1347

healthy donors.9 Thus, HHV-6 reactivation in these CFS patients is indicated, suggesting that HHV-6 may be contributing in the

pathogenesis of CFS. Short-term culture assays, as done here, may prove to be a reliable test for reactivation of HHV-6. Any symptomatic involvement of HHV-6 in CFS should be evaluable with the development of viral inactivation or intervention therapy. Laboratory of Tumor Cell Biology, National Cancer Institute, Bethesda

S. F. JOSEPHS*

Department of Microbiology, University of Nevada, Reno

B. HENRY

Department of Microbiology and Immunology, University of Kansas Medical School

N. BALACHANDRAN

Department of Neoplastic Disease, Hahnemann University, Philadelphia

D. STRAYER

Incline Village

D. PETERSON

Flecainide may have a useful role in the management of resistant

neuralgic pain in advanced malignant disease. Increasing the dose from 100 to 200 mg twice daily may increase the likelihood of achieving a good and sustained response.

Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892, USA

CLAIRE SINNOTT

Department of Palliative Medicine, St Thomas’ Hospital, London SE1 7EH, UK, and Royal Marsden Hospital, London SW3 1.

Division of General Medicine, Brigham and Women’s Hospital, Harvard University School of Medicine, Boston

POLLY EDMONDS IAN CROPLEY GEOFFREY HANKS

Dunlop R, Davies RJ, Hockley J, Turner P. Analgesic effects of oral flecainide. Lancet

1988; i: 420. 2. Cardiac arrhythmia suppression trial (CAST) investigators. Preliminary report: effect of encamide and flecainide on mortality in a randomised trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406-12.

SjR,—Following our open study A. L. KOMAROFF

D. V. ABLASHI

*Present address Universal Biotechnology Inc, Rockville, Maryland 1. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387-89. 2. Komaroff AL. Chronic fatigue syndromes: relationship to viral infections. J Virol Methods 1988; 21: 1-18. 3. Buchwald D, Komaroff AL. Review of laboratory findings for patients with chronic fatigue syndrome. Rev Infect Dis 1991; 13: S12-S18. 4 Salahuddm SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986; 234: 596-601. 5. Ablashi DV, Lusso P, Hung C-L, et al. Utilization of human hemapoeitic cell lines for the propagation and characterization of HBLV (human herpesvirus-6). Int J Cancer 1988; 42: 787-91. 6. Ablashi DV, Zompetta C, Lease C, et al. Human herpesvirus-6 (HHV-6) in chronic fatigue syndrome (CFS). In: Rozee KR, ed. Proceedings of the Chronic Fatigue Workshop (Toronto, 1989). Can Dis Wkly Rep 1991; 17 (suppl): 33-37. 7. Balachandran N, Amelse RE, Zhou WW, et al. Identification of proteins specific for human herpesvirus-6 infected human T cells. J Virol 1989; 63: 2835-40. 8 Josephs SF, Salahuddin SZ, Ablashi DV, et al. Genomic analysis of the human B-lymphotrophic virus (HBLV). Science 1986; 234: 601-03. 9. Levy JA, Ferro F, Greenspan D, Lennett ET. Frequent isolation of HHV-6 from saliva and the seroprevalence to the virus in the population. Lancet 1990; 335: 1047-50.

Flecainide in

following a study in myocardial infarction.2 However, this is a very different population and none of our patients have had any difficulties. 2 had ischaemic heart disease (of whom 1 experienced the side-effects noted above).

cancer nerve

pain

SIR,-Neuropathic pain associated with advanced malignant disease is often very difficult to manage. In a preliminary study1 flecainide showed promise, and following this report we used the drug in 21 patients (8 males and 13 females; aged 17-75 years [median 55]). In most cases flecainide was second-line therapy when anticonvulsant therapy had failed due to inadequate response (8) or unacceptable drowsiness (6). All patients were also on opioids. Flecainide was started at a dose of 100 mg twice daily. 9 patients responded well, this effect being sustained for 1-14 weeks (table). Only 1 patient had side-effects (confusion and nocturnal hallucinations) on flecainide therapy, which resolved when the drug was discontinued. Antiarrhythmic drugs can be proarrhythmic in some circumstances and concern has been voiced about flecainide

flecainide in

with

of the

analgesic effect of oral pain1 we embarked on a

patients double-blind, placebo-controlled trial. Patients cancer

nerve

were

invited

to

participate if they had cancer-related nerve pain that had not been treated with radiography or chemotherapy within the previous month and which had not responded to conventional analgesia. We were aware of the proarrhythmic potential of flecainide and patients were excluded if they had evidence of heart disease on the basis of history, physical examination, ECG, chest X-ray, and, if necessary, echocardiography or gated-blood-pool scintigraphy. The trial received ethical committee approval. Results from the CAST study were released shortly after our trial began.2 This study showed an increased incidence of sudden death in patients with symptom-free ventricular arrhythmias treated with flecainide after myocardial infarction. In view of the advice to discontinue the flecainide, we felt that a preliminary review of our results was appropriate. The 2 patients who received flecainide 100 mg 12-hourly both experienced complete relief of pain. 4 patients had received placebo; 1 patient had experienced some relief while others had not and required rescue analgesia. After further consideration of the CAST study our ethical committee permitted the trial to continue. We were then disappointed to learn that the supply of flecainide had been discontinued by the pharmaceutical company. Others (see above letter) have confirmed our initial observations about the efficacy of flecainide and we believe strongly that it is important to complete a controlled trial. A wide variety of medications have been recommended for cancer-related nerve pain but few have been subjected to rigorous trial.

