- Email: [email protected]
Bradycardia after rapid intravenous infusion of amphotericin B
372
determine a causal relation between pravastatin therapy and depression from experience in 4 patients followed for a short time. Neither our controlled studies nor our marketed product experience in a large number of patients indicate that treatment with pravastatin is associated with an increased risk of symptoms of depression. We will continue to monitor the Bristol-Myers Squibb world-wide drug-safety database for any new relevant information.
to
Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543, USA
KENNETH B. KASSLER-TAUB TREVOR WOODWARD JEFFREY S. MARKOWITZ
JK, et al. Six-month prevalence of psychiatric disorders in three communities. Gen Psychiatry 1984; 41: 959-67.
1. Myers
Neuropsychiatric symptoms during treatment with interleukin-2 and
interferon-&agr; SiR,—Neuropsychiatric symptoms during the treatment of metastatic cancers with high-dose intravenous recombinant interleukin-2 are common and often treatment-limiting. In a survey of 652 patients thus treated, a third became disoriented and 5 % had frank coma.1 Denicoffet al2 reported severe cognitive changes in 22 of 44 patients treated with intravenous bolus injections of interleukin-2. Agitation and delusions were frequent. Predominantly hallucinatory syndromes have also been reported.3 The vascular leak syndrome, one of the major toxicities of systemic high-dose interleukin-2, induces profound changes in cardiovascular and renal function, resulting in dyspnoea at rest, anuria, and hypotension requiring vasopressors.4 The vascular leak syndrome may also be responsible for the increases in brain water-content after treatment with interleukin-2, which can be demonstrated by nuclear magnetic resonance imaging.s These mechanisms may contribute to the observed changes in mental status. Interferon-a also causes neuropsychiatric symptoms,6 but the underlying pathophysiology is unknown. We report our experience in 101 patients with progressive metastatic renal cell carcinoma, who were treated with subcutaneous interleukin-2 and interferon-ot2b with or without subsequent intravenous 5-fluorouracil on an outpatient basis. Mean age was 57-4 years and 72 patients were male. All patients had normal computed tomography (CT) of the brain and no evidence of central nervous system disease before therapy. 4 patients had undergone resection of brain metastases. All patients received subcutaneous injections of 3 x 6 MU/m recombinant interferona2b (Schering-Plough) with 3 x 5-20 MID /m2 recombinant interleukin-2 (Eurocetus), both weekly, for at least 4 consecutive weeks per course. In 48 patients this schedule was followed by 3 x 6 MD /m2 recombinant interferon-%b with 750 mg/m2 5-fluorouracil every week for 4 weeks. 161 treatment courses were given. Neuropsychiatric toxicity was evaluated for every treatment week. Statistical analysis was by t and X2 tests. Minor or major difficulties in concentration were observed in 34 and 5 patients, respectively. 5 patients were transiently disoriented during therapy. Coma or seizures were not observed. 37 patients complained about mild paraesthesias, 4 patients had transient muscle weakness, and 1 patient had hemiparesis. Therapy was discontinued in all 6 patients with disorientation or hemiparesis, with only 1 patient in the first treatment course. CT revealed brain metastases in the patient with hemiparesis and in 1 with disorientation. No abnormality was detected in the other 4 patients with treatment-limiting toxicity. Neuropsychiatric symptoms in these patients usually resolved within 6 h after discontinuation of treatment, but persisted for 3 days in 1 patient. None of the patients with treatment-limiting neurotoxicity developed major signs of vascular leakage. Age, sex, and the sequential use of chemotherapy were not statistically associated with the development of neuropsychiatric symptoms. Paraesthesias but not difficulties in concentration were more common during the second or third course (p < 0-05). All 4 patients with resected brain metastases developed neuropsychiatric symptoms, including disorientation in 1.
Treatment-limiting neuropsychiatric symptoms during this outpatient regimen occurred less often than in patients treated with high-dose intravenous interleukin-2, resolved spontaneously after discontinuation of treatment, and may have indicated brain Thus, given the therapeutic efficacy of low-dose subcutaneous interleukin-2 in combination with interferon in renal cancer patients,’ therapeutic doses of interleukin-2 and interferon-a may not necessarily be associated with a high frequency of severe neuropsychiatric symptoms. MARTIN H. FENNER ENRIQUE LOPEZ HÄNNINEN HARTMUT H. KIRCHNER Departments of Haematology and Oncology, HUBERT POLIWODA Medizinische Hochschule Hannover, 3000 Hannover 61, Germany JENS ATZPODIEN
metastases.
Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high dose interleukin-2 based therapies in the treatment of 652 patients with cancer. Ann Surg 1989; 210: 274-85. 2. Denicoff KD, Rubinow DR, Papa MZ, et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987; 1.
107: 293-300. 3. Smith MJ, Khayat D. Residual acute confusional and
4. 5.
6. 7.
hallucinatory syndromes
induced by interleukin-2/&agr;-interferon treatment. Psycho-Oncology 1992; 1: 115-18. Adams F, Quesada JR, Gutterman JU. Neuropsychiatric manifestations of human leucocyte interferon therapy in patients with cancer. JAMA 1984; 252: 938-42. Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol 1991; 9: 694-704. Saris SC, Patronas NJ, Rosenberg SA, et al. The effect of intravenous interleukin-2 on brain water content. J Neurosurg 1989; 71: 169-74. Atzpodien J, Körfer A, Francks CR, Poliwoda H, Kirchner H. Home therapy with recombinant interleukin-2 and interferon-&agr;2b in advanced human malignancies. Lancet 1990; 335: 1509-12.
Bradycardia after rapid intravenous infusion of amphotericin B SIR,-Walker and colleagues1 have reported bradycardia in a 5 2 year-old boy given intravenous amphotericin B. This patient received a total anthracycline dose of 350 mg/m2 and total body irradiation and cyclophosphamide as conditioning for autologous bone marrow transplantation. The suggestion was that the arrhythmia resulted from the administration of amphotericin B in a patient with myocardial damage due to irradiation and cytotoxic drugs. Bethell and co-workers2 subsequently reported three cases of bradycardia after anthracyclines; in two the administration of amphotericin seemed to trigger the arrhythmia. We report a case of bradycardia related to the rapid intravenous infusion of amphotericin B, without involvement of other potentially cardiotoxic agents. A 56-year-old woman with no history of cardiac disease was given mitoxantrone (17 mg daily for 3 days) and cytarabine (280 mg daily for 7 days) for first induction therapy for acute myeloblastic leukaemia. 5 days after the diagnosis she became febrile and severely neutropenic and was empirically treated with piperacillin/ tazobactam plus amikacin. Because of persisting fever after 6 days she was given amphotericin B 50 mg intravenously as a 1 h infusion. Immediately after the infusion sinus bradycardia developed (34/min). An electrocardiogram did not show additional abnormalities and the patient had no symptoms related to the arrhythmia. She had a serum sodium of 136 mmol/l, potassium 3 mmol/1, and calcium 2-3 mmol/l, and her serum creatinine was 92 p.tnol/1. The heart rate returned to normal over the next 6 hours without any specific therapy. The same thing happened on the next two occasions when rapid administration of amphotericin B was given, and this treatment was therefore discontinued. No further arrhythmias were observed. The most commonly reported cardiovascular effects of amphotericin B are tachycardia and changes in blood pressure.3 Sinus bradycardia seems to be an exceedingly uncommon complication, although it has been observed in dogs given high doses,4and cardiac arrest after bradycardia has been observed in two fatal cases of amphotericin overdose in premature infants.5 The rapid 1 h infusion in our patient could have contributed. Ventricular fibrillation has been reported after rapid infusions of the drug, especially in patients with renal insufficiency.6 Evaluations of the safety of 1 h infusions do not permit definitive conclusions about
373
cardiovascular side-effects.7Nevertheless, bradycardia was not mentioned. The sequence of events in this case strongly implicates amphotericin B as the cause of the self-limiting bradycardia. In contrast to other reported cases of arrhythmia, potentially cardiotoxic agents were not used. The amount of mitoxantrone seems too small to have contributed to this patient’s bradycardia. Haematology and Clinical Pharmacology Services, Hospital General Vall d’Hebron, 08035 Barcelona, Spain
JUAN A. SOLER LUISA IBAÑEZ JAVIER ZUAZU ANTONI JULIÀ
1. Walker R, Milford D, Derbyshire P. Bradycardia after amphotericin, irradiation, and anthracycline. Lancet 1992; 340: 380. 2. Bethell H, Grace AA, Hall JA, Petch MC, Schofield PM. Bradycardia due to anthracyclines. Lancet 1992; 340: 858. 3. Cohen J. Antifungal chemotherapy. Lancet 1982; ii: 532-36. 4. Butler WT, Bennet JE, Hill GJ, Szwed CF, Cotlove E. Electrocardiographic and electrolytic abnormalities caused by amphotericin B in dog and man. Proc Soc Exp Biol Med 1964; 116: 857-63. 5. Perlman JM, Acarregui M, Gard JW. Fatal overdose of amphotericin B in two preterm infants. Develop Pharm Therap 1992; 17: 187-90. 6. Craven PC, Gremillion DH. Risk factors of ventricular fibrillation during rapid amphotericin B infusion. Antimicrob Agents Chemother 1985; 27: 868-71. 7. Oldfield EC, Garst PD, Hostettler C, White M, Samuelson D. Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion rates. Antimicrob Agents Chemother 1990; 34: 1402-06. 8. Ellis ME, Al-Hokail AA, Clink HM, et al. Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrob Agents Chemother 1992; 36: 172-79. 9. Cruz JM, Peacock JE Jr, Loomer L, et al. Rapid intravenous infusion of amphotericin B: a pilot study. Am J Med 1982; 93: 123-30.
