500
Editorial correspondence
Phenobarbital therapy for cholestasis To the Editor: In their report on the treatment of chronic cholestasis, Ghent, Bloomer, and Hsia' have used rather large doses of phenobarbital. Although no precise weights are given, it appears that both of their patients were receiving in excess of 10 mg/kg/day, consistent with the reported serum levels of 5.5 to 5.7 mg/dl. This is well above the usual recommended range of 1.0 to 2.5 mg/dl (for seizures) and above the generally accepted toxic range of 3.0 mg/dl.-' Phenobarbital decreases serum bilirubin and bile salt concentrations through its stimulation of glucuronyl transferase and its enhancement of bile secretion and excretion. The articles referenced indicate that conditions with predominantly unconjugated hyperbilirubinemia respond dramatically to relatively low doses of phenobarbital (references 5, 7, and 8) and that cholestatic conditions, though more variable, also will respond to "therapeutic" doses (relerences 9, 12, 16, 18, and 23). Unfortunately there are few data on serum drug levels and on drug side-effects in many of the reports, particularly those in which higher doses were used (references 13 and 14). The two children reported are mentally retarded, perhaps for a multitude of reasons. Although they have acquired enough tolerance to the phenobarbital to manifest no sedative effects at the high drug levels, one wonders what effects such levels have on the learning process. Little is known about learning and anticonvulsant therapy in children. Long-term phenobarbital therapy has been shown to retard growth in the developing infant rat brain while producing little sedation; no ataxia, and no retardation of somatic growth? With this in mind and with the lack of information on the dose-response relationship between phenobarbital and the various forms of hyperbilirubinemia, it would seem warranted to try managing such children with considerably lower, possibly less toxic, doses of the drug. Peter A. Blasco, M.D. Fellow The John F Kennedy Institute 707 N. Broadway Baltimore, MD 21205
REFERENCES 1. Ghent CN, Bloomer JR, and Hsia YE: Efficacy and safety of long-term phenobarbital therapy of familial cholestasis, J PEDIATR 93:127. 1978, 2. Buchtal F, and Lennox-Buchtal MA: Phenobarbital: relation of serum concentration to control of seizures, in Woodbury DM, Penny JK, and Schmidt RP, editors: Antiepileptic drugs, New York, 1972. Raven Press, pp 335-341. 3. Diaz J, and Schain RJ: Phenobarbital: Effects of long-term administration on behavior and brain of artifically, reared rats, Science 199:90, 1978.
The Journal of Pediatrics March 1979
Reply To the Editor: Dr. Blasco correctly points out that the doses of phenobarbital used in our patients and the serum levels obtained are higher than usual. These brothers were retarded both physically and mentally prior to phenobarbital therapy. The phenobarbital, at high dosage, dramatically promoted their mental performance by relieving their incessant itching, scratching, and sleep disturbances. So far, we have not observed any evidence of drug toxicity, and itching has returned each time the dose was decreased. The possible relationship between mental retardation and phenobarbital therapy raises an unanswered and presently unanswerable question. The recent animal evidence of neurotoxicity was not available to us at the time of study, but certainly justifies concern. Dr. Blasco appears to have missed the point that serum bile salt concentrations in our patients did not decrease even with long-term, high-dose phenobarbital therapy. The etiology of our patients' cholestasis is not necessarily the same as that in patients who had prompt reduction of bile salt concentrations in response to low-dose, short-term trials of phenobarbital. We agree that in general~the lowest effective dose of phenobarbital should be used, but in this distressing condition, we felt justified in maintaining the symptomatic relief afforded by higher doses to these patients, who have shown, if anything, improved mental development on therapy. C. N. Ghent, M.D. University Hospital P.O. Box 5339, Postal Stn., A London, Ont. N6A 5A5 Canada J. R. Bloomer, M.D. Yale University New Haven, CT Y. E. Hsia, B.M., M.R.C.P. University of Hawaii Honolulu, H1
"Transient hypothyroidism" in premature infants Because of the length of several of these letters, we have had to shorten several of them substantially. The number of papers submitted on this topic indicates that the controversy will continue for some time. We hope that authors will pool their data so that a definitive answer may be found in the near future. J.M.G. To the Editor: The papers on thyroid hormones in premature infants in the June, 1978, issue of TrtE JOURNAL1-:~fit very well with data which
Volume 94 Number 3
Editorial correspondence
have been collected in other laboratories during recent years." In premature infants without serious complications, both thyroxine (T,) and thyroid-stimulating hormone (TSH) follow the same pattern as in term infants, although on a lower level. In some premature infants with idiopathic respiratory distress syndrome or other serious conditions, T, may remain low for a long period, or drop again if the child's condition deteriorates. Our own studies indicate that the rise in T, in such infants very closely follows the improvement in the clinical condition. In adults T4 falls significantly during serious diseases or in stress situations, and increases again during the recovery period. 6-7 In our opinion the low T, in these situations represents an adaptive mechanism. The reduction in T, is the normal response of a diseased organism, be it in adults or in premature infants. In premature infants, however, the low levels of T, seem to be frequent and last for a long period of disease. In three infants we have also observed an elevated TSH during clinical recovery, in one infant as late as 41 days of age. Studies in the same infants later have shown normal T, and TSH levels. Our interpretation is that during the recovery phase the need for thyroid hormones increases. This leads to a TSH surge, less marked but more lasting than the one immediately following parturition. Looked upon this way, the low T~ and the high TSH do not represent hypothyroidism, but normal recovery from a diseased state. Until now too few infants have been followed closely enough to tell if elevated TSH is a frequent finding, and how long the TSH is elevated. It may well be, however, that the longer the adaptive process of thyroid depression, the longer the need for TSH stimulation. This may be particularly so if, because of early clinical pathology, the initial TSH surge was reduced or did not OCCUr.