South Auckland Hospice, Auckland, New Zealand

Department of Palliative Medicine, St Bartholomew’s Hospital, London EC1

Department of Clinical Pharmacology, St Bartholomew’s Hospital Medical College, London EC1A 7BE, UK

ROBERT J. DUNLOP

JOSEPHINE M. HOCKLEY TERESA TATE

PAUL TURNER

Dunlop R, Davies RJ, Hockley J, Turner P. Analgesic effects of oral flecainide. Lancet 1988; i: 420. 2. Cardiac arrhythmia suppression trial (CAST) investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomised trial of arrhythmia 1989; 321: 406-12. J suppression after myocardial infarction N Engl Med 1.

RESPONSE TO FLECAINIDEIN 9 PATIENTS

Treatment of childhood fevers SIR,-Dr Kramer and colleagues’ (March 9, p 591) report has aroused considerable comment in the UK lay and medical press. Despite their caveats, others have made sweeping generalisations that this proves that anti-pyresis for childhood fever is no better than placebo. The data as published show that the children given active analgesia/anti-pyretic show a statistically significant improvement in activity and alertness with a pronounced but non-significant improvement in mood and eating. The children given placebo had a reported increase in drinking that Kramer et al interpret as evidence of improved fluid balance-but this

1348

finding could be attributed to children with untreated sore throats drinking excessively to salve the pain. The study has many weaknesses, which Kramer et al point out. The results are dependent on honest questionnaire responses, with no evidence that integrity or internal control was attempted. Many paediatricians would question the need for anti-pyresis in children with such mild fevers. In an unpublished study of hospital management of febrile convulsions in which children were randomised to paracetamol or nothing, dependent on the date of admission, we found that the night nurses were giving most patients anti-pyresis because it made their charges more comfortable. We noted no difference in speed of resolution of fever nor length of stay in hospital and, like Kramer et al, we concluded that anti-pyresis had no evident deleterious effect on speed of recovery. Although fever seems to be an essential component of the immune response there are important biological consequences that stem directly from it: increased work of breathing, tachycardia, discomfort, associated inflammation, irritability, anorexia, and thirst. The febrile response has important evolutionary consequences for life-threatening (bacterial) infections but has dubious relevance to the viral fevers. There are good humanitarian reasons for separating the biologically important features from the evolutionarily redundant side-effects. Most febrile children are treated at home by their parents and never see a doctor or pharmacist. Anthropologists report that throughout all cultures parents have sought to treat febrile children. If this is part of normal human behaviour, it is very important that medical advisers do not misinterpret or generalise from specific studies. Parents need to be confident that by relieving fever symptoms they are doing no harm and are not interfering with the acquisition of active immunity. Kramer and colleagues’ findings accord with those of earlier studies that relief of fever does not interfere with the speed of recovery. If parents were to be persuaded that anti-pyresis is of no value (or even harmful), they might well begin to demand antibiotics. The ecological and environmental fallacy of this approach was shown during the 1960s with the rapid emergence of resistant organisms after inappropriate prescribing. Prescribing of drugs for children is done with caution. In treating the side-effects of fever, there are good reasons for consideration of whether anti-inflammatory rather than analgesic anti-pyretic drugs should be used. Non-steroidal anti-inflammatory drugs such as ibuprofen are increasingly being used in younger children and have longlasting potent anti-pyresis. Selly Oak Hospital, Selly Oak, Birmingham B29 6JD,

UK

R. SUNDERLAND

Effect of bolus volume on dynamic measurement of organ blood flow SiR,—Dr Miles and colleagues (March 16, p 643) describe a new three-dimensional technique for imaging regional perfusion with dynamic computed tomography (CT). This technique is based on a new nuclear medicine

method that measures organ blow flow either in absolute units (ie, ml/min) if an intravascular trace is used or as a fraction of cardiac output, for which any tracer can be used.1-3 A critical assumption on which the CT technique relies is that the interval between "take-off’ and peak height of the arterial curve, recorded from a region of interest over the aorta, is less than the minimum intravascular transit time of the organ. If this criterion is met, one can relate the input rate into the organ (which is proportional to the maximum gradient [gk] of the upslope of the first-pass time-activity curve recorded from the organ) to the peak height (gA) of the arterial (input) curve. While recognising the technical limitations imposed by the volume of contrast required to give an adequate signal from an organ, we have been concerned that as a result of the time needed to deliver a 50 ml bolus, the above assumption may not be met, and blood flow might therefore be underestimated. To examine this drawback further, we compared renal and splenic blood flow measured from a conventional narrow bolus of the type routinely used in nuclear medicine, with that obtained with the same radionuclide in the same patient with a 50 ml bolus delivered by hand as rapidly as possible.

