We have monitored patients receiving subcutaneous IL-2 in combination with interferon-alpha (IFNa) by weekly blood and urine cultures and other infective screens, if clinically indicated, to assess the effect of IL-2 on the frequency of infection in the absence of CVCs. 3 men and 4 women, median age 45 years (range 17-48) with metastatic cancer were treated with subcutaneous recombinant IL-2 (Cetus) 4-8 x 106 U/m2 subcutaneously thrice daily on day 1, and twice daily on days 2-5, 8-12, and 15-19 and recombinant IFNa (Schering-Plough) (3 x 106 U/m2 subcutaneously daily on days 3 and 5, and6X 106 Ulmz daily on days 8,10,12,15,17, and 19) on a 3-week cyc1e.6 The 7 patients received a total of 24 courses. 3 patients had positive blood cultures in 2 out of 2 sets (2 Staphylococcus epidermidis; 1 Pseudomonas aeruginosa), representing possible infection in 43% of patients and 13% of courses. Only 1 of these patients had symptoms with cellulitis at the site of subcutaneous injection needing oral flucloxacillin. 1 further patient had a chest infection (Haemophilus influenzae) needing antibiotics and 1 had a skin infection (phaemolytic streptococcus) in a subcutaneous metastasis. There have been no reports of an excess of infection in cancer patients receiving subcutaneous IFNa, and the high level of infection in our patients can be attributed to treatment with IL-2. This is in keeping with a reported increase in the frequency of infectious complications in patients with AIDS who were on IFNa or IL-2/ Since no CVCs were used in this study the infections were probably related to impaired cellular immunity caused by IL-2 administration.4.5 Subcutaneous regimens including IL-2 are of special interest because treatment can be given in outpatient departments. In our experience such schedules require careful monitoring because of the high frequency of positive blood cultures and/or overt infection; a belief that only patients with CVCs in situ are at serious risk of infection may lead to dangerous complacency. The role of prophylactic antibiotics in this context needs to be

investigated. Biological Therapies Unit, Department of Medicine. Royal Marsden Hospital, London SW3 6JJ, UK




1. Dutcher JP, Greekmore S, Weiss GR, et al. A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol 1989; 7: 477-85. 2. Hardy JR, Moore J, Lorentzos A, Ellis E, Jameson B, Gore ME. Infectious complications of interleukin-2 therapy Cytokine 1990, 2: 311 3. Bock SN, Lee RE, Risher B, et al. A prospective randomised trial evaluating prophylactic antibiotics to prevent triple-lumen catheter-related sepsis in patients treated with immunotherapy. J Clin Oncol 1990; 8: 161-69 4. Jablons D, Bolton E, Martins S, et al Interleukin-2 based immunotherapy alters circulating neutrophils Fc receptor expression and chemotaxis. J Immunol 1990; 144: 3630-36. 5. Klempner MS, Nonng R, Mier JW, Atkins MB. An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy N Engl J Med

1990; 332: 959-65. 6. Atzopodien J, Korfer A, Franks CR, Poliwoda H, Kirchnew H. Home therapy with recombinant interleukin-2 and interferon-&agr;2b in advanced human malignancies. Lancet 1990; 335: 1509-12 7. Murphy PM, Lane HC, Gallin JI, et al. Marked disparity in incidence of bacterial infections m patients with the acquired immunodeficiency syndrome receiving interleukin-2 or mterferon-alpha Ann Intern Med 1988; 108: 36-41.

Dantrolene for exertional heatstroke SIR,-Malignant hyperpyrexia and exertional heatstroke may be different manifestations of a common thermic stress syndrome that has different triggering factors. Dr Hopkins and colleagues’ observations (Dec 14, p 1491), which extend those of Denborough,’ provide further evidence for a shared mechanism at the biochemical level-namely, deregulation of control of myoplasmic calcium ion concentration. Is, therefore, dantrolene (the drug of choice for the treatment and prophylaxis of malignant hyperpyrexia), which acts by impairing calcium release from the sarcoplasmic reticulum, thereby uncoupling excitation and contraction in skeletal muscle cells, of therapeutic benefit in exertional heatstroke? Individual case reports suggest that this may indeed be so: dantrolene promptly reduces body temperature when standard cooling methods have failed,2 and it improves neurological status.! A small, uncontrolled trial of dantrolene versus standard cooling procedures in classic (ie,

non-exertional) heatstroke3showed that dantrolene reduced cooling times: duration of hyperthermia is probably the most important determinant of neurological outcome in heatstroke. Loss of calcium homoeostasis in muscle cells can unleash several destructive processes, such as impairment of n-iitochondrial respiration and ATP production, activation of phospholipase AZ with production of leukotrienes and prostaglandins (which promote cellular injury), increased production of free radicals, and activation of calcium-activated proteases-all of which may be implicated in the development of rhabdomyolysis.’ Theoretically, therefore, dantrolene might have a role in limiting muscle injury and its consequences in rhabdomyolysis by impairing calcium release. Parr and Willattss have reported its use to control the hypermetabolism of rhabdomyolysis induced by theophylline poisoning. Midland Centre for and Neurology,


Smethwick, Warley, West Midlands B67 7JX, UK



Denborough MA. Heat stroke and malignant hyperpyrexia. Med J Aust 1982,


204-05. 2.