We have found the term "delayed TSH surge" a better term than "transient hypothyroidism." This may be looked upon as a purely academic question, but we think it is important. We feel that if it is an adaptive mechanism, the condition should not be treated. The term transient hypothyroidism indicates pathology and thus suggests the need for treatment. Both Patients 5 and 6 in the paper of Delange et al, ~ and our own patients have recovered without treatment. There is at present no indication that these infants should be treated with thyroid hormones. We suggest that the term delayed TSH surge should be used instead of transient hypothyroidism, and that treatment should be postponed until we know more about the natural course. Thus, we believe one should be even more restrictive regarding therapy than was Weichsel ~ in his careful editorial in the same issue of the Journal.
F. F. Sommer, M.D. W. Lukas, M.D. S. Halvorsen, M.D. Department of Pediatrics University of Oslo Ullev~l Hospital Oslo 1, Norway REFERENCES
1. Cuestas RA: Thyroid function in healthy premature infants, J PEDIATR92:963, 1978.
2.
3.
4.
5.
6.
7.
8.
50 1
Uhrman S, Marks KH, Maisels MJ, Friedman Z, Murray F, Kulin HE, Kaplan M, and Utiger R: Thyroid function in the preterm infant: A longitudinal assessment, J PEDIATR 92:968, 1978. Delange F, Dodion J, Wolter R, Bourdoux P, Dalhem A, Glinoer D, and Ermans A-E: Transient hypothyroidism in the newborn infant, J PEDIATR 92:974, 1978. Lukas W, Skjelkv~le L, and Halvorsen S: Problems in screening newborn infants for hypothyroidism with thyroxine radioimmunoassay, IRCS Medical Science, Pediatrics 3:222, 1975. Lukas W, Melsom R, Sand T, and Halvorsen S: Thyroid function in the premature infant with IRDS, Fifth European Congress of Perinatal Medicine, Uppsala, Sweden, June 9, 1976. Burger A, Suter P, Nicod P, Valloton MB, Vagenakis A, and Braverman L: Reduced active thyroid hormone levels in acute illness Lancet 1:653, 1976. Aakvaag A, Sand T, Opstad PK, and Fonnum F: Hormonal changes in serum in young men during prolonged physical strain, Eur J Appl Physiol 39:283, 1978. Weichsel ME: Thyroid hormone replacement in the perinatal period: Neurologic considerations, J PEDIATR 92:1035, 1978.
