- Email: [email protected]
Prophylaxis against respiratory syncytial virus in premature infants
CORRESPONDENCE
3
4
5
deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY. Hum Reprod 1999; 14: 1710–16. Moro E, Marin P, Rossi P, Garolla A, Ferlin A. Y chromosome microdeletions in infertile men with varicocele. Mol Cell Endocrinol (in press). Foresta C, Moro E, Garolla A, Onisto M, Ferlin A. Y chromosome microdeletions in cryptorchidism and idiopathic infertility. J Clin Endocrinol Metab 1999; 84: 3660–65. Page DC, Silber S, Brown LG. Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod 1999; 14: 1722–26.
Lowering of LDL cholesterol Sir—Nick Payne and Chris McCabe (Oct 2, p 1207)1 claim that I asserted “that there is no scientific evidence supporting the recommendation for giving lower priority to lowering LDL cholesterol in people without symptomatic disease”, and that this assertion is scientifically incorrect. However, this statement is not even close to what I wrote.2 I stated that, sometimes, we accord more authority to judgments made by consensus conferences than they deserve. As an example, I cited the distinction between primary and secondary prevention of coronary disease made by the National Cholesterol Education Program, which ignores the particular (and, for those involved, the crucial) category of individuals with anatomic but symptomless coronary artery disease. The evidence from clinical trials clearly shows that such individuals will, on average, benefit from pharmacological therapy, whereas there is no evidence that non-pharmacological therapy that does not also produce marked LDL lowering will succeed. Indeed, the contrary is the case. The point Payne and McCabe go on to make is that, given the financial resources available, we have no choice but to prioritise (ie, to select) those who will receive potentially life-saving therapy and to separate them from those who will not (or at least, not at the state’s expense). I recognise the problem but I have concerns with the approach they suggest. Do not such strategies discourage others, such as encouraging greater price competition among pharmaceutical companies? Given the sums involved, at some point, should not our governments go generic? If they halve the price of the drug, twice as many can be treated. If we examine the process of care, I am confident even more can be saved. More important still, who should make the choices? How was it established that the citizens (ie, the
THE LANCET • Vol 355 • January 15, 2000
patients we serve) approve of the choices that experts such as Payne and McCabe have made for their lives? And what made them draw the line precisely where they did?3 As physicians and scientists, our job is to inform our fellow citizens and political leaders as best we can, about the benefits, risks, and costs of various strategies. I am not fond of the phrase “cost effective”, but if anything, it is a calculation that demands a societal, not a medical, judgment. Accordingly, I thoroughly applaud the efforts of Hazel Thornton4 and others5 for involving ordinary citizens in their consensus process. I do not deny there are hard choices. But there is still a wide gulf in how we choose to allocate our governmental expenditures, and if we only recognise it, I believe we retain a far larger capacity to improve health care than Payne and McCabe would seem to allow.1 It is, after all, the wealth we create that our governments dispense. Perhaps we should remind them of that. Allan D Sniderman McGill University, Royal Victoria Hospital, Cardiology Division, Montreal, Quebec, Canada H3A 1A1 (e-mail: [email protected]) 1 2
3
4
5
Payne N, McCabe C. Lowering of LDL cholesterol. Lancet 1999; 354: 1207–08. Sniderman AD. Clinical trials, consensus conferences, and clinical practice. Lancet 1999; 354: 327–30. Pickin DM, McCabe CJ, Ramsay LE, et al. Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment. Heart 1999; 82: 325–32. Thornton H. Clinical trials, consensus conferences, and clinical practice. Lancet 1999; 354: 1037. Clinical Synthesis Panel on HRT. Hormone replacement therapy. Lancet 1999; 354: 152–55.
