- Email: [email protected]
Zelen protocols
1574
children it may well provide a useful serial intracranial pressure abnormalities.
guide
to
-
SM, Marchbanks RJ, Burge DM. Long-term assessment of intracranial pressure using the tympanic membrane displacement measurement technique. Eur J Pediatr Surg 1991; 1 (suppl): 25-26. 2. Piatt JH. Physical examination of patients with cerebrospinal fluid shunts: is there useful information in pumping the shunt? Pediatrics 1. Moss
1992; 89: 470-73. 3. Reid A, Marchbanks RJ, Bateman DE, Martin AM, Brightwell AP, Pickard JD. Mean intracranial pressure monitoring by a non-invasive
audiological technique: a pilot study. J Neurol Neurosurg Psychiatry 1989; 52: 610-12.
Zelen
protocols
randomised trial, informed consent of the patient or guardian is usually obtained before allocation is made to one or other treatment. The subject has the right to be told the relevant risks and alternatives and to withhold consent, whatever the investigator believes are the benefits of participation.! To some clinicians this presents a difficulty in that the doctor may be perceived by the patient not to know the best choice, but recruitment is not ethical unless the experimental treatment is believed to be at least as effective as conventional therapy.Patients do not know at the time of consent which treatment they will receive and there is a chance that some will withdraw later if not given the treatment they then prefer. If clinicians are half-hearted in recruiting, or patients are resistant, the credibility of the trial suffers. In 1979, Zelen proposed alternative trial designs with randomisation before consent.3,4 In one form (double consent), all eligible patients are randomised to one of two possible treatments and are then asked for informed consent. If they agree, they are given their allotted treatment. If they do not, they are given the comparator or some suitable alternative. Clinicians may be more willing to approach suitable patients because they can discuss, at the outset, the merits of the specific treatment patients will receive in the trial. For the patient, the decision is simply whether or not to have the allotted treatment. Analysis is by intention to treat, irrespective of the treatment actually given, to avoid bias.4If there are few refusals, the reduction in the statistical power of the trial is offset by increased recruitment. However, if the overall refusal rate is 15%, twice the number of patients will have to be recruited.5 Double-blind trials are impossible with In
a
this approach. In another design (single consent), Zelen proposed that only patients allocated to the test treatment be asked for consent.3The comparator would be the best standard treatment, which any patient refusing consent would also receive. The notion that some patients would be studied without the investigators’ seeking consent provoked considerable controversy.5 The US Code of Federal Regulations and the EC Guidelines on Good Clinical Practice imply that, in any research on human beings, the subjects (or their guardian) should be informed of the risks and benefits and give consent.4,6 Patients in the control group
would still be part of a study, possibly requiring additional investigations, and their records would be reviewed, albeit for purely statistical purposes. In a review of trials in which these alternative designs had been adopted, Zelen found them of benefit in placebo-controlled studies and in comparisons of operations for breast cancer, an area
designs are unpopular.Other applications were less successful, and in one investigation the design was abandoned when the rate where randomised
of refusals reached 30%.4,5 Zelen noted two studies of extracorporeal membrane oxygenation in newborn babies with pulmonary hypertension in which consent was not sought from parents of babies allocated standard therapy; it was judged unethical to discuss a possibly life-saving procedure with the parents and then withhold it.7,8 In a randomised trial of arthroscopy of the knee vs medical management, recruitment with a conventional design yielded only 2 of 28 eligible patients in a year.9 Patients were then asked if they would accept arthroscopy before the randomisation envelope was opened. In the ensuing discussion with the patient, the assigned treatment was given prominence before consent was requested. Recruitment increased six-fold but half of the eligible patients declined before randomisation. Rifampicin has been shown in some cases to increase the bactericidal activity of antibiotic combinations including aminoglycosides against Pseudomonas spp in vitro and in laboratory anirnals.10 Korvick et al11 used the single-consent design in a trial of treatment of Pseudomonas bacteraemia with or without rifampicin in addition to a beta-lactam and an aminoglycoside. Patients allocated to the test group and already receiving standard therapy were asked for consent to the addition of rifampicin. 6 of 58 patients who were asked for consent refused and were given standard treatment but were analysed with the test group. Bacteriological failure was significantly less common in the group allocated to rifampicin (1/58 vs 9/63, p 0-02), irrespective of the severity of illness. The study design was said to be justified because recruitment was simplified and because no additional procedures were carried out on patients as the result of participation in the trial. Truly informed consent is seldom obtained, patients often failing to remember much of what they have been toldP However, in the Zelen designs, although the patient can refuse the allotted treatment, he or she cannot withdraw from the study and may not be asked for consent at all. The Zelen protocol increases recruitment when physicians are unwilling to participate in a conventional randomised study and few patients prefer one treatment over another. Opportunities for placebo-controlled trials are very limited. Assessments of new agents usually require investigations in addition to those made routinely, which could exclude the single-consent format. If recruitment in a randomised trial of antibiotics is slow =
1575
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
children it may well provide a useful serial intracranial pressure abnormalities.
