- Email: [email protected]
Enterobacter sakazakii in factories and households
Correspondence
Proportion of patients (%)
100
Losartan Atenolol
80
60
40
20
0 0
12
24
36 Study month
48
60
72
Figure: Proportion of patients receiving any diuretic over time
dose of study drug, add more hydrochlorothiazide, or add other antihypertensive agents (excluding angiotensin converting-enzyme inhibitors, angiotensin-receptor blockers, or blockers) as necessary to achieve a goal blood pressure of less than 140/ 90 mm Hg. As Kato and Eto note, in the group treated with 100 mg losartan, 44% also received hydrochlorothiazide, whereas in those treated with 100 mg atenolol, only 38% received hydrochlorothiazide. However, these counts do not include patients receiving 50 mg of study drug with diuretic, and reflect the patients’ status at the end of follow-up or at the last visit before occurrence of a primary endpoint. Because endpoints occurred more frequently and earlier in the atenolol group, it is informative to compare diuretic use between treatment groups throughout the trial (figure) without regard to concomitant study drug use. In LIFE, patients were on diuretics for 72% of the total follow-up time in the losartan group and for 70% of the time in the atenolol group. Most patients who received diuretic therapy did so within the first 6 months of the study, as specified by the protocol. The mean dose of hydrochlorothiazide used in each treatment group was the same, 20 mg. Therefore, the difference noted at endpoint occurrence or study end in the subgroup treated with 100 mg of losartan or atenolol does not completely or accurately reflect the use of diuretics in the study population over the course of the LIFE study. 414
To further assess the effect of diuretic use on outcomes in the LIFE study, we did an analysis adjusting for the concomitant use of hydrochlorothiazide as a time-varying covariate. This analysis showed only a small effect on the treatment difference. For stroke, the unadjusted risk reduction was 26% in favour of losartan, whereas the adjusted risk reduction was 25%. Unlike the ALLHAT study,1 in which the observed difference in stroke rate in favour of the diuretic was largely driven by the black subpopulation and was associated with a difference in blood pressure, the small difference in use of hydrochlorothiazide in the two treatment groups of the LIFE study, which achieved comparable blood pressure control, does not account for the advantage of losartan over atenolol on stroke or the primary composite endpoint. Thus, the incremental benefits in favour of losartan, in the LIFE study, are essentially independent of diuretic use.
recommendation from the authors at the end of the article: “The widespread nature of this micro-organism needs to be taken into account when designing preventive control measures.” Two other recommendations quickly come to mind: (1) enhancement of the promotion of and support for breastfeeding, and (2) inclusion of a warning on infant formulae and other breastmilk substitutes that the product might be contaminated by E sakazakii and other micro-organisms. I was wondering why the authors did not make such recommendations, when my eyes fell on the last paragraph of the article: “This research is part of a PhD research project . . . which is supported by the Nestlé Research Centre.” A few lines higher I read that no conflicts of interest were declared. Nestlé produces infant formula and other breastmilk substitutes. If this is not a conflict of interest, then what is?
Maaike Arts [email protected]
*Björn Dahlöf, Richard B Devereux, Sverre E Kjeldsen
UNICEF, 72 Ly Thuong Kiet Street, Hanoi, Vietnam
[email protected]
1
*Goteborg University Department of Medicine, Sahlgrenska Hospital/Ostra, 416 85 Goteborg, Sweden (BD); Weill Medical College of Cornell University, Division of Cardiology, New York, NY, USA (RBD); and Department of Cardiology, Ullevaal Hospital, Oslo, Norway (SEK)
Authors’ reply
1
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288: 2998–3007.
Enterobacter sakazakii in factories and households The isolation of Enterobacter sakazakii from various factories, including infant formula factories (Jan 3, p 39),1 and the related contamination of infant formulae with E sakazakii are causes for concern. I was surprised to see only one
Kandhai MC, Reij MW, Gorris LGM, Guillaume-Gentil O, van Schothorst M. Occurrence of Enterobacter sakazakii in food production environments and households. Lancet 2004; 363: 39–40.