Distress due to venepuncture SIR,-Your Jan 30 note on this topic confirms our misgivings about the interpretation of the British Paediatric Association (BPA) guidelines for the ethical conduct of medical research in children. Anyone working with children will know that experienced personnel using modem aids such as anaesthetic creams can make blood sampling by capillary or venepuncture a procedure of minimal risk to most infants and children. It may cause transient pain, but with preparation of both child and parents and a sympathetic and confident operator we doubt if the experience should rate highly in a child’s vicissitudes-of-life scale. A presidential commentary was added to the BPA guidelines; its aim was to remind less experienced investigators and members of research ethics committees (RECs) that there may be instances when a child (or an adult) is upset or apprehensive about blood-taking to a degree that amounts to dissent, but that these are exceptions which should not over-ride the commonplace observation that blood sampling is a minimal risk rather than low-risk procedure. Both sentimentality and insensitivity are unhelpful attitudes in responsible and medical care of children. Treatment of sick children is critically dependent on knowledge of the range of normality at various ages and child reference ranges often differ substantially from those in adults. Furthermore paediatricians are often hampered by lack of knowledge about drug-handling in infants and children-information which must usually be obtained by non-therapeutic research. (A recent example has been the debate about the safety of vitamin K: in a wise editorial Sir David Hull1 referred to blood concentrations of vitamin K in newborn babies. These results2 were obtained by analysis of non-therapeutic venepuncture samples taken from babies who had been given oral or intramuscular vitamin K.) Such research in children is essential to their health and welfare and it is arrogant to assume that they are less altruistic than the adults they become. We believe that neither children nor adults should be used as a means to an end; well-conducted research allows individuals, either through personal or proxy informed consent, to experience the satisfaction of participating in an exercise whose aim is to benefit their fellows and perhaps themselves. Children should be denied this experience no less than adults. The Paediatric Advisory Subcommittee of the South Western Region has warmly endorsed the statement of the BPA Council that, in the analysis of the benefit and risk ratio, the obtaining of blood samples for a properly constituted research programme was
likely to be a minimal-risk rather than low-risk procedure. The BPA ethical guidelines are a helpful resource for those involved in research with children and we hope that ambiguity in their interpretation does not inhibit ethical research in children, whose interests we all try to serve. University of Bristol, Institute of Child Health, Royal Hospital for Sick Children, Bristol BS2 8BJ, UK
M. G. MOTT
Southmead Bristol
T. L. CHAMBERS
Hospital,
1. Hull D. Vitamin K and childhood cancer. BMJ 1992; 305: 326-27. 2. McNinch AW, Upton C, Samuels M, et al. Plasma concentrations after oral
or
intramuscular vitamin K1 in neonates. Arch Dis Child 1985; 60: 814-18.