Prophylaxis against respiratory syncytial virus in premature infants Sir—Palivizumab prophylaxis for premature infants and infants with bronchopulmonary dysplasia during the respiratory syncytial virus (RSV) season reduces hospital admissions from 10·6% to 4·8%.1 Because of the high price of palivizumab and the benign course of most RSV infections, the costeffectiveness of such a strategy is questioned.2,3 L Bont and colleagues (Sept 18, p 1003)4 show that 29 (88%) of 33 infants who were mechanically ventilated for RSV infection had a postconceptional age of 44 weeks or less. Prophylaxis for premature infants may therefore be most effective during the first 2 months after discharge. In our regional paediatric centre, small infants with severe RSV infection
are commonly admitted to the neonatal intensive-care unit (ICU). During a 12-year period (1987–98), we had 46 such admissions: 11 infants needed mechanical ventilation, but none died. 33 (72%) infants who were admitted and nine (82%) infants who were ventilated had a postconceptional age of 44 weeks or less. 11 (24%) infants admitted and six (55%) ventilated infants were born at a gestational age of 35 weeks or less. One infant had bronchopulmonary dysplasia. During the 12-year period, 1656 newborn infants born at a gestational age less than 36 weeks were discharged home to our primary catchment area; 38 had a diagnosis of bronchopulmonary dysplasia. Seven infants were readmitted to the ICU because of RSV infection. None of these infants were born before 30 weeks and none had bronchopulmonary dysplasia. Three infants needed mechanical ventilation. By assuming a 5-month RSV season and a 57% reduction in RSV readmissions,1 we would need to treat about 170 infants with palivizumab to prevent one ICU readmission. Nearly all ICU admissions for RSV infection occur early in life. The investigators of the IMpact-RSV study should re-examine their data to see whether there was any benefit in continuing palivizumab prophylaxis in premature infants for more than 2 months after discharge. Premature infants are overrepresented among infants admitted to intensive care because of RSV infection, especially among those in need of mechanical ventilation. However, for the premature infant in our population, the risk of ICU readmission was small (about 1%). To use palivizumab to prevent such an event would require a large number necessary to treat and the cost for each readmission prevented would be very high, even if a short treatment course (two injections) were used. Although it may be wise to offer prophylaxis to the smallest and most vulnerable infants, especially if additional risk factors are present (smoking in the family, crowding, siblings in day care),5 measures to reduce RSV exposure are much more cost-effective.2 *Lars J Björklund, Magnus Lindroth, Staffan Polberger, Bo Selander Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, SE-221 85 Lund, Sweden (e-mail: [email protected]) 1
The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102: 531–37.
235
CORRESPONDENCE 2
3
4
5
Moler FW, Brown RW, Faix RG, Gilsdorf JR. Comments on palivizumab (Synagis). Pediatrics 1999; 103: 495–97. Joffe S, Ray GT, Escobar GJ, Black SB, Lieu TA. Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants. Pediatrics 1999; 104: 419–27. Bont L, van Vught AJ, Kimpen JLL. Prophylaxis against respiratory syncytial virus in premature infants. Lancet 1999; 354: 1003–04. Simoes EAF. Respiratory syncytial virus infection. Lancet 1999; 354: 847–52.
Chagas’ disease challenge Sir—Faced by the lack of a vaccination, chemoprophylaxis, or therapy suitable for large-scale use, the control strategy for Chagas’ disease is based on the interruption of the transmission of Trypanosoma cruzi by the elimination of domiciliary vectors—reduviid bugs— and systematic screening of blood donors. Since 1991, the southern countries of South America have been engaged in a major control effort against the main vector, Triatoma infestans.1 The Andean countries started a similar action in 1997.2 In the light of the remarkable progress in the control of Chagas’ disease during the past decade,3 WHO claimed that eradication could be expected in a few years. However, in the northern countries of South America the situation is more complex than in the south. If transmission is mainly due to Rhodnius prolixus, there is a diversity of other vector species implicated with silvatic and periurban habitats. Therefore, effective control relies first on good understanding of the epidemiological cycles with a global ecological approach, which unfortunately is still lacking. Multidisciplinary studies are necessary to describe the explicative variables of the ecosystem (climatology, vegetal and entomological biology, human ecology, geography, genetics, &c), which account for the presence or absence of vectors in wild habitats, and to assess the causal linkages between the environment, human activities, domiciliary adaptation of silvatic triatomines, and Chagas’ disease. These approaches begin to appear in network patterns in some north-south projects that integrate ecological and health indicators with the aim of defining epidemiological risk for tropical diseases such as American trypanosomosis in Latin America. Effective control also relies on a reliable identification of the vectors. Within R prolixus spp, the assignment of a major species is still highly controversial. Furthermore, accurate and reliable methods must be perfected
236
to understand the population genetics of the vector. The recolonisation hypothesis may, for instance, be tested by analysing the genetic structure of wild and domiciliary insect populations, and by estimating the dispersal abilities and hence gene flow of the vectors, with appropriate highly polymorphic genetic markers (ie, microsatellites). Such markers were recently isolated from R pallescens.4 We advocate that only the understanding of the match between ecological genetics and habitat characteristics of triatomines will enable us to predict the migration pathways of vectors. Pre-empting of the likelihood of domiciliation of the species would require that control strategies integrate a true policy of ecological management. Myriam Harry, Fernando Lema, *Christine A Romaña UFR de Sciences, Université de Paris XII, Creteil, France; Immunologie Structurale, Institut Pasteur, Paris; and *Philosophie des Sciences, Université de Picardie Jules Verne, 80025 Amiens, France (ECOMED Network) 1
2
3
4
Schmunis GA, Zicker F, Moncayo A. Interruption of Chagas’ disease transmission through vector elimination. Lancet 1996; 348: 1171. WHO. Andean countries initiative launched in Colombia. TDR News 1997; 53: 3. Schofield CJ, Dias JCP. The Southern Cone programme against Chagas disease. Adv Parasitol 1998; 42: 1–27. Harry M, Poyet G, Romaña CA, Solignac M. Isolation and characterization of microsatellite markers in the bloodsucking bug Rhodnius pallescens (Heteroptera, Reduviidae). Mol Ecol 1998; 7: 1784–88.