Maaike Arts asks why we did not include in our Research Letter other recommendations about Enterobacter sakazakii in infant formulae. We believe that our conclusion “The widespread nature of this micro-organism needs to be taken into account when designing preventive control measures” is the only one justified on the basis of the results we reported. The purpose of our study was to gain a better understanding of the ecology of E sakazakii as a starting point for designing effective control strategies. On the basis of the research we reported, we cannot substantiate the recommendations suggested by Arts. However, we would like to draw readers’ attentions to the joint FAO/WHO Expert Workshop on E sakazakii and other micro-organisms in powdered infant formula (held in www.thelancet.com Vol 364 July 31, 2004
Correspondence
Geneva, Switzerland, Feb 2–5, 2004) 1 as a potential source of information. With respect to the suggested conflict of interest, we are convinced that we clearly disclosed our affiliations and financial support as required by the journal. As stated in the original publication, “The sponsor had no role in the study design, data collection, data analysis, and data interpretation, or in writing the report.”
*M Chantal Kandhai, Martine W Reij, Leon G M Gorris, Olivier Guillaume-Gentil, Mike van Schothorst [email protected] *Wageningen University, Laboratory of Food Microbiology, PO Box 8129, 6700 EV Wageningen, Netherlands (MCK, MWR, LGMG, MvS); and Nestlé Research Centre, Quality and Safety Assurance Department, Lausanne, Switzerland (OGG) 1
Food and Agriculture Organization/ World Health Organization. Joint FAO/ WHO workshop on Enterobacter sakazakii and other microorganisms in powdered infant formula, Geneva, 2–5 February 2004. http://who.int/ foodsafety/micro/ meetings/feb2004 /en/ (accessed April 21, 2004).
Therefore, ipratropium is the likely mydriatic agent, not salbutamol. Third, Weir and colleagues’ patient might have been overinvestigated for his pharmacological mydriasis, given that he had a CT and an MRI scan, presumably of the head alone. If Weir and colleagues had instilled one drop of 1% pilocarpine into each eye, the resulting miosis of the normal left eye and lack of response in the pharmacologically dilated right eye would have yielded the diagnosis within 20 min. A neurologically dilated pupil will constrict in this situation.4
Daya Papalkar, Neil S Sharma, Ju-Lee Ooi, Shanel Sharma, *Ian C Francis [email protected] Department of Ophthalmology, Prince of Wales Hospital, Sydney, New South Wales, Australia (DP, NSS, J-LO, SS, ICF); University of New South Wales, Sydney, New South Wales, Australia (DP, NSS, J-LO, SS, ICF); and *Chatswood Grove Eye Clinic, Suite 12, 12–14 Malvern Avenue, Chatswood 2067 NSW, Australia (ICF) 1
2
Pupil blown by a puffer 3
In their Clinical Picture (June 5, p 1853),1 R E P Weir and colleagues describe a 6-year-old boy with pharmacological mydriasis due to inhaleradministered ipratropium bromide. We would like to raise some points about this case. First, the paper does not report a new event. Ipratropium administered via metered-dose inhaler by an unsupervised child has previously been shown to cause transient unilateral mydriasis.2 Other researchers have replicated ipratropium-induced mydriasis by directing the drug into the eye by metered-dose inhaler.3 Second, Weir and colleagues mention that in all reported cases of nebuliserassociated mydriasis, ipratropium has been used in combination with salbutamol. This statement is potentially misleading, since the dilator pupillae muscle is innervated by 1 receptors, and salbutamol is a 2 agonist. www.thelancet.com Vol 364 July 31, 2004
4
Weir REP, Whitehead DEJ, Zaidi FH, Greaves BBG. Pupil blown by a puffer. Lancet 2004; 363: 1853. Bond DW, Vyas H, Venning HE. Mydriasis due to self-administered inhaled ipratropium bromide. Eur J Pediatr 2002; 161: 178. Samaniego F, Newman LS. Migratory anisocoria—a novel clinical entity. Am Rev Respir Dis 1986; 134: 844. Lee AG, Brazis PW. Clinical pathways in neuro-ophthalmology, 1st edn. New York: Thieme, 1998: 361.
