Short-term propofol infusions in children

have been treated with similar radiotherapy and surgical techniques. The only difference in treatment between the groups was the adjuvant systemic therapy. All premenopausal women received chemotherapy and all postmenopausal women received tamoxifen: the explanation for why the postmenopausal women do not show better control rates in this trial probably lies here. If hormone receptor status had been determined for all postmenopausal patients and if those who were receptor negative had received chemotherapy, the control rates could have been improved. Rose and colleagues3 have shown that when cyclophosphamide, methotrexate, and 5-fluorouracil, and tamoxifen were given, overall survival and local control were not improved. However, unless hormone receptor status is measured and receptor-negative patients selected for chemotherapy, a benefit may not be readily evident. The large number of hormone-positive patients that are likely in the postmenopausal group would otherwise dilute any benefit from chemotherapy. S Sarat Chander Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India 400 012 (e-mail: [email protected]) 1

2

3

Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999; 353: 1641–48. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997; 337: 949–55. Rose C, Hansen PS, Dombernowsky P, et al. A randomized DBCG trial of adjuvant tamoxifen (TAM)+radiotherapy vs TAM alone vs TAM+CMF in postmenopausal breast cancer patients with high risk of recurrence. Eur J Cancer 1994; 30A (suppl 2): S28.

Authors’ reply Sir—In reply to I H Kunkler, we do not have prospectively recorded details about the type of locoregional failure (spot, multiple spot, or field change type). Further, we did not record the extent of salvage treatment or the course of the disease after first recurrence. Therefore, we cannot provide the curves for cumulative metastases-free and cumulative locoregional recurrence-free survival in the two groups. However, the pattern of dissemination and survival after isolated locoregional recurrence has been described in similar high risk patients included in the 82c trial, together with the failure pattern in patients belonging to a low-risk group.1 Overall, this analysis indicated that loco-

866

regional recurrences in high-risk patients (stage II or III) are much more aggressive than locoregional recurrences in low-risk patients with respect to time to development of recurrence and prognosis irrespective of primary treatment. Our table 4 shows that although locoregional recurrences are much less frequent in irradiated patients, they seem to carry a poorer prognosis, since the proportion of patients with concurrent distant metastases is larger in the irradiated group than in the nonirradiated group. This finding means that patients who recur locoregionally after initial optimum locoregional and systemic treatment seem to be the really poor prognostic group that is resistant to salvage treatment. This poor outlook might also hold true for a similar proportion of non-irradiated patients, whereas the rather large proportion of patients in whom locoregional recurrences could have been prevented by initial irradiation seems to belong to a more favourable prognostic group in which to obtain optimum locoregional control matters. Carl Atkins correctly points to the importance of radiation-induced morbidity. The analyses of cardiac morbidity and mortality in both the 82b and the 82c trials have now been completed.2 The results show no evidence of increased ischaemic heart disease or mortality in irradiated patients compared with non-irradiated patients. Further long-term morbidity, especially lymphoedema and impairment of shoulder movement have been evaluated in some patients included in the two protocols.3 With respect to Sarat Chander, unfortunately hormone receptor status was not available for all patients in the 82c trial but analyses of the data are in progress. Data from 82b trial have been analysed with respect to the effect of hormone receptor status in relation to chemotherapy with and without endocrine therapy and with and without locoregional radiotherapy.4 These results, similarly to the preliminary results from 82c trial, as cited by Chander, indicate that more extensive systemic treatment can not sufficiently prevent locoregional recurrences, and that hormone receptor status is appropriate to obtain to find the most effective systemic treatment. Again these data also clearly show the need for a treatment strategy that can assure both the best locoregional tumour control and systemic tumour control. Marie Overgaard Department of Oncology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark (e-mail: [email protected])

1

Kamby C, Sengeløv L. Patterns of dissemination and survival following isolated loco regional recurrence of breast cancer. Breast Cancer Res Treat 1997; 45: 181–92. 2 Højris I, Overgaard M, Juul Christensen J, Overgaard J. Morbidity and mortality of ischaemic heart disease in high-risk breast cancer patients after adjuvant systemic treatment with or without postmastectomy irradiation: analysis of the DBCG 82b and c radiotherapy trials. Lancet (in press). 3 Højris I, Andersen J, Overgaard M, Overgaard J. Late treatment related morbidity in breast cancer patients randomized to postmastectomy radiotherapy and systemic treatment versus systemic treatment alone. Acta Oncologia (in press). 4 Andersson M, Kamby C, Jensen M-B, et al. Tamoxifen in high-risk premenopausal women with primary breast cancer receiving adjuvant chemotherapy. Report from the Danish Breast Cancer Co-operative Group DBCG 82b Trial. Eur J Cancer (in press).