Neutral protamine Hagedorn insulin Sir—We would like to add to Peter Jehle and colleagues’ (Nov 6, p 1604)1 report with our experiments with neutral protamine Hagedorn (NPH) and zinc insulins.2 We investigated whether the suspension of four insulins from different manufacturers showed any differences in the number of cycles necessary for complete resuspension (NPH insulin in pens from Hoechst and Novo Nordisk, NPH insulin in vials from Hoechst, and zinc insulin in vials from Novo Nordisk). Furthermore, we investigated whether the optical assessment of resuspension is adequate for recognition of sufficient mixture. After sedimentation, every cartridge and vial was tipped one to 100 times. After defined cycles a small amount was removed from the top, diluted with distilled water and measured by absorption (280 nm). For validation, insulin was measured by RIA (Kabi Pharmacia insulin RIA, Uppsala,
Sweden). As tipping frequency increased, the absorption (and insulin concentration measured by RIA) rose to a set point implicating adequate and homogeneous resuspension (five experiments for each insulin preparation). To reach a stable absorption, NPH insulin in vials (Hoechst) has to be tipped at least ten times, zinc insulin in vials (Novo Nordisk) at least 15 times, and NPH insulin in cartridges (Hoechst and Novo Nordisk) at least 20 times. Optical assessment of adequate resuspension was reached about eight cycles earlier. We conclude that optical assessment of complete resuspension is not adequate. Like Jehle we recommend tipping the insulin cartridges for NPH insulin at least 20 times for complete resuspension. Because of the greater diameter of vials compared with the cartridges, insulin in vials (NPH and zinc insulin) has to be tipped less often. Ester Laubach, Peter Schwandt, *Michael M Ritter Medical Department II, University Hospital, Munich, and *Medical Department, Hospital Ibbenbüren, Germany 1
2
Jehle PM, Micheler C, Jehle DR, Breitig D, Boehm BO. Inadequate suspension of neutral protamine Hagedorn (NPH) insulin in pens. Lancet 1999; 354: 1604–07. Laubach E, Vogeser M, Schwandt P, Ritter MM. Durchmischung von Verzögerungs-insulinen vor Injektion. Diabetes Stoffwechsel 1998; 7 (suppl 1): 117–18.
Renal effects of cyclooxygenase-type-2 inhibition Sir—Licia Periuzzi and colleagues (Nov 6, p 1615)1 report that cyclooxygenase-type-2 (COX-2) inhibition with nimesulide may cause neonatal end-stage renal failure when used as tocolytic during pregnancy. Nimesulide has been suggested to be a preferential, but not selective, COX-2 inhibitor.2 In doses used in clinical practice nimesulide may lose its COX-2 selectivity. However, this point has been debated.2,3 Overall, the described renal side-effects of nimesulide may be caused partially or completely by COX-1 inhibition. Bernhard K Krämer Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany (e-mail: [email protected]) 1
Peruzzi L, Gianoglio B, Porcellini MG, Coppo R. Neonatal end-stage renal failure associated with maternal ingestion of cyclooxygenase-type-1 selective inhibitor
THE LANCET • Vol 355 • January 15, 2000
3
4
5
deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY. Hum Reprod 1999; 14: 1710–16. Moro E, Marin P, Rossi P, Garolla A, Ferlin A. Y chromosome microdeletions in infertile men with varicocele. Mol Cell Endocrinol (in press). Foresta C, Moro E, Garolla A, Onisto M, Ferlin A. Y chromosome microdeletions in cryptorchidism and idiopathic infertility. J Clin Endocrinol Metab 1999; 84: 3660–65. Page DC, Silber S, Brown LG. Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod 1999; 14: 1722–26.
