437
fenoterol could be due to it decreasing the risk of hospital admission rather than increasing the risk of death. Though this possibility has to be considered, there is little evidence to support it. In the second but not the first study fenoterol was associated with a lower frequency of prior admission in controls. The striking fmding is that in patients with one or more of the risk factors (prior admission, oral steroids, or three or more drugs), those who were also prescribed fenoterol show a reversal of the pattern-ie, their risk of death increased much more than their risk of hospital admission. To dismiss the hypothesis that fenoterol is in some way responsible for this increase in death rate, we need a counter-hypothesis that can be supported by the data. There is no evidence that patients prescribed oral steroids and fenoterol have more severe asthma than patients prescribed steroids alone. If fenoterol is either an effective drug, or a drug used in the competent therapy of severe asthmatics, it should show a similar pattern of association to oral steroids. It shows a very different pattern, being more commonly prescribed for asthmatic patients who subsequently die. The New Zealand studies would be helped by having information on factors which have been shown to differ between deaths and hospital admissions, such as previous respiratory arrests and life-threatening attacks, and psychosocial factors.4 These may be good measures of residual confounding for the comparison that has been made. The studies would be also helped by having a sample representative of the inception cohort of patients with asthma, but the extra confounding introduced would need to be carefully controlled. The arguments against the causal interpretation of these studies depend more on their limitations, in that much more information is desirable, than on objective evidence pointing to a non-causal explanation, and the studies leave many important issues unresolved.1 However, given the lack of strong evidence of clinical advantages of the drug in relation to alternatives, the actions taken in New Zealand and Australia to restrict its use seem
prudent.
Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
J. MARK ELWOOD
JM. Prescribed fenoterol and deaths from asthma m New Zealand: second report Wellington New Zealand Department of Health, 1989. 2 Pearce NE, Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-1981. Thorax 1990; 45: 170-75. 3 Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-82 case-control study. Lancet 1989; i: 917-22. 4 Rea HH, Scragg R, Jackson R, Beaglehole R, Fenwick J, Sutherland DC. A case-control study of deaths from asthma. Thorax 1986, 41: 833-39. 1 Elwood
Controlled release
prostaglandin E2 pessaries
SIR,-Following publication of two letters in The Lancet of July 14 (p 119) reporting difficulties with controlled release prostaglandin E2 pessaries (’Propess’), Roussel Laboratories withdrew the product, with immediate effect, on July 19. The company cited the incidence of maternal and fetal complications and difficulties in retrieving the pessary. Dr Khouzam and Dr Ledward report adverse reactions in three
patients and suggest that "dose dumping" is frequent with these pessaries even though they are marketed as slow-release
preparations. Dumping would be substantiated if high levels of prostaglandin E2 and its metabolites were shown to accumulate rapidly in vivo, but this explanation has yet to be confirmed. We used propess pessaries in 41 women. At first we used them in 22 primigravidae of average age 24 with a mean gestation and Bishop score of 40 weeks and 4, respectively. The interval between insertion and delivery averaged 21-4 h and labour lasted 877 h. Oxytocin was required in 8 patients. 16 women had spontaneous vertex deliveries, 3 were delivered by caesarean section,1 by assisted breech delivery,I by forceps, and 1 by vacuum extraction. There were no cases of uterine hypertonicity or fetal distress attributable to the pessaries. Recovery was easy in 14 women and difficult in 3; the pessary was expelled at full dilatation in 1 woman but it was not recovered in 4 patients despite a thorough search. At that stage we expressed our concern to Roussel and suggested that a string be attached. Since that initial experience we extended use to multigravidae. 19
multigravidae with an average Bishop score of 4 have been induced and all had spontaneous vertex deliveries. In 3 women the labour was rapid with progress from 3 cm to full dilatation in less than 2 h. There was 1 case of fetal distress; the baby had trisomy 13. In
induction to delivery averaged 11-3 h. Propess recovery easy in 13 of these women. 1 woman reported losing the pessary when she went to the toilet and other pessaries may have been "lost" this way without the women being aware of the fact. Our experience with these pessaries has been favourable but we do agree with your correspondents that further research is required and that a method for its safe and rapid retrieval is needed. A retrieval device is undergoing clinical evaluation. Ideally, a trial comparing the safety and efficacy of this pessary and with ’Prostin’ vaginal tablets and gel (Upjohn) should be mounted.