Short-term propofol infusions in children Sir—In his April 3 commentary,1 David Hatch states that avoidance of highdose, long-term infusions of propofol in paediatric practice is sensible. Although we support this view, we would like to emphasise that low-dose infusions given for short periods in children are not necessarily safe. We report the admission to our paediatric intensivecare unit of an 18-month-old child who had features of propofol infusion syndrome after a 5 h infusion of propofol. This child, who was born with arthrogryposis multiplex congenita, underwent elective surgery for bilateral talipes correction under general anaesthesia with propofol and a laryngeal mask airway. After an initial bolus she received an infusion of propofol for 5 h at a mean hourly rate of 6 mg/kg. After surgery, percutaneous oxygen saturation fell and blood-gas analysis indicated metabolic acidosis. She required emergency endotracheal intubation and positive-pressure ventilation, although she had no loss of cardiac output. A chest radiograph was consistent with acute lung injury and pulmonary aspiration of gastric contents. Metabolic acidosis was severe and required constant bicarbonate infusion for 36 h. The calculated base deficit was 17 mmol/L with a measured anion gap of 21 mmol/L and serum lactate concentration of 3·4 mmol/L. The child developed persistent arrhythmias, predominantly bradyarrhythmias, and required volume resuscitation and inotropic support. She developed oligoanuria requiring peritoneal dialysis

THELANCET • Vol 354 • September 4, 1999

and required mechanical ventilation for 14 days. Serum triglyceride concentration on the day of admission was high (3·4 mmol/L). Serum concentrations of aminoacids and organic acids were normal. Because of her arthrogryposis, a muscle biopsy was done, which showed decreased complex IV activity, cytochrome oxidase ratio 0·004 (reference range 0·014–0·034), and suggested possible mitochondrial respiratory-chain enzyme deficiency. These results were interpreted with caution because the sample had a high fat content. Urine was negative for myoglobin, and microbiological and virological tests were negative. The child’s clinical features (lactic acidosis, myocardial failure, renal failure, and hypertriglyceridaemia) are consistent with propofol infusion syndrome.2 However, our report like previous reports shows little evidence to prove a direct link between propofol and multisystem illness. Cray and reported a similar colleagues3 idiosyncratic multisystem reaction to propofol and detected an unknown compound in the child’s blood, which they presumed to be a metabolite of propofol. Furthermore, sepsis, malignant hyperthermia, and hypoxia may have contributed. The presence of arthrogryposis in our case suggests an underlying neuromuscular defect, although results of tests on muscle were inconclusive. Cray and colleagues also described a mitochondrial respiratorychain defect but suggested that it was a possible mechanism of damage caused by propofol rather than an underlying neuromuscular defect. Genetic predisposition in certain children may render them susceptible to an often fatal idiosyncratic reaction in response to propofol infusion. Complete recovery after supportive care also suggests a toxin-mediated illness in our patient. Although there are reports on the safe use of propofol in children, the adverse reactions to propofol cannot be ignored. As is the case with so many other nonlicensed drugs in paediatric practice, propofol infusions in children need to be the subject of a controlled trial. Nilesh Mehta, Claudine DeMunter, Parviz Habibi, Simon Nadel, *Joseph Britto Department of Paediatrics, Imperial College School of Medicine at St Mary’s Hospital, London W2 1NY, UK (e-mail: [email protected]) 1 2 3

Hatch DJ. Propofol infusion syndrome in children. Lancet 1999; 353: 1117–18. Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth 1998; 8: 491–99. Cray SH, Robinson BH, Cox PN. Lactic acidemia and bradyarrhythmia in a child sedated with propofol. Crit Care Med 1998; 26: 2087–92.