To the Editor: We read with interest the papers by Cuestas ~and Uhrmann et al 2 concerning thyroid function in premature infants. In 1977 we published data indicating that (1) the early postnatal changes in serum thyroid-stimulating hormone (TSH) levels and (2) the TSH response to exogenous thyrotropinreleasing hormone (TRH) were similar in healthy term, smallfor-gestational age, and premature infants 1 to 6 days of age. ~ 4 Peak serum TSH values (30 minutes after TRH administration) were in all but one very premature infant higher during the first week of life than later in infancy, probably due to increased endogenous TRH secretion shortly after birth.' Basal total serum thyroid (T,) and tri-iodo-thyronine (T~) levels were significantly lower in premature than in term infants during the first week of life? One reason for this is lower serum concentrations of thyroid hormone-binding globulin (TBG), prealbumin, and albumin in premature infants compared with those of term infants? Calculations of ratios between thyroid hormone and thyroid hormone-binding protein serum concentrations indicated a less pronounced saturation of the hormone-binding proteins in premature infants compared with that of term infants. ~ This is probably not due to a decreased thyroid hormone secretion in premature infants, since TSH stimulation of the thyroid gland (after TRH injection) induces similar increases in serum thyroid hormone concentrations in term, small-for-gestational age, and premature newborn infants. 4 Increased utilization of the thyroid hormones in healthy premature infants compared to that in term infants might be another cause of the different thyroid hormone levels. Uhrmann et al ~ observed low serum TSH, low thyroid hormone concentrations, and decreases in serum T, and T:, levels during the acute stage of idiopathic respiratory distress syndrome
Editorial correspondence
Phenobarbital therapy for cholestasis To the Editor: In their report on the treatment of chronic cholestasis, Ghent, Bloomer, and Hsia' have used rather large doses of phenobarbital. Although no precise weights are given, it appears that both of their patients were receiving in excess of 10 mg/kg/day, consistent with the reported serum levels of 5.5 to 5.7 mg/dl. This is well above the usual recommended range of 1.0 to 2.5 mg/dl (for seizures) and above the generally accepted toxic range of 3.0 mg/dl.-' Phenobarbital decreases serum bilirubin and bile salt concentrations through its stimulation of glucuronyl transferase and its enhancement of bile secretion and excretion. The articles referenced indicate that conditions with predominantly unconjugated hyperbilirubinemia respond dramatically to relatively low doses of phenobarbital (references 5, 7, and 8) and that cholestatic conditions, though more variable, also will respond to "therapeutic" doses (relerences 9, 12, 16, 18, and 23). Unfortunately there are few data on serum drug levels and on drug side-effects in many of the reports, particularly those in which higher doses were used (references 13 and 14). The two children reported are mentally retarded, perhaps for a multitude of reasons. Although they have acquired enough tolerance to the phenobarbital to manifest no sedative effects at the high drug levels, one wonders what effects such levels have on the learning process. Little is known about learning and anticonvulsant therapy in children. Long-term phenobarbital therapy has been shown to retard growth in the developing infant rat brain while producing little sedation; no ataxia, and no retardation of somatic growth? With this in mind and with the lack of information on the dose-response relationship between phenobarbital and the various forms of hyperbilirubinemia, it would seem warranted to try managing such children with considerably lower, possibly less toxic, doses of the drug. Peter A. Blasco, M.D. Fellow The John F Kennedy Institute 707 N. Broadway Baltimore, MD 21205
REFERENCES 1. Ghent CN, Bloomer JR, and Hsia YE: Efficacy and safety of long-term phenobarbital therapy of familial cholestasis, J PEDIATR 93:127. 1978, 2. Buchtal F, and Lennox-Buchtal MA: Phenobarbital: relation of serum concentration to control of seizures, in Woodbury DM, Penny JK, and Schmidt RP, editors: Antiepileptic drugs, New York, 1972. Raven Press, pp 335-341. 3. Diaz J, and Schain RJ: Phenobarbital: Effects of long-term administration on behavior and brain of artifically, reared rats, Science 199:90, 1978.
The Journal of Pediatrics March 1979
Reply To the Editor: Dr. Blasco correctly points out that the doses of phenobarbital used in our patients and the serum levels obtained are higher than usual. These brothers were retarded both physically and mentally prior to phenobarbital therapy. The phenobarbital, at high dosage, dramatically promoted their mental performance by relieving their incessant itching, scratching, and sleep disturbances. So far, we have not observed any evidence of drug toxicity, and itching has returned each time the dose was decreased. The possible relationship between mental retardation and phenobarbital therapy raises an unanswered and presently unanswerable question. The recent animal evidence of neurotoxicity was not available to us at the time of study, but certainly justifies concern. Dr. Blasco appears to have missed the point that serum bile salt concentrations in our patients did not decrease even with long-term, high-dose phenobarbital therapy. The etiology of our patients' cholestasis is not necessarily the same as that in patients who had prompt reduction of bile salt concentrations in response to low-dose, short-term trials of phenobarbital. We agree that in general~the lowest effective dose of phenobarbital should be used, but in this distressing condition, we felt justified in maintaining the symptomatic relief afforded by higher doses to these patients, who have shown, if anything, improved mental development on therapy. C. N. Ghent, M.D. University Hospital P.O. Box 5339, Postal Stn., A London, Ont. N6A 5A5 Canada J. R. Bloomer, M.D. Yale University New Haven, CT Y. E. Hsia, B.M., M.R.C.P. University of Hawaii Honolulu, H1