Lowering of LDL cholesterol Sir—Nick Payne and Chris McCabe (Oct 2, p 1207)1 claim that I asserted “that there is no scientific evidence supporting the recommendation for giving lower priority to lowering LDL cholesterol in people without symptomatic disease”, and that this assertion is scientifically incorrect. However, this statement is not even close to what I wrote.2 I stated that, sometimes, we accord more authority to judgments made by consensus conferences than they deserve. As an example, I cited the distinction between primary and secondary prevention of coronary disease made by the National Cholesterol Education Program, which ignores the particular (and, for those involved, the crucial) category of individuals with anatomic but symptomless coronary artery disease. The evidence from clinical trials clearly shows that such individuals will, on average, benefit from pharmacological therapy, whereas there is no evidence that non-pharmacological therapy that does not also produce marked LDL lowering will succeed. Indeed, the contrary is the case. The point Payne and McCabe go on to make is that, given the financial resources available, we have no choice but to prioritise (ie, to select) those who will receive potentially life-saving therapy and to separate them from those who will not (or at least, not at the state’s expense). I recognise the problem but I have concerns with the approach they suggest. Do not such strategies discourage others, such as encouraging greater price competition among pharmaceutical companies? Given the sums involved, at some point, should not our governments go generic? If they halve the price of the drug, twice as many can be treated. If we examine the process of care, I am confident even more can be saved. More important still, who should make the choices? How was it established that the citizens (ie, the
THE LANCET • Vol 355 • January 15, 2000
patients we serve) approve of the choices that experts such as Payne and McCabe have made for their lives? And what made them draw the line precisely where they did?3 As physicians and scientists, our job is to inform our fellow citizens and political leaders as best we can, about the benefits, risks, and costs of various strategies. I am not fond of the phrase “cost effective”, but if anything, it is a calculation that demands a societal, not a medical, judgment. Accordingly, I thoroughly applaud the efforts of Hazel Thornton4 and others5 for involving ordinary citizens in their consensus process. I do not deny there are hard choices. But there is still a wide gulf in how we choose to allocate our governmental expenditures, and if we only recognise it, I believe we retain a far larger capacity to improve health care than Payne and McCabe would seem to allow.1 It is, after all, the wealth we create that our governments dispense. Perhaps we should remind them of that. Allan D Sniderman McGill University, Royal Victoria Hospital, Cardiology Division, Montreal, Quebec, Canada H3A 1A1 (e-mail: [email protected]) 1 2
3
4
5
Payne N, McCabe C. Lowering of LDL cholesterol. Lancet 1999; 354: 1207–08. Sniderman AD. Clinical trials, consensus conferences, and clinical practice. Lancet 1999; 354: 327–30. Pickin DM, McCabe CJ, Ramsay LE, et al. Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment. Heart 1999; 82: 325–32. Thornton H. Clinical trials, consensus conferences, and clinical practice. Lancet 1999; 354: 1037. Clinical Synthesis Panel on HRT. Hormone replacement therapy. Lancet 1999; 354: 152–55.
