Ibuprofen versus sumatriptan for high-altitude headache

provide improved immunosuppression or merely more immunosuppression? The higher incidence of opportunistic infections in the mycophenolate mofetil-treated patients suggests the latter. There are established methods of testing whether immunosuppressant drugs act synergistically or additively when used in combination but the design of this study precludes their use.’ I

C G Winearls Oxford Regional Renal Unit, Oxford Radcliffe Hospital Trust, Headington, Oxford OX3 7LI, UK

1

Berenbaum MC.

Synergy, additivism and antagonism in immunosuppression: a critical review. Clin Exp Immunol 1977;

28:

1-18.

High-dose frusemide for cardiac failure SiR-Many patients, especially elderly people, need further diuretic treatment in addition to angiotensin-convertingenzyme (ACE) inhibitors. Among elderly people with advanced disease, a lack of response to low-dose frusemide is common. The options are to use a larger dose of frusemide or to add another diuretic agent. High-dose frusemide therapy (250-400 mg per day), given by mouth, by intravenous bolus, or by continuous infusion is effective in refractory congestive cardiac failure.’ Many physicians are, however, reluctant to use high-dose frusemide, mainly because of concerns about renal function. The alternative approach is to use a combination of diuretics, usually frusemide with a thiazide or potassiumsparing agent. Although this approach can be effective, 2 severe electrolyte disturbances can occur. We reviewed 15 geriatric inpatients (eight male, six female; mean age 83 [65-93] years) admitted to a rehabilitation unit with left, congestive, or biventricular cardiac failure, who were treated with moderate to high doses of frusemide. All 15 patients were on clinically optimum doses of ACE inhibitors at discharge and 12 were being so treated on admission. 13 had atrial fibrillation and were receiving digoxin. The average daily frusemide dose was 193 mg (SD 136, maximum 500) on admission and 297 mg (181, 750) at Mean serum creatinine was 161 discharge (p<0006). ’

jjLmol/L (56-7, 325) on admission and 160 jjLmol/L (77-7, 392) at discharge (not significant). There was an average weight loss of 5-6 kg and an average rise in the Barthel score of 4 points. 11 patients returned to their previous home (six) or hostal (five), three were relocated to a hostel (one) or nursing home (two), and one patient had an acute myocardial infarction and died in hospital. There were no significant electrolyte disturbances apart from hypokalaemia that responded to potassium supplementation. In the setting of cardiac failure resistant to an optimum dose of an ACE inhibitor and low-dose frusemide, although the addition of a thiazide diuretic may be a useful adjunct, we conclude that the use of high-dose frusemide was an effective and safe approach to management of severe cardiac

Ibuprofen

versus

sumatriptan for high-altitude

headache SiR-Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to be superior for treatment of high-altitude headache than placebo.’ Bartsch and colleagues2 recently proposed that sumatriptan a 5-HTB receptor agonist, might be even more effective than ibuprofen.- To test this hypothesis, we compared oral ibuprofen and sumatriptan in a randomised, double-blind, within-patient crossover trial. 33 volunteers (18 men, 15 females, mean age 29, range 19-52) were transported from 200 m to an altitude of 3480 m (by bus and cable car) and stayed there for 18 h. Medical history and clinical examination of the subjects revealed no evidence of existing acute or chronic diseases. Nutrition and physical activity were standardised 12 h before and during the altitude sojourn. 5-15 h after arrival at altitude, 13 (9 males, 4 females, mean age 36, range 23-52) developed headache. Treatment was started when a headache score of 2 (0=none, l=mild, 2=moderate, 3=severe) and an acute mountain sickness score3 greater than 2 were reached. The patients were randomised to ibuprofen (600 mg) and sumatriptan (100 mg), respectively. Scoring was repeated 2 h after drug intake. If patients needed further medication, they were given the drug not initially administered. Heart rate, blood pressure, and oxygen saturation were measured in all subjects before and during the altitude sojourn. Score