Authors’ reply Our Clinical Picture was of a well child with two episodes of unilateral pupil dilatation associated with spacer inhaler use. The cases cited as precedents by Daya Papalkar and colleagues were of a 9-month-old boy whose left pupil became dilated after his mother spilt ipratropium onto his face from a nebuliser and not an inhaler,1 and of an ataxic child with a single episode of bilateral fixed pupils from use of a combination of ipratropium, fluticasone propionate, and salmeterol inhalers.2 This second case could have been caused by systemic absorption, whereas ours was more likely to have been caused by digital-topical administration.
receptors are the most abundant adrenoreceptors on the human dilator muscles.3 However, 2 agonists have been shown to cause human iris sphincter relaxation after previous cholinergic contraction.3 Although further study is needed, in-vitro use of delayed salbutamol introduction after ipratropium use, showed a two-fold potentiation of bovine iris sphincter relaxation.4 Our patient had an MRI investigation without sedation within a multidisciplinary setting. Non-constriction to pilocarpine 1% correlates with pharmacological and conceivably traumatic mydriatic pupil dilation. Miosis after pilocarpine instillation in undiagnosed partial third-nerve palsy, ophthalmic migraine, or partial traumatic mydriasis would hinder subsequent neurological observations and optic-disc examination to exclude raised intracranial pressure. Pilocarpine eyedrops in combination with pharmacological dilating eyedrops have been used to induce and diagnose intermittent angle-closure glaucoma (now abandoned practice). The natural history of the duration of ipratropiuminhaler-induced pupil dilation proved, coincidentally, useful.
*R E P Weir, D E J Whitehead, F H Zaidi, B B G Greaves [email protected] *Department of Physiological Optics, Institute of Ophthalmology, University College London, London EC1V 9EL, UK (REPW); Department of Ophthalmology, William Harvey and Kent & Canterbury Hospitals, UK (BBGG); Department of Plastic Surgery, Wexham Park Hospital, Wexham, UK (DEJW); and Department of Ophthalmology, Imperial College, London, UK (FHZ) 1
2
3
4
Ryan CA. Ipratropium bromide induced unilateral mydriasis. Irish Med J 1997; 90: 76. Bond DW, Vyas H, Venning HE. Mydriasis due to self-administered inhaled ipratropium bromide. Eur J Pediatr 2002; 161: 178. Van Alphen GW. The adrenergic receptors of the intraocular muscles of the human eye. Invest Ophthalmol 1976; 15: 502–05. Barilan A, Nachman-Rubinstein R, Oron Y, Geyer O. Muscarinic blockers potentiate beta-adrenergic relaxation of bovine iris sphincter. Graefes Arch Clin Exp Ophthalmol 2003; 241: 226–31.
415
Proportion of patients (%)
100
Losartan Atenolol
80
60
40
20
0 0
12
24
36 Study month
48
60
72
Figure: Proportion of patients receiving any diuretic over time
dose of study drug, add more hydrochlorothiazide, or add other antihypertensive agents (excluding angiotensin converting-enzyme inhibitors, angiotensin-receptor blockers, or blockers) as necessary to achieve a goal blood pressure of less than 140/ 90 mm Hg. As Kato and Eto note, in the group treated with 100 mg losartan, 44% also received hydrochlorothiazide, whereas in those treated with 100 mg atenolol, only 38% received hydrochlorothiazide. However, these counts do not include patients receiving 50 mg of study drug with diuretic, and reflect the patients’ status at the end of follow-up or at the last visit before occurrence of a primary endpoint. Because endpoints occurred more frequently and earlier in the atenolol group, it is informative to compare diuretic use between treatment groups throughout the trial (figure) without regard to concomitant study drug use. In LIFE, patients were on diuretics for 72% of the total follow-up time in the losartan group and for 70% of the time in the atenolol group. Most patients who received diuretic therapy did so within the first 6 months of the study, as specified by the protocol. The mean dose of hydrochlorothiazide used in each treatment group was the same, 20 mg. Therefore, the difference noted at endpoint occurrence or study end in the subgroup treated with 100 mg of losartan or atenolol does not completely or accurately reflect the use of diuretics in the study population over the course of the LIFE study. 414
To further assess the effect of diuretic use on outcomes in the LIFE study, we did an analysis adjusting for the concomitant use of hydrochlorothiazide as a time-varying covariate. This analysis showed only a small effect on the treatment difference. For stroke, the unadjusted risk reduction was 26% in favour of losartan, whereas the adjusted risk reduction was 25%. Unlike the ALLHAT study,1 in which the observed difference in stroke rate in favour of the diuretic was largely driven by the black subpopulation and was associated with a difference in blood pressure, the small difference in use of hydrochlorothiazide in the two treatment groups of the LIFE study, which achieved comparable blood pressure control, does not account for the advantage of losartan over atenolol on stroke or the primary composite endpoint. Thus, the incremental benefits in favour of losartan, in the LIFE study, are essentially independent of diuretic use.
