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sufficient eligible patients, a Zelen protocol could rescue the project, but its adoption simply to reduce the work of recruiting patients might not find much support from local ethics committees.

despite

1. Fost N. Consent as a barrier to research. N Engl J Med 1979; 300: 1272-73. 2. Taylor KM, Margolese RG, Soskolne CL. Physicians’ reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 1984; 310: 1363-67. 3. Zelen M. A new design for randomized clinical trials. N Engl J Med 1979; 300: 1242-45. 4. Zelen M. Randomized consent designs for clinical trials: an update. Stat Med 1990; 9: 645-56. 5. Ellenberg SS. Randomization designs in comparative clinical trials. N Engl J Med 1984; 310: 1404-08. 6. Commission of the European Communities. Good clinical practice for trials on medicinal products in the European Community. Brussels: CEC, 1990. Chapter 1: 15-16. 7. Bartlett RH, Roloff DW, Cornell RG, Andrews AF, Dillon OW, Zwischenberger SB. Extracorporeal circulation in neonatal respiratory failure: a prospective randomized trial. Pediatrics 1985; 76: 479-87. 8. O’Rourke PP, Crone RK, Vacanti JP, et al. A prospective randomized study of extracorporeal membrane oxygenation (ECMO) and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn. Pediatrics 1989; 84: 957-63. 9. Chang RW, Falconer J, Stulberg SD, Arnold WJ, Dyer AR. Prerandomization: an alternative to classic randomization. J Bone Joint Surg 1990; 72A: 1451-55. 10. Fu KP, Lasinski ER, Zoganas HC, Kimble EF, Konopka EA. Efficacy of rifampicin in experimental Bacteroides fragilis and Pseudomonas aeruginosa mixed infections. J Antimicrob Chemother 1985; 15: 579-85. 11. Korvick JA, Peacock JE, Muder RR, Wheeler RR, Yu VL. Addition of rifampin to combination antibiotic therapy for Pseudomonas aeruginosa bacteremia: prospective trial using the Zelen protocol. Antimicrob Agents Chemother 1992; 36: 620-25. 12. Cassileth BR, Zupkis RV, Sutton-Smith K, March V. Informed consent: why are its goals imperfectly realized? N Engl J Med 1980; 302: 896-900.

Essential trace elements and thyroid hormones and metabolism of thyroid hormones, specific enzyme and transport processes have to work in concert. The importance of the trace element iodine, which forms an integral part of both thyroxine (T4) and triiodothyronine (T3), is well established, and the adverse effects of iodine deficiency continue to affect about 300 million people world wide. Selenium is important in thyroid hormone production, especially in the conversion of T4 to the active T3, and there is now some evidence to suggest that a third trace element, zinc, may likewise be involved in thyroid homoeostasis.l All T4 is synthesised in the thyroid, whereas under normal circumstances 80% of plasma T3 is derived from 5’-monodeiodination of T4 in liver, kidney, and probably muscle. T4 may also undergo 5-monodeiodination in these tissues to produce the metabolically inactive isomer reverse T3. The enzyme responsible for peripheral conversion of T4 to T3 in liver and kidney is type 1 iodothyronine deiodinase (IDI), and in 1987 it was shown that the activity of hepatic IDI was greatly reduced in selenium deficiency.3 IDI is a selenoenzyme,4 and only the second to be described in animals, the first being the family of glutathione peroxidases responsible for protecting the cell from peroxidative For the

