraldehyde fumes, especially in warm climates, is inadequate. Manufacturers should provide details of possible side-effects that could arise from glutaraldehyde vapour and the precautions that should be taken to keep the air concentration below the recommended limit. There is an urgent need to develop affordable and effective methods of containing glutaraldehyde fumes. We thank the respondents, Prof J. Kaimenyi for support and interest, and the director, Kenya Medical Research Institute, for permission to report these details.
Kenya Medical Research Institute, Medical Research Centre, PO Box 20752, Nairobi, Kenya, and Division of Oral and Maxillofacial Surgery,
College of Health Sciences, University of Nairobi
D. L. MWANIKI S. W. GUTHUA
-
BL
EM, Gorman SP. Sterilization with glutaraldehyde. In- Block SS, ed. Disinfection, sterilisation and preservation. Philadelphia Lea and Febiger, 1983:
1. Scot
65-88. 2. Guidelines on sterilization and disinfection effective against human immunodeficiency virus (HIV). WHO AIDS series 2. Geneva: WHO, 1989 3. Recommendations for preventing transmission of infection with human Tlymphotropic virus Type III/Lymphadenopamy-associated virus m the workplace. MMWR 1985; 34: 684. 4. Martindale the extra pharmacopoeia. In: Reynolds EF, ed. London: Pharmaceutical Press, 1982: 563-65. 5. Porter JAH. Acute respiratory distress following formalin inhalation. Lancet 1975, ii: 603-04. 6. Hendrick DJ, Lane DJ. Formalin asthma in hospital staff. BMJ 1975, 1: 607-08. 7. Editorial. The hazards of formaldehyde. Lancet 1981; i: 926-27. 8. Osterloh J, Kaysen G, Becker CE. Handling formalin in dialysis units. Dialysis Transplant 1983; 12: 353-61.
Occupational asthma SIR,-We report
two
cases
in
radiographers
of work-related asthma
in
0
5
15 30 602345678910 11 12 13
10 minutes
hours
Time after
challenge
Bronchial provocation testing in 0-0 control, •—• = 11 %
case
1.
glutaraldehyde BL= baseline
reported but, although it is likely that, under the best conditions, concentrations of glutaraldehyde in radiographic departments are below the occupational exposure standard of 0.7 mg/m3, higher levels may occur during maintenance or where ventilation is inadequate. Concentrations can also vary with the been
brand of developer used since these differ in their degree of glutaraldehyde conjugation. Occupational exposure in endoscopy staff, using 2% solutions of activated glutaraldehyde as a biocide, causes eye and nasal symptoms2 and occasionally wheezing,3 but formal bronchial challenge tests have not been reported. Symptoms have, however, been reported among staff working within the limits.4 Radiographic fixatives contain acetic and hydrochloric acids and ammonium thiosulphate, none of which is a known respiratory sensitiser, and the mechanism of provocation in our second case is unclear. There has been no systematic survey of respiratory symptoms among radiographers but concern about occupational respiratory disease has been expressed within the profession.5 current exposure
radiographers, each case attributable to a different agent. A 25-year-old woman, a radiographer for 5 years, presented with a 12-month history of episodic, work-related breathing difficulties. She had hayfever, but not asthma, since adolescence and had immediate skin-test reactions to inhalant allergens. Her forced expiratory volume in 1 s (FEVl) was 2-8 litres, forced vital capacity (FVC) 3-3 litres, and the dose of histamine that provoked a 20% fall in FEVl by 20% (PC20) was 10 mg/ml. Serial peak flow measurements suggested a relation with work. After single-blind inhalation testing, exposure to an inert control substance provoked no changes in FEVl or bronchial reactivity (figure). Exposure on two separate days for 5 min to 11 % glutaraldehyde (used at her work place) provoked a late asthmatic response associated with a reduction by over 50% in her pretest histamine PC20 at 3 h. The second patient, aged 24, had also been a radiographer for 5 years. She had a history of hayfever and "bronchitis" during childhood. Shortly after starting employment in a specialist radiographic unit with poor ventilation she developed episodic wheezing at work. A severe episode followed exposure to fixative chemicals during repair of a leaking machine. She had immediate skin-test reactions to inhalant allergens; her histamine PC20, was over 16 mg/ml. Single-blind inhalation testing with the two-part radiographic fixative solution provoked a fall in FEV! (maximum 35%) immediately after exposure; her lung function returned to normal after 1 h. There were no changes in her histamine PC20, at 3 h or 24 h. These findings were reproducible and showed a dose-response effect. Challenges with 2% and 1 % glutaraldehyde and a three-part mixture of developing fluid produced no changes in her FEV or in histamine PC20. Glutaraldehyde is used as a hardener during developing, and the one previously reported case of occupational asthma in a radiographer was only tentatively ascribed to this compound.l The patient had been challenged with a mixture of developers and fixatives which had provoked an isolated early fall of 8% in FEV 1 . In our first patient, glutaraldehyde (in a concentration that did not provoke a fall in FEVl in the second patient) reproducibly provoked a late asthmatic response with reduced PC20, confirming this
during pregnancy.’
the cause of asthma, probably because of a hypersensitivity response. Environmental measurements have not
An indirect way to fmd out the relation between oestrogen concentrations during pregnancy and the mammary-gland size of
compound
as
Department of Occupational and Environmental Medicine, National Heart and Lung Institute, London SW3 6NP, UK, Occupational Health Department, St Thomas’ Hospital,
London, and Occupational Health Department, Royal United Hospitals, Bath 1.
P. CULLINAN
J. HAYES J. CANNON I. MADAN D. HEAP A. NEWMAN TAYLOR
Tngg CJ, Heap DC, Herdman MJ, Davies RJ. A radiographer’s asthma. Resp Med
1992; 86: 167-69. 2. Norback D. Skin and respiratory symptoms from exposure to alkaline glutaraldehyde in medical services. Scand J Work Env Health 1988; 14: 366-71. 3. Benson WG. Case report: exposure to glutaraldehyde. J Soc Occup Med 1984; 34: 63-64. 4. Jachuck SJ, Bound GL, Steel J, Blain PG Occupational hazard in hospital staff exposed to 2% glutaraldehyde in an endoscopy unit. J Soc Occ Med 1989; 39: 69-71. 5. Gordon M. Reactions to chemical fumes in radiology departments. Radiography 1987; 53: 85-89.
Prenatal influences and breast
cancer
SIR,-Dr Ekbom and colleagues (Oct 24, p 1015) report evidence of prenatal influences on breast cancer. They correlate indicators of high oestrogen concentration during pregnancy, such as birthweight, birth length, and placental weight, and the incidence of breast cancers in these adults. They suggest that pregnancy oestrogens may well be more strongly related to fetal mammary gland size than to overall fetal size. We have demonstrated great variation in the structural development of the infant breasts and suggested that this reflects the variation in oestrogen concentrations