recommendation from the authors at the end of the article: “The widespread nature of this micro-organism needs to be taken into account when designing preventive control measures.” Two other recommendations quickly come to mind: (1) enhancement of the promotion of and support for breastfeeding, and (2) inclusion of a warning on infant formulae and other breastmilk substitutes that the product might be contaminated by E sakazakii and other micro-organisms. I was wondering why the authors did not make such recommendations, when my eyes fell on the last paragraph of the article: “This research is part of a PhD research project . . . which is supported by the Nestlé Research Centre.” A few lines higher I read that no conflicts of interest were declared. Nestlé produces infant formula and other breastmilk substitutes. If this is not a conflict of interest, then what is?
Maaike Arts [email protected]
*Björn Dahlöf, Richard B Devereux, Sverre E Kjeldsen
UNICEF, 72 Ly Thuong Kiet Street, Hanoi, Vietnam
[email protected]
1
*Goteborg University Department of Medicine, Sahlgrenska Hospital/Ostra, 416 85 Goteborg, Sweden (BD); Weill Medical College of Cornell University, Division of Cardiology, New York, NY, USA (RBD); and Department of Cardiology, Ullevaal Hospital, Oslo, Norway (SEK)
Authors’ reply
1
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288: 2998–3007.
Enterobacter sakazakii in factories and households The isolation of Enterobacter sakazakii from various factories, including infant formula factories (Jan 3, p 39),1 and the related contamination of infant formulae with E sakazakii are causes for concern. I was surprised to see only one
Kandhai MC, Reij MW, Gorris LGM, Guillaume-Gentil O, van Schothorst M. Occurrence of Enterobacter sakazakii in food production environments and households. Lancet 2004; 363: 39–40.
Maaike Arts asks why we did not include in our Research Letter other recommendations about Enterobacter sakazakii in infant formulae. We believe that our conclusion “The widespread nature of this micro-organism needs to be taken into account when designing preventive control measures” is the only one justified on the basis of the results we reported. The purpose of our study was to gain a better understanding of the ecology of E sakazakii as a starting point for designing effective control strategies. On the basis of the research we reported, we cannot substantiate the recommendations suggested by Arts. However, we would like to draw readers’ attentions to the joint FAO/WHO Expert Workshop on E sakazakii and other micro-organisms in powdered infant formula (held in www.thelancet.com Vol 364 July 31, 2004
Correspondence
Geneva, Switzerland, Feb 2–5, 2004) 1 as a potential source of information. With respect to the suggested conflict of interest, we are convinced that we clearly disclosed our affiliations and financial support as required by the journal. As stated in the original publication, “The sponsor had no role in the study design, data collection, data analysis, and data interpretation, or in writing the report.”
*M Chantal Kandhai, Martine W Reij, Leon G M Gorris, Olivier Guillaume-Gentil, Mike van Schothorst [email protected] *Wageningen University, Laboratory of Food Microbiology, PO Box 8129, 6700 EV Wageningen, Netherlands (MCK, MWR, LGMG, MvS); and Nestlé Research Centre, Quality and Safety Assurance Department, Lausanne, Switzerland (OGG) 1
Food and Agriculture Organization/ World Health Organization. Joint FAO/ WHO workshop on Enterobacter sakazakii and other microorganisms in powdered infant formula, Geneva, 2–5 February 2004. http://who.int/ foodsafety/micro/ meetings/feb2004 /en/ (accessed April 21, 2004).