THELANCET • Vol 354 • September 4, 1999

Acute coronary syndromes Sir—The unresolved debate about primary-invasive approach versus primary-medical approach in patients who present with an acute coronary syndrome is clearly shown by the opposing statements in The Lancet’s June supplement on this challenging topic. Freek Verheught (June 12, suppl II, p 16)1 states that: “This applies both to the high-risk patients, in whom a routine invasive strategy of this approach may be harmful (for example, in VANQWISH)”. By contrast, if Joseph Delehanty and colleagues (June 12, p 24)2 had an acute coronary syndrome, they would favour an invasive strategy: “Individuals at high risk of myocardial infarction or death should undergo an early invasive intervention”. If I had an acute coronary syndrome, I would hopefully have the opportunity to decide on the unanimous results of trials that compare these different approaches. Hannes Gaenzer Department of Internal Medicine, University of Innsbruck, 6020 Innsbruck, Austria 1

2

Verheught FWA. Acute coronary syndromes: interventions. Lancet 1999; 363 (suppl II): 16–19. Delehanty JM, Ling FS, Berk BC. If I had an acute coronary syndrome. Lancet 1999; 353 (suppl II): 24–26.

Sir—In the well-crafted review and update on the diagnosis of acute coronary syndromes by Peter Klootwijk and Christian Hamm (p 10)1 I found an unexpected phrase that I cannot let pass without retort. They point out that physicians can now use rapid testing systems for troponins at the bedside and generate test results within 15–20 min. I disagree with their indication that pointof-care testing in a hospital setting is typically done “independent of a clinical chemistry facility”. Whether at a bedside, an emergency room, or in a laboratory, I expect that qualitative or quantitative biochemical tests used to support medical decisions should be assessed and implemented with the cooperation and guidance of laboratory staff. The laws and regulations surrounding the legal need to involve the clinical laboratory in bedside testing vary in different countries and locales. Consultation of laboratory physicians and clinical scientists is particularly relevant for the implementation of cardiac troponin-I testing and the establishment of interpretation thresholds, because of variation between manufacturers that generates from two-fold to more than 20-fold differences in concentration.2 As a consequence of this variation the value

of troponin tests shown in clinical trials is mostly manufacturer-specific. Qualitative tests are not exempt from standardisation issues, because they are designed to indicate positive or negative results at a concentration threshold that is prone to this variability. I sympathise with the investigators because these analytical issues are difficult to convey when reviewing the outcomes of clinical trials. I expect that through the efforts of the International Federation of Clinical Chemistry and Laboratory Medicine and other national organisations that cardiac-marker testing will soon have internationally accepted standards and I hope the codependent relationship between the laboratory and the ward staff will continue to be mutually recognised. Andrew W Lyon Department of Pathology, University of Saskatchewan and Department of Laboratory Medicine, Saskatoon District Health, Saskatoon, SK S7N 5E5, Canada (e-mail: [email protected]) 1

2

Klootwijk P, Hamm C. Acute coronary syndromes: diagnosis. Lancet 1999; 353 (suppl II): 10–15. Apple FS. Clinical and analytical standardization issues confronting cardiac troponin I. Clin Chem 1999; 45: 18–19.

Lipodystrophy in HIV-1infected patients Sir—Andrew Carr and colleagues (June 19, p 2093)1 report the results of a longitudinal study of 113 HIV-1infected patients who were receiving protease inhibitors and were followed up for 21 months (92 cases of lipodystrophy) and 45 treatment-naïve patients who were followed up for 28 months (one case of lipodystrophy). They propose a classification of lipodystrophy associating the clinical anomalies with metabolic disorders that would make the results of different studies sufficiently homogeneous for comparisons to be made. Comparison between patients with and without lipodystrophy showed that the former had taken protease inhibitors and had been HIV-1-seropositive for longer, but that their CD4-cell counts and virus loads were similar. Development of lipodystrophy did not seem to be associated with the particular protease inhibitor used, but onset was more rapid with ritonavir or saquinavir. Some of our findings corroborate those of Carr and colleagues. We used the same clinical (with patients selfreporting) and biological selection criteria, and diagnosed 61 (26·2%) lipodystrophy cases among our 233

867