Prophylaxis against respiratory syncytial virus in premature infants Sir—Palivizumab prophylaxis for premature infants and infants with bronchopulmonary dysplasia during the respiratory syncytial virus (RSV) season reduces hospital admissions from 10·6% to 4·8%.1 Because of the high price of palivizumab and the benign course of most RSV infections, the costeffectiveness of such a strategy is questioned.2,3 L Bont and colleagues (Sept 18, p 1003)4 show that 29 (88%) of 33 infants who were mechanically ventilated for RSV infection had a postconceptional age of 44 weeks or less. Prophylaxis for premature infants may therefore be most effective during the first 2 months after discharge. In our regional paediatric centre, small infants with severe RSV infection
are commonly admitted to the neonatal intensive-care unit (ICU). During a 12-year period (1987–98), we had 46 such admissions: 11 infants needed mechanical ventilation, but none died. 33 (72%) infants who were admitted and nine (82%) infants who were ventilated had a postconceptional age of 44 weeks or less. 11 (24%) infants admitted and six (55%) ventilated infants were born at a gestational age of 35 weeks or less. One infant had bronchopulmonary dysplasia. During the 12-year period, 1656 newborn infants born at a gestational age less than 36 weeks were discharged home to our primary catchment area; 38 had a diagnosis of bronchopulmonary dysplasia. Seven infants were readmitted to the ICU because of RSV infection. None of these infants were born before 30 weeks and none had bronchopulmonary dysplasia. Three infants needed mechanical ventilation. By assuming a 5-month RSV season and a 57% reduction in RSV readmissions,1 we would need to treat about 170 infants with palivizumab to prevent one ICU readmission. Nearly all ICU admissions for RSV infection occur early in life. The investigators of the IMpact-RSV study should re-examine their data to see whether there was any benefit in continuing palivizumab prophylaxis in premature infants for more than 2 months after discharge. Premature infants are overrepresented among infants admitted to intensive care because of RSV infection, especially among those in need of mechanical ventilation. However, for the premature infant in our population, the risk of ICU readmission was small (about 1%). To use palivizumab to prevent such an event would require a large number necessary to treat and the cost for each readmission prevented would be very high, even if a short treatment course (two injections) were used. Although it may be wise to offer prophylaxis to the smallest and most vulnerable infants, especially if additional risk factors are present (smoking in the family, crowding, siblings in day care),5 measures to reduce RSV exposure are much more cost-effective.2 *Lars J Björklund, Magnus Lindroth, Staffan Polberger, Bo Selander Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, SE-221 85 Lund, Sweden (e-mail: [email protected]) 1
The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102: 531–37.
235
CORRESPONDENCE 2
3
4
5
Moler FW, Brown RW, Faix RG, Gilsdorf JR. Comments on palivizumab (Synagis). Pediatrics 1999; 103: 495–97. Joffe S, Ray GT, Escobar GJ, Black SB, Lieu TA. Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants. Pediatrics 1999; 104: 419–27. Bont L, van Vught AJ, Kimpen JLL. Prophylaxis against respiratory syncytial virus in premature infants. Lancet 1999; 354: 1003–04. Simoes EAF. Respiratory syncytial virus infection. Lancet 1999; 354: 847–52.
Chagas’ disease challenge Sir—Faced by the lack of a vaccination, chemoprophylaxis, or therapy suitable for large-scale use, the control strategy for Chagas’ disease is based on the interruption of the transmission of Trypanosoma cruzi by the elimination of domiciliary vectors—reduviid bugs— and systematic screening of blood donors. Since 1991, the southern countries of South America have been engaged in a major control effort against the main vector, Triatoma infestans.1 The Andean countries started a similar action in 1997.2 In the light of the remarkable progress in the control of Chagas’ disease during the past decade,3 WHO claimed that eradication could be expected in a few years. However, in the northern countries of South America the situation is more complex than in the south. If transmission is mainly due to Rhodnius prolixus, there is a diversity of other vector species implicated with silvatic and periurban habitats. Therefore, effective control relies first on good understanding of the epidemiological cycles with a global ecological approach, which unfortunately is still lacking. Multidisciplinary studies are necessary to describe the explicative variables of the ecosystem (climatology, vegetal and entomological biology, human ecology, geography, genetics, &c), which account for the presence or absence of vectors in wild habitats, and to assess the causal linkages between the environment, human activities, domiciliary adaptation of silvatic triatomines, and Chagas’ disease. These approaches begin to appear in network patterns in some north-south projects that integrate ecological and health indicators with the aim of defining epidemiological risk for tropical diseases such as American trypanosomosis in Latin America. Effective control also relies on a reliable identification of the vectors. Within R prolixus spp, the assignment of a major species is still highly controversial. Furthermore, accurate and reliable methods must be perfected
236
to understand the population genetics of the vector. The recolonisation hypothesis may, for instance, be tested by analysing the genetic structure of wild and domiciliary insect populations, and by estimating the dispersal abilities and hence gene flow of the vectors, with appropriate highly polymorphic genetic markers (ie, microsatellites). Such markers were recently isolated from R pallescens.4 We advocate that only the understanding of the match between ecological genetics and habitat characteristics of triatomines will enable us to predict the migration pathways of vectors. Pre-empting of the likelihood of domiciliation of the species would require that control strategies integrate a true policy of ecological management. Myriam Harry, Fernando Lema, *Christine A Romaña UFR de Sciences, Université de Paris XII, Creteil, France; Immunologie Structurale, Institut Pasteur, Paris; and *Philosophie des Sciences, Université de Picardie Jules Verne, 80025 Amiens, France (ECOMED Network) 1
2
3
4
Schmunis GA, Zicker F, Moncayo A. Interruption of Chagas’ disease transmission through vector elimination. Lancet 1996; 348: 1171. WHO. Andean countries initiative launched in Colombia. TDR News 1997; 53: 3. Schofield CJ, Dias JCP. The Southern Cone programme against Chagas disease. Adv Parasitol 1998; 42: 1–27. Harry M, Poyet G, Romaña CA, Solignac M. Isolation and characterization of microsatellite markers in the bloodsucking bug Rhodnius pallescens (Heteroptera, Reduviidae). Mol Ecol 1998; 7: 1784–88.