Therefore, ipratropium is the likely mydriatic agent, not salbutamol. Third, Weir and colleagues’ patient might have been overinvestigated for his pharmacological mydriasis, given that he had a CT and an MRI scan, presumably of the head alone. If Weir and colleagues had instilled one drop of 1% pilocarpine into each eye, the resulting miosis of the normal left eye and lack of response in the pharmacologically dilated right eye would have yielded the diagnosis within 20 min. A neurologically dilated pupil will constrict in this situation.4
Daya Papalkar, Neil S Sharma, Ju-Lee Ooi, Shanel Sharma, *Ian C Francis [email protected] Department of Ophthalmology, Prince of Wales Hospital, Sydney, New South Wales, Australia (DP, NSS, J-LO, SS, ICF); University of New South Wales, Sydney, New South Wales, Australia (DP, NSS, J-LO, SS, ICF); and *Chatswood Grove Eye Clinic, Suite 12, 12–14 Malvern Avenue, Chatswood 2067 NSW, Australia (ICF) 1
2
Pupil blown by a puffer 3
In their Clinical Picture (June 5, p 1853),1 R E P Weir and colleagues describe a 6-year-old boy with pharmacological mydriasis due to inhaleradministered ipratropium bromide. We would like to raise some points about this case. First, the paper does not report a new event. Ipratropium administered via metered-dose inhaler by an unsupervised child has previously been shown to cause transient unilateral mydriasis.2 Other researchers have replicated ipratropium-induced mydriasis by directing the drug into the eye by metered-dose inhaler.3 Second, Weir and colleagues mention that in all reported cases of nebuliserassociated mydriasis, ipratropium has been used in combination with salbutamol. This statement is potentially misleading, since the dilator pupillae muscle is innervated by 1 receptors, and salbutamol is a 2 agonist. www.thelancet.com Vol 364 July 31, 2004
4
Weir REP, Whitehead DEJ, Zaidi FH, Greaves BBG. Pupil blown by a puffer. Lancet 2004; 363: 1853. Bond DW, Vyas H, Venning HE. Mydriasis due to self-administered inhaled ipratropium bromide. Eur J Pediatr 2002; 161: 178. Samaniego F, Newman LS. Migratory anisocoria—a novel clinical entity. Am Rev Respir Dis 1986; 134: 844. Lee AG, Brazis PW. Clinical pathways in neuro-ophthalmology, 1st edn. New York: Thieme, 1998: 361.
Authors’ reply Our Clinical Picture was of a well child with two episodes of unilateral pupil dilatation associated with spacer inhaler use. The cases cited as precedents by Daya Papalkar and colleagues were of a 9-month-old boy whose left pupil became dilated after his mother spilt ipratropium onto his face from a nebuliser and not an inhaler,1 and of an ataxic child with a single episode of bilateral fixed pupils from use of a combination of ipratropium, fluticasone propionate, and salmeterol inhalers.2 This second case could have been caused by systemic absorption, whereas ours was more likely to have been caused by digital-topical administration.
receptors are the most abundant adrenoreceptors on the human dilator muscles.3 However, 2 agonists have been shown to cause human iris sphincter relaxation after previous cholinergic contraction.3 Although further study is needed, in-vitro use of delayed salbutamol introduction after ipratropium use, showed a two-fold potentiation of bovine iris sphincter relaxation.4 Our patient had an MRI investigation without sedation within a multidisciplinary setting. Non-constriction to pilocarpine 1% correlates with pharmacological and conceivably traumatic mydriatic pupil dilation. Miosis after pilocarpine instillation in undiagnosed partial third-nerve palsy, ophthalmic migraine, or partial traumatic mydriasis would hinder subsequent neurological observations and optic-disc examination to exclude raised intracranial pressure. Pilocarpine eyedrops in combination with pharmacological dilating eyedrops have been used to induce and diagnose intermittent angle-closure glaucoma (now abandoned practice). The natural history of the duration of ipratropiuminhaler-induced pupil dilation proved, coincidentally, useful.
*R E P Weir, D E J Whitehead, F H Zaidi, B B G Greaves [email protected] *Department of Physiological Optics, Institute of Ophthalmology, University College London, London EC1V 9EL, UK (REPW); Department of Ophthalmology, William Harvey and Kent & Canterbury Hospitals, UK (BBGG); Department of Plastic Surgery, Wexham Park Hospital, Wexham, UK (DEJW); and Department of Ophthalmology, Imperial College, London, UK (FHZ) 1
2
3
4
Ryan CA. Ipratropium bromide induced unilateral mydriasis. Irish Med J 1997; 90: 76. Bond DW, Vyas H, Venning HE. Mydriasis due to self-administered inhaled ipratropium bromide. Eur J Pediatr 2002; 161: 178. Van Alphen GW. The adrenergic receptors of the intraocular muscles of the human eye. Invest Ophthalmol 1976; 15: 502–05. Barilan A, Nachman-Rubinstein R, Oron Y, Geyer O. Muscarinic blockers potentiate beta-adrenergic relaxation of bovine iris sphincter. Graefes Arch Clin Exp Ophthalmol 2003; 241: 226–31.
415