synthesis

numerous

damage.5 Like glutathione peroxidase, selenium is incorporated at the active site of IDIas the specific aminoacid selenocysteine and the selenium moiety is crucial for the deiodination reaction.6 Discovery of selenium as an essential trace element in thyroid hormone production suggests that the clinical features of selenium deficiency such as myopathy may not be wholly attributable to diminished glutathione peroxidase activity and thus increased peroxidative damage as was originally proposed, but that abnormal thyroid hormone metabolism may also be important. The effects of selenium deficiency on thyroid hormone concentrations are not as profound as those of iodine deficiency. However, a relative lack of both elements leads to severe hypothyroidism and goitre in rats,and there is evidence to suggest that in certain geographical areas selenium deficiency may be a factor in the pathogenesis of myxoedematous endemic cretinism.8 Perhaps zinc will soon become the third trace element to have a clearly defined role in thyroid hormone production. Licastro and colleagues1 studied children with Down’s syndrome and found that plasma concentrations of zinc and the zinc-dependent thymic hormone, thymulin, were significantly lower than those in control children. Significantly higher concentrations of thyrotropin but lower concentrations of reverse T3 were found in the Down’s syndrome children than in control children. Similar observations9--l’ had been reported previously, but Licastro et al went on to show that, by giving dietary zinc sulphate supplements for 4 monthstreatment that largely restored plasma zinc and thymulin to the values found in the control childrenconcentrations of thyrotropin and reverse T3 returned to normal. The cause of the low plasma zinc in Down’s syndrome is unclear but it is not nutritional deficiency; decreased intestinal absorption is a

possibility.12 How does zinc influence thyroid hormone metabolism? In animals, the activity of IDIis increased in zinc deficiency and, since the enzyme is involved in the catabolism of reverse T3 to diiodothyronine by 5’-monodeiodination, this may partly explain the low reverse T3 in Down’s syndrome.13 IDIis also important in the overall turnover of T4 since it catalyses both 5-monodeiodination and 5’-monodeiodination. Consequently, increased catabolism of T4 in peripheral tissues may need to be balanced by increased thyroidal synthesis stimulated by thyrotropin. Much still needs to be explained, especially since it seems that the abnormalities in thyroid function in zinc-deficient laboratory animals are not the same as in children with Down’s syndrome.14,15 Zinc clearly has a role in thyroid hormone homoeostasis, if not as critical as that of iodine and selenium. 1. Licastro F, Mocchenegiani E, Zannotti M, Arena G, Masi M, Fabris N. Zinc affects the metabolism of thyroid hormones in children with Down’s syndrome: normalisation of thyroid stimulating hormone and reverse triiodothyronine plasmic levels by dietary supplementation. Int J Neurosci 1992; 65: 259-68.

of

zinc

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2. Visser TJ. Metabolism of thyroid hormones. In: Cook BA, King RJB, Van der Molen HJ, eds. Hormones and their action, part I. Amsterdam: Elsevier, 1988: 81-103. 3. Beckett GJ, Beddows SE, Morrice C, Nicol F, Arthur JR. Inhibition of hepatic deiodination of thyroxine caused by selenium deficiency in rats. Biochem J 1987; 248: 443-47. 4. Arthur JR, Nicol F, Beckett GJ. Hepatic iodothyronine 5’deiodinase: the role of selenium. Biochem J 1990; 272: 537-40. 5. Sunde RA. Molecular biology of selenoproteins. Annu Rev Nutr 1990; 10: 451-74. 6. Berry MJ, Banu L, Larsen PR. Type I iodothyronine deiodinase is a selenocysteine-containing enzyme. Nature 1991; 349: 438-40. 7. Arthur JR, Nicol F, Rae PWH, Beckett GJ. Effects of combined selenium and iodine deficiencies on the thyroid gland of the rat. J Endocrinol 1990; 124 (suppl): 240. 8. Goyes P, Golstein J, Nsombola B, Vis H, Dumont JE. Selenium deficiency as a possible factor in the pathogenesis of myxedematous endemic cretinism. Acta Endocrinol 1984; 114: 497-502. 9. Pueschel SM, Pezzullo JC. Thyroid dysfunction in Down’s syndrome. Am J Dis Child 1985; 139: 636-39. 10. Cutler AT, Benezra-Obeiter R, Brink SJ. Thyroid function in young children with Down’s syndrome. Am J Dis Child 1986; 140: 479-83. 11. Halsted JA, Smith JC. Plasma-zinc in health and disease. Lancet 1970; i: 322-24. 12. Antila E, Westermarck T. On the etiopathogenesis and therapy of Down’s syndrome. Int J Dev Biol 1989; 33: 183-88. 13. Oliver JW, Sachan DS, Su P, Applehaus FM. Effects of zinc deficiency on thyroid function. Drug Nutr Interact 1987; 5: 113-24. 14. Jordan D, Suck C, Veisseire M, Chazot G. Zinc may play a role in the regulation of thyrotropin function. Hormone Res 1986; 24: 263-68. 15. Morley JE, Gordon J, Hershman JM. Zinc deficiency, chronic starvation and hypothalamic-pituitary thyroid function. Am J Clin Nutr 1980; 33: 1767-70.