Traditional and molecular
cytogenetics in prenatal diagnosis
SIR,-Dr Berry and colleagues (Nov 28, p 1361) point out that a higher chromosome resolution is usually obtained by investigation of cultured blood lymphocytes rather than amniocytes, so there is a risk of underdiagnosis of subtle structural chromosome abnormalities of clinical relevance by the technology used for the routine cytogenetic prenatal screening programme. We agree that this is an important notion and have for 4 years added a rider to this effect to all our prenatal reports, which reads "there is a residual small risk of a minor structural chromosome abnormality, which may remain undetected". Initially this rider created some alarm among obstetricians, which, however, soon settled. Have any other laboratories
introduced the same policy? We are aware of only one case of a structural chromosome abnormality that was not detected by chromosome analysis of amniocytes in a total of 13 000 prenatal diagnoses in our laboratory (del,15ql2 in a child with Prader-Willi
syndrome). Berry et al also comment that the risk of such underdiagnosis especially affects the prenatal screening programme for maternal age, where the major concern is trisomies such as in Down’s syndrome, and the diagnosis of structural chromosome abnormalities is a byproduct of the technique. In the past there has been no way of identifying trisomies other than by analysis of whole chromosome complements in metaphases from in-vitro cultured amniocytes. However, it is now possible to diagnose the common trisomies by interphase analysis with fluorescence in-situ hybridisation (FISH), this is a new molecular cytogenetic technique with the advantage that it is very much more rapid than traditional analyses because tissue culture is not needed. Thus the time-lag between amniocentesis and chromosomal diagnosis may be reduced from weeks to a day or, at most, a few days. Whether or not it is a disadvantage that this technology is more selective, diagnosing only those numerical chromosome abnormalities, for which the specific probes are used, is a matter for discussion. Regional Genetic Laboratory and Consultancy Services, East Birmingham Hospital, Birmingham B9 5ST, UK 1.
MAJ HULTÉN PAUL LEEDHAM
Klinger K, Landes G, Shook D, et al. Rapid detection of chromosome aneuploidies in uncultured amniocytes by using fluorescence in situ hybridization (FISH). Am J Hum Genet 1992; 51: 55-56.
Is it time for
population-based prenatal screening for fragile-X?
SiR,—The fragile-X phenotype is associated with an abnormally high number of repeating CGG sequences on one of the X-chromosomes. The number of those repeating sequences can be estimated with DNA analysis to assess whether an individual is unaffected, a carrier (pre-mutation), or affected (full mutation).1-3 When a female carrier’s X-chromosome with the pre-mutation is present in the fertilised ovum, the number of CGG sequences can further increase, leading to a full mutation in the offspring. This does not happen when the pre-mutation X-chromosome is contributed by the man (normal transmitting male). Furthermore,
determine a causal relation between pravastatin therapy and depression from experience in 4 patients followed for a short time. Neither our controlled studies nor our marketed product experience in a large number of patients indicate that treatment with pravastatin is associated with an increased risk of symptoms of depression. We will continue to monitor the Bristol-Myers Squibb world-wide drug-safety database for any new relevant information.
to
Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543, USA
KENNETH B. KASSLER-TAUB TREVOR WOODWARD JEFFREY S. MARKOWITZ
JK, et al. Six-month prevalence of psychiatric disorders in three communities. Gen Psychiatry 1984; 41: 959-67.
1. Myers
Neuropsychiatric symptoms during treatment with interleukin-2 and