guide
to
-
SM, Marchbanks RJ, Burge DM. Long-term assessment of intracranial pressure using the tympanic membrane displacement measurement technique. Eur J Pediatr Surg 1991; 1 (suppl): 25-26. 2. Piatt JH. Physical examination of patients with cerebrospinal fluid shunts: is there useful information in pumping the shunt? Pediatrics 1. Moss
1992; 89: 470-73. 3. Reid A, Marchbanks RJ, Bateman DE, Martin AM, Brightwell AP, Pickard JD. Mean intracranial pressure monitoring by a non-invasive
audiological technique: a pilot study. J Neurol Neurosurg Psychiatry 1989; 52: 610-12.
Zelen
protocols
randomised trial, informed consent of the patient or guardian is usually obtained before allocation is made to one or other treatment. The subject has the right to be told the relevant risks and alternatives and to withhold consent, whatever the investigator believes are the benefits of participation.! To some clinicians this presents a difficulty in that the doctor may be perceived by the patient not to know the best choice, but recruitment is not ethical unless the experimental treatment is believed to be at least as effective as conventional therapy.Patients do not know at the time of consent which treatment they will receive and there is a chance that some will withdraw later if not given the treatment they then prefer. If clinicians are half-hearted in recruiting, or patients are resistant, the credibility of the trial suffers. In 1979, Zelen proposed alternative trial designs with randomisation before consent.3,4 In one form (double consent), all eligible patients are randomised to one of two possible treatments and are then asked for informed consent. If they agree, they are given their allotted treatment. If they do not, they are given the comparator or some suitable alternative. Clinicians may be more willing to approach suitable patients because they can discuss, at the outset, the merits of the specific treatment patients will receive in the trial. For the patient, the decision is simply whether or not to have the allotted treatment. Analysis is by intention to treat, irrespective of the treatment actually given, to avoid bias.4If there are few refusals, the reduction in the statistical power of the trial is offset by increased recruitment. However, if the overall refusal rate is 15%, twice the number of patients will have to be recruited.5 Double-blind trials are impossible with In
a
this approach. In another design (single consent), Zelen proposed that only patients allocated to the test treatment be asked for consent.3The comparator would be the best standard treatment, which any patient refusing consent would also receive. The notion that some patients would be studied without the investigators’ seeking consent provoked considerable controversy.5 The US Code of Federal Regulations and the EC Guidelines on Good Clinical Practice imply that, in any research on human beings, the subjects (or their guardian) should be informed of the risks and benefits and give consent.4,6 Patients in the control group
would still be part of a study, possibly requiring additional investigations, and their records would be reviewed, albeit for purely statistical purposes. In a review of trials in which these alternative designs had been adopted, Zelen found them of benefit in placebo-controlled studies and in comparisons of operations for breast cancer, an area
designs are unpopular.Other applications were less successful, and in one investigation the design was abandoned when the rate where randomised
of refusals reached 30%.4,5 Zelen noted two studies of extracorporeal membrane oxygenation in newborn babies with pulmonary hypertension in which consent was not sought from parents of babies allocated standard therapy; it was judged unethical to discuss a possibly life-saving procedure with the parents and then withhold it.7,8 In a randomised trial of arthroscopy of the knee vs medical management, recruitment with a conventional design yielded only 2 of 28 eligible patients in a year.9 Patients were then asked if they would accept arthroscopy before the randomisation envelope was opened. In the ensuing discussion with the patient, the assigned treatment was given prominence before consent was requested. Recruitment increased six-fold but half of the eligible patients declined before randomisation. Rifampicin has been shown in some cases to increase the bactericidal activity of antibiotic combinations including aminoglycosides against Pseudomonas spp in vitro and in laboratory anirnals.10 Korvick et al11 used the single-consent design in a trial of treatment of Pseudomonas bacteraemia with or without rifampicin in addition to a beta-lactam and an aminoglycoside. Patients allocated to the test group and already receiving standard therapy were asked for consent to the addition of rifampicin. 6 of 58 patients who were asked for consent refused and were given standard treatment but were analysed with the test group. Bacteriological failure was significantly less common in the group allocated to rifampicin (1/58 vs 9/63, p 0-02), irrespective of the severity of illness. The study design was said to be justified because recruitment was simplified and because no additional procedures were carried out on patients as the result of participation in the trial. Truly informed consent is seldom obtained, patients often failing to remember much of what they have been toldP However, in the Zelen designs, although the patient can refuse the allotted treatment, he or she cannot withdraw from the study and may not be asked for consent at all. The Zelen protocol increases recruitment when physicians are unwilling to participate in a conventional randomised study and few patients prefer one treatment over another. Opportunities for placebo-controlled trials are very limited. Assessments of new agents usually require investigations in addition to those made routinely, which could exclude the single-consent format. If recruitment in a randomised trial of antibiotics is slow =
1575
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