changes within groups were analysed with Wilcoxon’s signed rank tests. To compare differences for continuous variables we used t tests. All statistical tests were 2-tailed. After intake of ibuprofen, nearly complete relief of the headache occurred in these patients (n=7) within 2 h. In contrast, no decrease of the headache score was found in patients (n=6) treated with sumatriptan. 5 of these patients needed further medication and achieved complete relief within 2 h of subsequent ibuprofen intake (figure). A significant reduction of the acute mountain sickness score was observed within the ibuprofen group (mean 4-3 [SD 049] vs 0-57 [0-98], p=0018). No such reduction occurred within the sumatriptan group. No assessments except headache score were made for the sumatriptan group after ibuprofen intake. The mean values of heart rate, blood pressure, and oxygen saturation did not differ between the group with headache and the group without headache throughout the investigation. However, heart rates tended to decrease 2 h after treatment with ibuprofen (88-7 [16.7] vs 75-0 [15-3], p=0.1) probably due to the decrease in painrelated sympathetic adrenergic stimulation. No heart rate changes occurred in the group treated with sumatriptan. No adverse effects were observed.

failure. *G Waterer, M Donaldson Departments of *Neurology and Geriatrics, Royal Perth Hospital, Perth, Western Australia 6001

1 2

Gerlag PG, van Meijel JJM. High-dose frusemide in the treatment of refractory congestive heart failure. Arch Intern Med 1988; 148: 286-91. Oster JR, Epstein M, Smoler S. Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention. Ann Intern Med

with

1983; 99: 405-06.

p values calculated with Wilcoxon’s

254

Figure: Changes sumatriptan sumatriptan

in

(SD) headache scores after treatment ibuprofen, or ibuprofen after previous

mean

or

signed rank

tests.

These results confirm the efficacy of ibuprofen,’ but do conform to the supposition of Bartsch and colleagues that high-altitude headache might respond to stimulation of 5-HT, receptors by sumatriptan.2 Either their hypothesis is wrong or different trial conditions are responsible for the contrary results. In contrast to our investigation the experiment of Bartsch and colleagues was not controlled and therefore a placebo effect cannot be excluded. On the other hand, their patients suffered from longer lasting and more severe headache than those in our experiment. Based on the speculation that severe headache causes an impaired bloodbrain barrier, a central site of action of sumatriptan could explain the different effects observed.4 If sumatriptan acts peripherally, we should have detected this. It remains to be seen whether a new 5-HTj receptor agonist that penetrates the blood-brain barrier more easily than sumatriptan will be effective also for the treatment of less severe altitude headache.’5 not

*Martin Burtscher, Rudolf Likar, Wemer Nachbauer, Wolfgang Schaffert, Michael Philadelphy *Department of Sport Science, University of Innsbruck, A-6020 Innsbruck, Austria; Society for Mountain Medicine

and Austnan

1 Broom JR, Stoneham MD, Beeley JM, Milledge JS, Hughes AS. High altitude headache: treatment with ibuprofen. Aviat Space Environ Med 1994; 65: 19-20. 2 Bärtsch P, Maggi S, Kleger G-R, Ballmer PE, Baumgartner RW. Sumatriptan for high-altitude headache. Lancet 1994; 344: 1445. 3 Roach RC, Bärtsch P, Hackett PH, Oelz O. The Lake Louise acute mountain sickness scoring system. In: Sutton JR, Houston CS, Coates G, eds. Hypoxia and molecular medicine. Burlington, VT: Queen City Printers, 1993: 272-74. 4 Kaube H, Hoskin KL, Goadsby PJ. Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption. Br J Pharmacol 1993; 109: 788-92. 5 Olesen J. Understanding the biologic basis of migraine. N Engl J Med 1994; 331: 1713-14.

High and low doses of ibuprofen produced similar results, with no significant change being detected: the median (25th to 75th centiles) change in CBV was 0 (0-1 to -0-1) mL/100 g; and in [Cyt02], 0 (0 to -0-1) µmol/L. CBVR was 0-13 (0-10 to 0-21) mL 100 g-’ kPa-’ before and 0-16 (0-09 to 0-17) after treatment. Control injections of indomethacin, on the other hand, induced significant falls in all variables similar to those seen in previous studies: the change in CBV was -0-4 (-0-3 to -0-5) mL/100 g; and in [CytO2], -0-2 (0 to -0-5) µmol/L. CBVR fell from 0-17 (0-13 to 0-19) mL 100 g’’ kPa-’ before treatment to 0-06 (0-05 to 0-07). The cerebral effects of ibuprofen and indomethacin were significantly different (Kruskal-Wallis analysis of variance with Dunn’s multiple comparison test, p<0001). However, there was no apparent difference in rate of PDA closure: both indomethacin and ibuprofen induced closure of the PDA in 57% of treated infants. Unlike indomethacin, ibuprofen appears to induce closure of PDA without imparing cerebral haemodynamics and oxygenation. These results suggest that indomethacin may not be the best available drug for treating PDA in sick preterm infants. They are also relevant to researchers the of administration investigating prophylactic inhibitors to prostaglandin synthase prevent periventricular haemorrhage. This study was supported by the British Heart Foundation and Hammamatsu Photonics KK.