Thromboembolism

during

angiography A minor event sometimes gives new life to an old controversy. Such has been the case with thromboembolism in diagnostic and interventional clinical angiography. This potentially disastrous complication is well recognised by angiographers and much is known about its aetiology, but little had been written or said about it for 15 years or so until a report from the USA in 1987 of a chance observation by Robertson/ He noted that when blood is allowed to contaminate a contrast-containing syringe it may in time clot and, if accidentally reinjected into the patient, may produce a clinically important embolic event; moreover, such clotting was most likely to arise with non-ionic contrast agents. Presumably the same applies to catheters used for injection of non-ionic contrast agents. These agents, introduced into radiological practice in Europe in the early 1980s and in the USA in the mid-1980s, had hitherto been regarded as a substantial advance in terms of patient tolerance2 and frequency of anaphylactoid reactions.3 Now it seemed that they might, on the contrary, represent a greater specific danger in angiography than did their predecessors. In the fertile ground provided by the US medicolegal arena the controversy successfully took root again; both radiologists and cardiologists in the USA have been greatly worried by the issue and this concern has begun to spread to other countries. To weigh up the evidence we need to understand the aetiology of thromboembolic events and something of the pharmacology of the iodinated intravascular contrast agents.

Most of the clinical data on thromboembolic events come from coronary and cerebral angiography, where the consequences can be most serious. Such events are not always easily distinguishable from dissection or dislodgment of a plaque, and even if there is thromboembolism it is difficult to know the source (inside catheter or syringe, exterior of catheter tip, or within static blood in the vessel distal to the catheter

tip). In the 1970s several research groups had noted that presumed thromboembolic complications represented a sizeable proportion of all adverse events in angiography, and that the frequency was about 0-25% in cardiac studies carried out by the brachial route but could be much higher for femoral catheterisation. Judkins and Gander4 argued that angiographic technique was all important; that inexperienced operators tended to select the femoral route for cardiac studies; and that systemic heparinisation was commonly used in brachial procedures because of anxiety about complications with this vessel. Their main conclusions were that, although systemic heparinisation was likely to be helpful, the skill and speed of the operator were the most crucial factors. They opined firmly that centres in which the overall complication rate of coronary angiography exceeded 0-3% should stop doing the procedure; after this forceful statement the number of published reports of angiographic complications declined. A subsequent large survey by Adams and Abrams5 suggested that Judkins and Gander’s warning had had a salutary effect, since the thromboembolic complication rate in percutaneous femoral studies seemed to have fallen to about the rate seen with transbrachial studies. This, they suggested, was due to a combination of greater attention to technique and more general use of systemic heparinisation. Nevertheless, disgreement about heparin use and dose in diagnostic and interventional angiography

persists.6 The root cause of thromboembolism is formation of thrombus on the foreign surfaces provided by catheters, guidewires, and syringes that come into contact with blood. In the 1970s detailed studies of the aetiological role of these surfaces in thromboembolism showed that there were important differences between various material and surface finishes. Polyethylene comes at the less thrombogenic end of the spectrum and Teflon at the more thrombogenic end.7 Heparincoated impregnated catheters are significantly less thrombogenic but are very expensive.8 Stainless steel guidewires are less thrombogenic when polished and much more thrombogenic when Teflon coated.9 It is important to note that throughout the 1970s and 1980s the role of angiographic contrast agents was seen as exclusively positive. Angiographers appreciated that these agents exerted an anticoagulant effectl° and they were even recommended as flushing solutions for catheters. X-ray absorbing iodinated organic compounds are