multigravidae, was
Freedom Fields Hospital, Plymouth PL4 7JJ, UK
W. R. BARAVILALA C. BAKER J. M. MORSMAN
In vivo assessment of N-acetylaspartate in brain in spongy degeneration (Canavan’s
disease) by proton spectroscopy SIR,-In spongy degeneration of the neuroaxis, a rare autosomal recessive disorder known as Canavan’s disease, an inborn error of myelin formation and/or glial metabolism causes vacuolisation and cystic degeneration of oligodendroglia and swelling of astrocytes. Clinically the demyelination manifests as psychomotor deterioration, blindness, and spasticity, loss of control of the characteristically enlarged head being a frequent first sign.’1 Magnetic resonance imaging (MRI) demonstrates diffuse, symmetrical abnormalities of the white-matter.2-4 Canavan’s disease has been linked with abnormally high concentrations of N-acetylaspartate (NAA) in the cerebrospinal fluid (CSF), plasma, and urine 5,6 the elevated levels of which are thought to reflect accumulation in the brain as a result of aspartoacylase deficiency.5,6 The final diagnosis can be made on clinical and biochemical fmdings, but hitherto a direct role for brain accumulation of NAA has had to be concluded from the CSF/plasma ratio of NAA (or brain biopsy). We wondered if magnetic resonance spectroscopy (MRS) would help, especially since progress in volume selection techniques7.8now permits a non-invasive biochemical tissue analysis in a clinical setting. We report here MRS studies on a 7-month-old boy with Canavan’s disease characterised by loss of head control, hypotonicity and spasticity, an increasing head circumference, diffuse hypointensity of the supratentorial white-matter, and increased levels of NAA in urine (3-5 mmol/mmol creatinine; normal
fenoterol could be due to it decreasing the risk of hospital admission rather than increasing the risk of death. Though this possibility has to be considered, there is little evidence to support it. In the second but not the first study fenoterol was associated with a lower frequency of prior admission in controls. The striking fmding is that in patients with one or more of the risk factors (prior admission, oral steroids, or three or more drugs), those who were also prescribed fenoterol show a reversal of the pattern-ie, their risk of death increased much more than their risk of hospital admission. To dismiss the hypothesis that fenoterol is in some way responsible for this increase in death rate, we need a counter-hypothesis that can be supported by the data. There is no evidence that patients prescribed oral steroids and fenoterol have more severe asthma than patients prescribed steroids alone. If fenoterol is either an effective drug, or a drug used in the competent therapy of severe asthmatics, it should show a similar pattern of association to oral steroids. It shows a very different pattern, being more commonly prescribed for asthmatic patients who subsequently die. The New Zealand studies would be helped by having information on factors which have been shown to differ between deaths and hospital admissions, such as previous respiratory arrests and life-threatening attacks, and psychosocial factors.4 These may be good measures of residual confounding for the comparison that has been made. The studies would be also helped by having a sample representative of the inception cohort of patients with asthma, but the extra confounding introduced would need to be carefully controlled. The arguments against the causal interpretation of these studies depend more on their limitations, in that much more information is desirable, than on objective evidence pointing to a non-causal explanation, and the studies leave many important issues unresolved.1 However, given the lack of strong evidence of clinical advantages of the drug in relation to alternatives, the actions taken in New Zealand and Australia to restrict its use seem
prudent.
Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
J. MARK ELWOOD
JM. Prescribed fenoterol and deaths from asthma m New Zealand: second report Wellington New Zealand Department of Health, 1989. 2 Pearce NE, Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-1981. Thorax 1990; 45: 170-75. 3 Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-82 case-control study. Lancet 1989; i: 917-22. 4 Rea HH, Scragg R, Jackson R, Beaglehole R, Fenwick J, Sutherland DC. A case-control study of deaths from asthma. Thorax 1986, 41: 833-39. 1 Elwood
Controlled release
prostaglandin E2 pessaries
SIR,-Following publication of two letters in The Lancet of July 14 (p 119) reporting difficulties with controlled release prostaglandin E2 pessaries (’Propess’), Roussel Laboratories withdrew the product, with immediate effect, on July 19. The company cited the incidence of maternal and fetal complications and difficulties in retrieving the pessary. Dr Khouzam and Dr Ledward report adverse reactions in three
patients and suggest that "dose dumping" is frequent with these pessaries even though they are marketed as slow-release
preparations. Dumping would be substantiated if high levels of prostaglandin E2 and its metabolites were shown to accumulate rapidly in vivo, but this explanation has yet to be confirmed. We used propess pessaries in 41 women. At first we used them in 22 primigravidae of average age 24 with a mean gestation and Bishop score of 40 weeks and 4, respectively. The interval between insertion and delivery averaged 21-4 h and labour lasted 877 h. Oxytocin was required in 8 patients. 16 women had spontaneous vertex deliveries, 3 were delivered by caesarean section,1 by assisted breech delivery,I by forceps, and 1 by vacuum extraction. There were no cases of uterine hypertonicity or fetal distress attributable to the pessaries. Recovery was easy in 14 women and difficult in 3; the pessary was expelled at full dilatation in 1 woman but it was not recovered in 4 patients despite a thorough search. At that stage we expressed our concern to Roussel and suggested that a string be attached. Since that initial experience we extended use to multigravidae. 19
multigravidae with an average Bishop score of 4 have been induced and all had spontaneous vertex deliveries. In 3 women the labour was rapid with progress from 3 cm to full dilatation in less than 2 h. There was 1 case of fetal distress; the baby had trisomy 13. In
induction to delivery averaged 11-3 h. Propess recovery easy in 13 of these women. 1 woman reported losing the pessary when she went to the toilet and other pessaries may have been "lost" this way without the women being aware of the fact. Our experience with these pessaries has been favourable but we do agree with your correspondents that further research is required and that a method for its safe and rapid retrieval is needed. A retrieval device is undergoing clinical evaluation. Ideally, a trial comparing the safety and efficacy of this pessary and with ’Prostin’ vaginal tablets and gel (Upjohn) should be mounted.
multigravidae, was
Freedom Fields Hospital, Plymouth PL4 7JJ, UK
W. R. BARAVILALA C. BAKER J. M. MORSMAN
In vivo assessment of N-acetylaspartate in brain in spongy degeneration (Canavan’s
disease) by proton spectroscopy SIR,-In spongy degeneration of the neuroaxis, a rare autosomal recessive disorder known as Canavan’s disease, an inborn error of myelin formation and/or glial metabolism causes vacuolisation and cystic degeneration of oligodendroglia and swelling of astrocytes. Clinically the demyelination manifests as psychomotor deterioration, blindness, and spasticity, loss of control of the characteristically enlarged head being a frequent first sign.’1 Magnetic resonance imaging (MRI) demonstrates diffuse, symmetrical abnormalities of the white-matter.2-4 Canavan’s disease has been linked with abnormally high concentrations of N-acetylaspartate (NAA) in the cerebrospinal fluid (CSF), plasma, and urine 5,6 the elevated levels of which are thought to reflect accumulation in the brain as a result of aspartoacylase deficiency.5,6 The final diagnosis can be made on clinical and biochemical fmdings, but hitherto a direct role for brain accumulation of NAA has had to be concluded from the CSF/plasma ratio of NAA (or brain biopsy). We wondered if magnetic resonance spectroscopy (MRS) would help, especially since progress in volume selection techniques7.8now permits a non-invasive biochemical tissue analysis in a clinical setting. We report here MRS studies on a 7-month-old boy with Canavan’s disease characterised by loss of head control, hypotonicity and spasticity, an increasing head circumference, diffuse hypointensity of the supratentorial white-matter, and increased levels of NAA in urine (3-5 mmol/mmol creatinine; normal