J

1

Edwards AD, Wyatt JS, Richardson C, et al. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990; 335:

2

McCormick DC, Edwards AD, Brown GC, et al. Effect of indomethacin on cerebral oxidised cytochrome oxidase in preterm infants. Pediatr Res 1993; 33: 603-08. Horbar JD. Prophylactic indomethacin in preterm infants for PIVH. In: Sinclair JD, Bracken MB, Soll RJ, Horbar JD, eds. Neonatal module. Cochrane Database of Systematic Reviews. Review No 04509, April 20, 1993. Oxford: Update Software, 1994, disk issue 1. Chemtob S, Beharry K, Bama T, Varma DR, Aranda JV. Differences in the effects in the newborn piglet of various nonsteroidal antiinflammatory drugs in cerebral blood flow but not on cerebrovascular prostaglandins. Pediatr Res 1991; 30: 106-11.

1491-95.

3

Ibuprofen treatment of patent ductus arteriosus SIR In preterm infants patent ductus arteriosus (PDA) is a common problem that leads to increased morbidity and mortality. Conventional treatment with intravenous indomethacin causes a decline in cerebral perfusion, reduced of mitochondrial and oxygenation, disruption cerebrovascular control.’,2 The risk of ischaemic injury after indomethacin led a recent reviewer to stress the importance of research into alternative drugs for use in newborn infants.3 The action of indomethacin on PDA is mediated by inhibition of prostaglandin synthesis,, but the deleterious cerebral effects appear to be due to a different mechanism which may be unique to indomethacin. We have therefore studied the cerebral effects of a different prostaglandin synthesis inhibitor, ibuprofen, in preterm infants born between 23 and 28 (median 26) weeks postconceptional age. The study compared the effects of ibuprofen 5 mg/kg (n=12) or 10 mg/kg (n=6), with indomethacin 0-1 mg/kg (n=15). The drugs were infused intravenously over 15 minutes during therapy for echocardiographically proven PDA. Near infrared spectroscopy (NIRO 500, Hammamatsu Photonics KK) was used to observe the effect of treatment on cerebral perfusion, indicated by changes in cerebral blood volume (CBV), and cerebral mitochondrial oxygenation, determined by the change in concentration of oxidised cytochrome aa3([Cyt02]). In six cases receiving ibuprofen and four indomethacin, the response of CBV to changes in arterial carbon dioxide tension (CBVR) was also measured as an index of dynamic cerebrovascular control.

Patel, K A Marks, I Roberts, D Azzopardi, *A D Edwards

Department of Paediatrics and Neonatal Medicine, Royal Postgraduate Medical School, London W12 ONN, UK

4

Cutaneous dysplastic naevi: risk factor for uveal melanoma SIR-Many studies have looked at the phenotypic features of individuals who are prone to develop cutaneous melanoma. 1,2 One of the main factors in melanoma risk assessment is the presence of dysplastic naevi (clinically

atypical moles).3 Risk factors for uveal melanoma are less well defined, et al4 observed that exposure to sunlight increases the odds of intraocular malignant melanoma, and atypical naevi are more common in uveal melanoma patients than in controls.5 We have assessed the presence of dysplastic naevi among 75 consecutive uveal melanoma patients (36 women, 39 men; mean age 45-4 years) and 86 consecutive cutaneous melanoma patients (47 women, 39 men; 47-3 years). Controls were recruited from among patients referred to other clinics (78 women, 65 men; 46-2 years). Atypical naevi were found in greater proportions of the uveal melanoma (17 of 75) and of cutaneous melanoma (19 of 86) groups than in the control group (9 of 143). The relative risks of uveal melanoma and cutaneous melanoma were 4-36 (95% CI 1-84-10-4) and 4-22 (1-81-9-84),

though Tucker

respectively. 255