Lydiatt JS, Hill GE. Treatment of heat stroke with dantrolene. JAMA 1981, 246:

41-42. 3. Channa AB, Seraj MA, Saddique AA, Kadiwal GH, Shaikh MH, Samarkandi AH Is dantrolene effective in heat stroke patients? Crit Care Med 1990; 18: 290-92. 4. Odeh M The role of reperfusion-induced injury in the pathogenesis of the crush syndrome. N Engl J Med 1991; 324: 1417-22. 5. Parr MJA, Willatts SM. Fatal theophylline poisoning with rhabdomyolysis. a potential role for dantrolene treatment. Anaesthesia 1991; 46: 557-59.

Antithrombin III and arterial disease SIR,-Dr Cortellaro and colleagues (Dec 14, p 1525) confirm a direct rather than inverse correlation between antithrombin III and plasma fibrinogen in the PLAT study,’ and we agree that their findings further emphasise the complex relation between prothrombotic and antithrombotic mechanisms in arterial disease. We would, however, urge caution in comparisons of the prospective findings on antithrombin III in PLAT and the Northwick Park Heart Study (NPHS). PLAT is based on patients of both sexes with pre-existing coronary, cerebral, or peripheral arterial disease and their later experience of a range of similar events. Our report2 was of men initially free of clinically manifest ischaemic heart disease (IHD) and their subsequent IHD mortality. As Cortellaro et al themselves acknowledge,’ relations between clotting factors and onset3 or recurrence4 of arterial disease may differ at different sites. After myocardial infarction, for example, prognosis is probably mainly determined by infarct size and complications such as heart failure.’ T. W. MEADE J. COOPER G. J. MILLER MRC Epidemiology and Medical Care Unit, D. J. HOWARTH Northwick Park Hospital, Y. STIRLING Harrow HA1 3UJ, UK 1. Cortellaro M, Boschetti C, Cofrancesco E, et al The PLAT study: a multidisciplinary study of hemostatic function and conventional risk factors m vascular disease patients Atherosclerosis 1991; 90: 109-18. 2. Meade TW, Cooper J, Miller GJ, Howarth DJ, Stirling Y. Antithrombin III and arterial disease. Lancet 1991; 338: 850-51. 3. Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease. principal results of the Northwick Park Heart Study. Lancet 1986, ii. 533-37. 4. Haines AP, Howarth D, North WRS, et al. Haemostatic variables and the outcome of myocardial infarction Thromb Haemost 1983; 50: 800-03.

Fractals, chaos, and fetal heart rate SjR,—Your Dec 7 editorial on fractals prompts me to present my preliminary application of fractals and chaos theory in the analysis of fetal heart rate (FHR). My interest in fractals was stimulated by the apparent failure of even complex linear methods to provide reproducible analyses of FHR recordings. You did not emphasise the important link between fractals and chaos theory when considering dynamic processes such as beating of the heart. The object of chaos theory is to identify order in seeming disorder. A time series of beat-to-beat intervals from a healthy fetal or adult heart does not reveal any systematic order and this can easily lead to the conclusion that the underlying complex system fires randomly.


Fig 1 (above)-Evolution of curve of FHR for observed intervals 1-500.

Fig 2 (right)-Log-log plot of L(s) against "measuring stick" length, s. The slope of least squares fit straight line is - 0 7226, giving a fractal dimension of 1 7226."

However, there is a constraint to the randomness, since we expect adjacent beat-to-beat intervals to range within a few milliseconds of each other. Both the cardiac arteriovenous structure and the His-Purkinje nerve complex have been identified as static fractal structures.’ Therefore, it would not be surprising to find that the dynamic process of heart rate control also exhibited fractal structure. With the "coastline" method, first described by Richardson,2Ihave identified a fractal dimension in FHR