interferon-&agr; SiR,—Neuropsychiatric symptoms during the treatment of metastatic cancers with high-dose intravenous recombinant interleukin-2 are common and often treatment-limiting. In a survey of 652 patients thus treated, a third became disoriented and 5 % had frank coma.1 Denicoffet al2 reported severe cognitive changes in 22 of 44 patients treated with intravenous bolus injections of interleukin-2. Agitation and delusions were frequent. Predominantly hallucinatory syndromes have also been reported.3 The vascular leak syndrome, one of the major toxicities of systemic high-dose interleukin-2, induces profound changes in cardiovascular and renal function, resulting in dyspnoea at rest, anuria, and hypotension requiring vasopressors.4 The vascular leak syndrome may also be responsible for the increases in brain water-content after treatment with interleukin-2, which can be demonstrated by nuclear magnetic resonance imaging.s These mechanisms may contribute to the observed changes in mental status. Interferon-a also causes neuropsychiatric symptoms,6 but the underlying pathophysiology is unknown. We report our experience in 101 patients with progressive metastatic renal cell carcinoma, who were treated with subcutaneous interleukin-2 and interferon-ot2b with or without subsequent intravenous 5-fluorouracil on an outpatient basis. Mean age was 57-4 years and 72 patients were male. All patients had normal computed tomography (CT) of the brain and no evidence of central nervous system disease before therapy. 4 patients had undergone resection of brain metastases. All patients received subcutaneous injections of 3 x 6 MU/m recombinant interferona2b (Schering-Plough) with 3 x 5-20 MID /m2 recombinant interleukin-2 (Eurocetus), both weekly, for at least 4 consecutive weeks per course. In 48 patients this schedule was followed by 3 x 6 MD /m2 recombinant interferon-%b with 750 mg/m2 5-fluorouracil every week for 4 weeks. 161 treatment courses were given. Neuropsychiatric toxicity was evaluated for every treatment week. Statistical analysis was by t and X2 tests. Minor or major difficulties in concentration were observed in 34 and 5 patients, respectively. 5 patients were transiently disoriented during therapy. Coma or seizures were not observed. 37 patients complained about mild paraesthesias, 4 patients had transient muscle weakness, and 1 patient had hemiparesis. Therapy was discontinued in all 6 patients with disorientation or hemiparesis, with only 1 patient in the first treatment course. CT revealed brain metastases in the patient with hemiparesis and in 1 with disorientation. No abnormality was detected in the other 4 patients with treatment-limiting toxicity. Neuropsychiatric symptoms in these patients usually resolved within 6 h after discontinuation of treatment, but persisted for 3 days in 1 patient. None of the patients with treatment-limiting neurotoxicity developed major signs of vascular leakage. Age, sex, and the sequential use of chemotherapy were not statistically associated with the development of neuropsychiatric symptoms. Paraesthesias but not difficulties in concentration were more common during the second or third course (p < 0-05). All 4 patients with resected brain metastases developed neuropsychiatric symptoms, including disorientation in 1.
Treatment-limiting neuropsychiatric symptoms during this outpatient regimen occurred less often than in patients treated with high-dose intravenous interleukin-2, resolved spontaneously after discontinuation of treatment, and may have indicated brain Thus, given the therapeutic efficacy of low-dose subcutaneous interleukin-2 in combination with interferon in renal cancer patients,’ therapeutic doses of interleukin-2 and interferon-a may not necessarily be associated with a high frequency of severe neuropsychiatric symptoms. MARTIN H. FENNER ENRIQUE LOPEZ HÄNNINEN HARTMUT H. KIRCHNER Departments of Haematology and Oncology, HUBERT POLIWODA Medizinische Hochschule Hannover, 3000 Hannover 61, Germany JENS ATZPODIEN
metastases.
Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high dose interleukin-2 based therapies in the treatment of 652 patients with cancer. Ann Surg 1989; 210: 274-85. 2. Denicoff KD, Rubinow DR, Papa MZ, et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 1987; 1.
107: 293-300. 3. Smith MJ, Khayat D. Residual acute confusional and
4. 5.
6. 7.
hallucinatory syndromes
induced by interleukin-2/&agr;-interferon treatment. Psycho-Oncology 1992; 1: 115-18. Adams F, Quesada JR, Gutterman JU. Neuropsychiatric manifestations of human leucocyte interferon therapy in patients with cancer. JAMA 1984; 252: 938-42. Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol 1991; 9: 694-704. Saris SC, Patronas NJ, Rosenberg SA, et al. The effect of intravenous interleukin-2 on brain water content. J Neurosurg 1989; 71: 169-74. Atzpodien J, Körfer A, Francks CR, Poliwoda H, Kirchner H. Home therapy with recombinant interleukin-2 and interferon-&agr;2b in advanced human malignancies. Lancet 1990; 335: 1509-12.