In patients undergoing routine 99mTc-methylene-diphosphonate (MdP) bone scanning, the dose (550 MBq) was divided into two portions. The first (at least half the total dose) was given in 50 ml saline through a 19 gauge butterfly needle inserted securely into an antecubital vein. Data were recorded dynamically in a frame time of 1 s for 40 s from a gamma camera positioned under the supine patient and connected to a computer. When the count rate had stabilised, about 2 min after the first injection, the second portion was given in not more than 0-5 ml. The internal volume of the

intravenous line was sufficient to accommodate this bolus before it was flushed into the antecubital vein with 20 ml of saline "chaser". Dynamic data recording was recommenced for a further 40 s. Organ blood flow is directly proportional to gk/gA. Since the peak of a curve is equal to its maximum gradient following integration, gA is conveniently obtained from the peak of the raw arterial curve. In CT, this is the peak of the aortic Hounsfield unit-time curve. The nuclear medicine technique originally described uses three separate estimates of gA derived from curves recorded over the lung (which closely reflects an arterial region 4), left ventricle, and upper abdominal aorta. For any particular arterial region, the gk/gA ratio should be identical for each of the two injections if the assumption described here is met for both. Using the lung curve, we found that the 50 ml bolus gave a value for blood flow to the right kidney (RBF) that was less than that given by the 0-5 ml bolus, with a mean ratio of 0-64 (SEM 0-04, n = 9). A 50 ml bolus gave curves of such poor quality that it was difficult to define gA values that were based on the left ventricle and aorta. Nevertheless, corresponding ratios for the left ventricle and aorta were 0-58 (0-08) and 0-53 (0° 10), respectively. In a further 9 patients, however, a 20 ml bolus gave a value for RBF similar to that of a 0-5 ml bolus. Thus the mean ratio of RBF measured from these two bolus volumes, based on the lung, was 0-99 (0-08). Corresponding ratios for the left ventricle and aorta were 0-98 (0-08) and 0-82 (0-11),

respectively. Since the minimum intravascular transit time through the spleen may well be longer than the kidney, the assumption in question may

be less critical for dynamic CT measurement of splenic blood flow (SBF) than for RBF. However, the bolus volume-related differences for kidney were also seen for spleen. With a 50 ml bolus, SBF, based on the lung, was 0-56 (0-08) of the value given by the 0-5 ml bolus; based on the left ventricle it was 0.52 (0°1), and based on the aorta it was 0-48 (0-12). The corresponding values obtained with a 20 ml bolus for SBF were 1-01 (0° 10),12 (0-12), and 0-79 (0-09) for the lung, left ventricle, and aorta, respectively. A 50 ml bolus of contrast probably substantially underestimates perfusion on dynamic first-pass CT. This would be consistent with the respective values recorded by Miles5 for the renal cortex and medulla. The renal cortical values are less than those recorded by intra-arterial xenon-133 wash-out, whereas the values for the medulla, through which the minimum intravascular transit time is presumably longer than that through the cortex, are in good agreement with xenon-133 data.6 The error could be reduced to a minimum if a smaller bolus volume was given, although this might critically limit the target to background signal ratio and replace one error with another. In any event, the advantages of threedimensional perfusion imaging are considerable and we hope that further development of the technique will overcome these difficulties. Department of Diagnostic Radiology, Hammersmith Hospital, London W12 0HS, UK

S. D. BELL A. M. PETERS

J, de Souza M, Peters M, Wilmot D, Hausen D, Gilday D Quantitative of blood flow in pediatric recipients of renal transplants. J Nucl Med 1990; 31: 580-85. 2. Peters AM, Brown J, Crossman D, et al. Non-invasive measurement of renal blood flow with Tc-99m DTPA in the evaluation of patients with suspected renovascular hypertension. J Nucl Med 1990; 31: 1980-85 3. Peters AM, Heckmatt JZ, Hasson N, et al. Renal haemodynamics of cyclosporin A nephrotoxicity m children with juvenile dermatomyositis. Clin Sci (in press) 4 Bell SD, Peters AM. Blood flow measurement from first pass time-activity curves influence of bolus spreading. Nucl Med Commun 1990; 11: 477-80. 5. Miles KA. Measurement of tissue perfusion by dynamic computed tomography. Br J Radiol 1991; 64: 409-12 6. Blaufox MD, Fromowitz A, Gruskin A, Meng C-H, Elkin M. Validation of use of xenon-133 to measure intra-renal distribution of blood flow. Am J Physiol 1970; 1. Ash

assessment

219: 440-44.