Neutral protamine Hagedorn insulin Sir—We would like to add to Peter Jehle and colleagues’ (Nov 6, p 1604)1 report with our experiments with neutral protamine Hagedorn (NPH) and zinc insulins.2 We investigated whether the suspension of four insulins from different manufacturers showed any differences in the number of cycles necessary for complete resuspension (NPH insulin in pens from Hoechst and Novo Nordisk, NPH insulin in vials from Hoechst, and zinc insulin in vials from Novo Nordisk). Furthermore, we investigated whether the optical assessment of resuspension is adequate for recognition of sufficient mixture. After sedimentation, every cartridge and vial was tipped one to 100 times. After defined cycles a small amount was removed from the top, diluted with distilled water and measured by absorption (280 nm). For validation, insulin was measured by RIA (Kabi Pharmacia insulin RIA, Uppsala,
Sweden). As tipping frequency increased, the absorption (and insulin concentration measured by RIA) rose to a set point implicating adequate and homogeneous resuspension (five experiments for each insulin preparation). To reach a stable absorption, NPH insulin in vials (Hoechst) has to be tipped at least ten times, zinc insulin in vials (Novo Nordisk) at least 15 times, and NPH insulin in cartridges (Hoechst and Novo Nordisk) at least 20 times. Optical assessment of adequate resuspension was reached about eight cycles earlier. We conclude that optical assessment of complete resuspension is not adequate. Like Jehle we recommend tipping the insulin cartridges for NPH insulin at least 20 times for complete resuspension. Because of the greater diameter of vials compared with the cartridges, insulin in vials (NPH and zinc insulin) has to be tipped less often. Ester Laubach, Peter Schwandt, *Michael M Ritter Medical Department II, University Hospital, Munich, and *Medical Department, Hospital Ibbenbüren, Germany 1
2
Jehle PM, Micheler C, Jehle DR, Breitig D, Boehm BO. Inadequate suspension of neutral protamine Hagedorn (NPH) insulin in pens. Lancet 1999; 354: 1604–07. Laubach E, Vogeser M, Schwandt P, Ritter MM. Durchmischung von Verzögerungs-insulinen vor Injektion. Diabetes Stoffwechsel 1998; 7 (suppl 1): 117–18.
Renal effects of cyclooxygenase-type-2 inhibition Sir—Licia Periuzzi and colleagues (Nov 6, p 1615)1 report that cyclooxygenase-type-2 (COX-2) inhibition with nimesulide may cause neonatal end-stage renal failure when used as tocolytic during pregnancy. Nimesulide has been suggested to be a preferential, but not selective, COX-2 inhibitor.2 In doses used in clinical practice nimesulide may lose its COX-2 selectivity. However, this point has been debated.2,3 Overall, the described renal side-effects of nimesulide may be caused partially or completely by COX-1 inhibition. Bernhard K Krämer Klinik und Poliklinik für Innere Medizin II, University of Regensburg, D-93042 Regensburg, Germany (e-mail: [email protected]) 1
Peruzzi L, Gianoglio B, Porcellini MG, Coppo R. Neonatal end-stage renal failure associated with maternal ingestion of cyclooxygenase-type-1 selective inhibitor
THE LANCET • Vol 355 • January 15, 2000