Bradycardia after rapid intravenous infusion of amphotericin B SIR,-Walker and colleagues1 have reported bradycardia in a 5 2 year-old boy given intravenous amphotericin B. This patient received a total anthracycline dose of 350 mg/m2 and total body irradiation and cyclophosphamide as conditioning for autologous bone marrow transplantation. The suggestion was that the arrhythmia resulted from the administration of amphotericin B in a patient with myocardial damage due to irradiation and cytotoxic drugs. Bethell and co-workers2 subsequently reported three cases of bradycardia after anthracyclines; in two the administration of amphotericin seemed to trigger the arrhythmia. We report a case of bradycardia related to the rapid intravenous infusion of amphotericin B, without involvement of other potentially cardiotoxic agents. A 56-year-old woman with no history of cardiac disease was given mitoxantrone (17 mg daily for 3 days) and cytarabine (280 mg daily for 7 days) for first induction therapy for acute myeloblastic leukaemia. 5 days after the diagnosis she became febrile and severely neutropenic and was empirically treated with piperacillin/ tazobactam plus amikacin. Because of persisting fever after 6 days she was given amphotericin B 50 mg intravenously as a 1 h infusion. Immediately after the infusion sinus bradycardia developed (34/min). An electrocardiogram did not show additional abnormalities and the patient had no symptoms related to the arrhythmia. She had a serum sodium of 136 mmol/l, potassium 3 mmol/1, and calcium 2-3 mmol/l, and her serum creatinine was 92 p.tnol/1. The heart rate returned to normal over the next 6 hours without any specific therapy. The same thing happened on the next two occasions when rapid administration of amphotericin B was given, and this treatment was therefore discontinued. No further arrhythmias were observed. The most commonly reported cardiovascular effects of amphotericin B are tachycardia and changes in blood pressure.3 Sinus bradycardia seems to be an exceedingly uncommon complication, although it has been observed in dogs given high doses,4and cardiac arrest after bradycardia has been observed in two fatal cases of amphotericin overdose in premature infants.5 The rapid 1 h infusion in our patient could have contributed. Ventricular fibrillation has been reported after rapid infusions of the drug, especially in patients with renal insufficiency.6 Evaluations of the safety of 1 h infusions do not permit definitive conclusions about
373
cardiovascular side-effects.7Nevertheless, bradycardia was not mentioned. The sequence of events in this case strongly implicates amphotericin B as the cause of the self-limiting bradycardia. In contrast to other reported cases of arrhythmia, potentially cardiotoxic agents were not used. The amount of mitoxantrone seems too small to have contributed to this patient’s bradycardia. Haematology and Clinical Pharmacology Services, Hospital General Vall d’Hebron, 08035 Barcelona, Spain
JUAN A. SOLER LUISA IBAÑEZ JAVIER ZUAZU ANTONI JULIÀ
1. Walker R, Milford D, Derbyshire P. Bradycardia after amphotericin, irradiation, and anthracycline. Lancet 1992; 340: 380. 2. Bethell H, Grace AA, Hall JA, Petch MC, Schofield PM. Bradycardia due to anthracyclines. Lancet 1992; 340: 858. 3. Cohen J. Antifungal chemotherapy. Lancet 1982; ii: 532-36. 4. Butler WT, Bennet JE, Hill GJ, Szwed CF, Cotlove E. Electrocardiographic and electrolytic abnormalities caused by amphotericin B in dog and man. Proc Soc Exp Biol Med 1964; 116: 857-63. 5. Perlman JM, Acarregui M, Gard JW. Fatal overdose of amphotericin B in two preterm infants. Develop Pharm Therap 1992; 17: 187-90. 6. Craven PC, Gremillion DH. Risk factors of ventricular fibrillation during rapid amphotericin B infusion. Antimicrob Agents Chemother 1985; 27: 868-71. 7. Oldfield EC, Garst PD, Hostettler C, White M, Samuelson D. Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion rates. Antimicrob Agents Chemother 1990; 34: 1402-06. 8. Ellis ME, Al-Hokail AA, Clink HM, et al. Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrob Agents Chemother 1992; 36: 172-79. 9. Cruz JM, Peacock JE Jr, Loomer L, et al. Rapid intravenous infusion of amphotericin B: a pilot study. Am J Med 1982; 93: 123-30.