regulation. Fetal heart beat intervals were derived from the audio output of a Hewlett Packard 8040 cardiotocograph in a 37-week uncomplicated pregnancy. Beat-to-beat intervals were timed with a modified version of a previously reported system. The analysis was done on a Toshiba 386 lap-top computer with software written in ’Turbo Pascal 5-5’. Plotted sequentially, the intervals give the impression of a conventional FHR/time trace (fig 1). I then estimated the length of the curve repeatedly using a shorter "measuring stick" each time. As the measuring stick shortened so it followed more closely the contour of the curve, yielding a longer curve length estimate. The fractal dimension (d=1-n) was calculated from the relation between measuring stick length (s) and curve length estimate (L[s]) (fig 2): L(s) =a.s -n.4 The fractal dimension is proportional to the irregularity of the curve. The plot of beat-to-beat interval against evolution in fig 1 represents about 3-5min of data but, in the absence of a time scale, it is qualitatively indistinguishable from data collected more conventionally over 30 or more minutes and plotted in the same way. This infers fractal scaling and prompts re-asking of the question-how long does an FHR recording need to be? The heart rate control system in the fetus, unlike that in the adult, is a developing fractal structure. Besides having potential for the early detection of abnormalities, fractal analysis may be able to assist in describing the maturation of the fetal cardiac system. Department of Obstetrics and Gynaecology, University of Wales College of Medicine, Cardiff CF4 4XN, UK


1. West BJ. Fractal physiology and chaos m medicine. Singapore: World Scientific, 1990. 2 Richardson LF. The problem of contiguity: an appendix of statistics of deadly quarrels. Systems Science Institute, University of Louisville, General Systems Yearbook, No 6. 1961; 139-87 3 Gough NAJ, Dawson AJ, Tomkms TJ. Antepartum fetal heart rate recording and subsequent fast transmission by a distributed microprocessor-based dedicated

system Int J Bio-Med Comput 1986; 18: 61-65. 4 Mandelbrot BB. The fractal geometry of nature. New York.



Elderly patients and chronic haemodialysis SiR,—The initiation of chronic haemodialysis in elderly patients, rather than continuing conservative treatment until death, remains controversial." Many nephrologists, especially those who have practised in an era of limited resources, use an age limit for the initiation of dialysis, and in most places old patients have a much reduced likelihood of receiving dialysis.4 Is this justified, at a time of increased availability of dialysis, better long-term survival and

quality of life due to erythropoietin (EPO), and improved success with grafts? We have attempted to assess the value of life in patients over the age of 74. Of 148 patients on long-term haemodialysis at two centres, 62 (42%) were aged 65 years or more, 21 being older than 74. In this group of 21 the mean age when treatment started was 76 (range 72-87) and the average length of dialysis had been 28 months (range 2-58). In 1977 not one patient of such an advanced age had been treated on maintenance dialysis in either department; in 1987 4% of patients were older than 74. Functional status was evaluated by Karnofsky score,5 and scores ranged from 90% (able to carry on normal activities) to 20% (very sick, hospital admission necessary). The mean was 64% (occasional assistance). 7 patients had a score of 80% or more. 14 (66 %) said they were "happy with their life" since they had adapted satisfactorily to their disease and the resulting disability. Only 3 patients felt unable to enjoy life to the full because of severe bone pain and/or peripheral vascular disease. 19 patients emphasised that their "life was worth living". As an example of successful dialysis despite advanced age, we report our oldest patient (born in 1900), who was put on dialysis in 1987. He was brought to us by his relatives after another centre had recommended conservative treatment. His end-stage renal disease was due to nephrosclerosis. When admitted, his Karnofsky score was 20% due to overhydration, uraemia, encephalopathy, and severe renal anaemia, but he was much improved with maintenance dialysis and EPO treatment.6 At 91 years of age this patient still leads an active life. In the summer he goes to Italy and is dialysed at a holiday resort. His Karnofsky score is 80%. Chronic haemodialysis can offer a good quality of life to the elderly, and doctors should not automatically exclude from longterm dialysis old patients. Since it is very difficult to distinguish permanent brain disease from the symptoms of untreated uraemia and cerebral ischaemia, we recommend a positive attitude to the initiation of treatment in the incompetent patient, even if medical benefit cannot be predicted. Those responsible for budgeting health-care expenditure may have to allow for increased costs to dialyse more elderly patients in the future. JÖRG H. HORINA A-8036 Graz, Austria


Krankenhaus Wiener Neustadt, Wiener Neustadt


Department of Medicine, Karl Franzens University,

1. Editorial. Who shall be dialysed? Lancet 1984; i: 717. 2. Neu S, Kjellstrand CM. Stopping long-term dialysis. N Engl J Med 1986; 314: 14-20. 3. Kilner JF. Ethical issues m the initiation and termination of treatment. Am J Kidney Dis 1990; 15: 218-227. 4. Kjellstrand CM. Giving life-giving death. ethical problems of high-technology medicine. Acta Med Scand 1988; 725 (suppl): 1-88. 5. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: Macleod CM, ed. Evaluation of chemotherapeutic agents. New York: Columbia University, 1949. 191-205. 6. Horina JH, Fazekas F, Niederkorn K, et al. Cerebral hemodynamic changes following treatment with erythropoietin Nephron 1991; 58: 407-12.

Fractals, chaos, and fetal heart rate.

182 We have monitored patients receiving subcutaneous IL-2 in combination with interferon-alpha (IFNa) by weekly blood and urine cultures and other i...
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