Distress due to venepuncture SIR,-Your Jan 30 note on this topic confirms our misgivings about the interpretation of the British Paediatric Association (BPA) guidelines for the ethical conduct of medical research in children. Anyone working with children will know that experienced personnel using modem aids such as anaesthetic creams can make blood sampling by capillary or venepuncture a procedure of minimal risk to most infants and children. It may cause transient pain, but with preparation of both child and parents and a sympathetic and confident operator we doubt if the experience should rate highly in a child’s vicissitudes-of-life scale. A presidential commentary was added to the BPA guidelines; its aim was to remind less experienced investigators and members of research ethics committees (RECs) that there may be instances when a child (or an adult) is upset or apprehensive about blood-taking to a degree that amounts to dissent, but that these are exceptions which should not over-ride the commonplace observation that blood sampling is a minimal risk rather than low-risk procedure. Both sentimentality and insensitivity are unhelpful attitudes in responsible and medical care of children. Treatment of sick children is critically dependent on knowledge of the range of normality at various ages and child reference ranges often differ substantially from those in adults. Furthermore paediatricians are often hampered by lack of knowledge about drug-handling in infants and children-information which must usually be obtained by non-therapeutic research. (A recent example has been the debate about the safety of vitamin K: in a wise editorial Sir David Hull1 referred to blood concentrations of vitamin K in newborn babies. These results2 were obtained by analysis of non-therapeutic venepuncture samples taken from babies who had been given oral or intramuscular vitamin K.) Such research in children is essential to their health and welfare and it is arrogant to assume that they are less altruistic than the adults they become. We believe that neither children nor adults should be used as a means to an end; well-conducted research allows individuals, either through personal or proxy informed consent, to experience the satisfaction of participating in an exercise whose aim is to benefit their fellows and perhaps themselves. Children should be denied this experience no less than adults. The Paediatric Advisory Subcommittee of the South Western Region has warmly endorsed the statement of the BPA Council that, in the analysis of the benefit and risk ratio, the obtaining of blood samples for a properly constituted research programme was
likely to be a minimal-risk rather than low-risk procedure. The BPA ethical guidelines are a helpful resource for those involved in research with children and we hope that ambiguity in their interpretation does not inhibit ethical research in children, whose interests we all try to serve. University of Bristol, Institute of Child Health, Royal Hospital for Sick Children, Bristol BS2 8BJ, UK
M. G. MOTT
Southmead Bristol
T. L. CHAMBERS
Hospital,
1. Hull D. Vitamin K and childhood cancer. BMJ 1992; 305: 326-27. 2. McNinch AW, Upton C, Samuels M, et al. Plasma concentrations after oral
or
intramuscular vitamin K1 in neonates. Arch Dis Child 1985; 60: 814-18.
Traditional and molecular
cytogenetics in prenatal diagnosis
SIR,-Dr Berry and colleagues (Nov 28, p 1361) point out that a higher chromosome resolution is usually obtained by investigation of cultured blood lymphocytes rather than amniocytes, so there is a risk of underdiagnosis of subtle structural chromosome abnormalities of clinical relevance by the technology used for the routine cytogenetic prenatal screening programme. We agree that this is an important notion and have for 4 years added a rider to this effect to all our prenatal reports, which reads "there is a residual small risk of a minor structural chromosome abnormality, which may remain undetected". Initially this rider created some alarm among obstetricians, which, however, soon settled. Have any other laboratories
introduced the same policy? We are aware of only one case of a structural chromosome abnormality that was not detected by chromosome analysis of amniocytes in a total of 13 000 prenatal diagnoses in our laboratory (del,15ql2 in a child with Prader-Willi
syndrome). Berry et al also comment that the risk of such underdiagnosis especially affects the prenatal screening programme for maternal age, where the major concern is trisomies such as in Down’s syndrome, and the diagnosis of structural chromosome abnormalities is a byproduct of the technique. In the past there has been no way of identifying trisomies other than by analysis of whole chromosome complements in metaphases from in-vitro cultured amniocytes. However, it is now possible to diagnose the common trisomies by interphase analysis with fluorescence in-situ hybridisation (FISH), this is a new molecular cytogenetic technique with the advantage that it is very much more rapid than traditional analyses because tissue culture is not needed. Thus the time-lag between amniocentesis and chromosomal diagnosis may be reduced from weeks to a day or, at most, a few days. Whether or not it is a disadvantage that this technology is more selective, diagnosing only those numerical chromosome abnormalities, for which the specific probes are used, is a matter for discussion. Regional Genetic Laboratory and Consultancy Services, East Birmingham Hospital, Birmingham B9 5ST, UK 1.
MAJ HULTÉN PAUL LEEDHAM
Klinger K, Landes G, Shook D, et al. Rapid detection of chromosome aneuploidies in uncultured amniocytes by using fluorescence in situ hybridization (FISH). Am J Hum Genet 1992; 51: 55-56.
Is it time for
population-based prenatal screening for fragile-X?
SiR,—The fragile-X phenotype is associated with an abnormally high number of repeating CGG sequences on one of the X-chromosomes. The number of those repeating sequences can be estimated with DNA analysis to assess whether an individual is unaffected, a carrier (pre-mutation), or affected (full mutation).1-3 When a female carrier’s X-chromosome with the pre-mutation is present in the fertilised ovum, the number of CGG sequences can further increase, leading to a full mutation in the offspring. This does not happen when the pre-mutation X-chromosome is contributed by the man (normal transmitting male). Furthermore,