"Transient hypothyroidism" in premature infants Because of the length of several of these letters, we have had to shorten several of them substantially. The number of papers submitted on this topic indicates that the controversy will continue for some time. We hope that authors will pool their data so that a definitive answer may be found in the near future. J.M.G. To the Editor: The papers on thyroid hormones in premature infants in the June, 1978, issue of TrtE JOURNAL1-:~fit very well with data which
Volume 94 Number 3
Editorial correspondence
have been collected in other laboratories during recent years." In premature infants without serious complications, both thyroxine (T,) and thyroid-stimulating hormone (TSH) follow the same pattern as in term infants, although on a lower level. In some premature infants with idiopathic respiratory distress syndrome or other serious conditions, T, may remain low for a long period, or drop again if the child's condition deteriorates. Our own studies indicate that the rise in T, in such infants very closely follows the improvement in the clinical condition. In adults T4 falls significantly during serious diseases or in stress situations, and increases again during the recovery period. 6-7 In our opinion the low T, in these situations represents an adaptive mechanism. The reduction in T, is the normal response of a diseased organism, be it in adults or in premature infants. In premature infants, however, the low levels of T, seem to be frequent and last for a long period of disease. In three infants we have also observed an elevated TSH during clinical recovery, in one infant as late as 41 days of age. Studies in the same infants later have shown normal T, and TSH levels. Our interpretation is that during the recovery phase the need for thyroid hormones increases. This leads to a TSH surge, less marked but more lasting than the one immediately following parturition. Looked upon this way, the low T~ and the high TSH do not represent hypothyroidism, but normal recovery from a diseased state. Until now too few infants have been followed closely enough to tell if elevated TSH is a frequent finding, and how long the TSH is elevated. It may well be, however, that the longer the adaptive process of thyroid depression, the longer the need for TSH stimulation. This may be particularly so if, because of early clinical pathology, the initial TSH surge was reduced or did not OCCUr.
We have found the term "delayed TSH surge" a better term than "transient hypothyroidism." This may be looked upon as a purely academic question, but we think it is important. We feel that if it is an adaptive mechanism, the condition should not be treated. The term transient hypothyroidism indicates pathology and thus suggests the need for treatment. Both Patients 5 and 6 in the paper of Delange et al, ~ and our own patients have recovered without treatment. There is at present no indication that these infants should be treated with thyroid hormones. We suggest that the term delayed TSH surge should be used instead of transient hypothyroidism, and that treatment should be postponed until we know more about the natural course. Thus, we believe one should be even more restrictive regarding therapy than was Weichsel ~ in his careful editorial in the same issue of the Journal.
F. F. Sommer, M.D. W. Lukas, M.D. S. Halvorsen, M.D. Department of Pediatrics University of Oslo Ullev~l Hospital Oslo 1, Norway REFERENCES
1. Cuestas RA: Thyroid function in healthy premature infants, J PEDIATR92:963, 1978.
2.
3.
4.
5.
6.
7.
8.
50 1
Uhrman S, Marks KH, Maisels MJ, Friedman Z, Murray F, Kulin HE, Kaplan M, and Utiger R: Thyroid function in the preterm infant: A longitudinal assessment, J PEDIATR 92:968, 1978. Delange F, Dodion J, Wolter R, Bourdoux P, Dalhem A, Glinoer D, and Ermans A-E: Transient hypothyroidism in the newborn infant, J PEDIATR 92:974, 1978. Lukas W, Skjelkv~le L, and Halvorsen S: Problems in screening newborn infants for hypothyroidism with thyroxine radioimmunoassay, IRCS Medical Science, Pediatrics 3:222, 1975. Lukas W, Melsom R, Sand T, and Halvorsen S: Thyroid function in the premature infant with IRDS, Fifth European Congress of Perinatal Medicine, Uppsala, Sweden, June 9, 1976. Burger A, Suter P, Nicod P, Valloton MB, Vagenakis A, and Braverman L: Reduced active thyroid hormone levels in acute illness Lancet 1:653, 1976. Aakvaag A, Sand T, Opstad PK, and Fonnum F: Hormonal changes in serum in young men during prolonged physical strain, Eur J Appl Physiol 39:283, 1978. Weichsel ME: Thyroid hormone replacement in the perinatal period: Neurologic considerations, J PEDIATR 92:1035, 1978.
To the Editor: We read with interest the papers by Cuestas ~and Uhrmann et al 2 concerning thyroid function in premature infants. In 1977 we published data indicating that (1) the early postnatal changes in serum thyroid-stimulating hormone (TSH) levels and (2) the TSH response to exogenous thyrotropinreleasing hormone (TRH) were similar in healthy term, smallfor-gestational age, and premature infants 1 to 6 days of age. ~ 4 Peak serum TSH values (30 minutes after TRH administration) were in all but one very premature infant higher during the first week of life than later in infancy, probably due to increased endogenous TRH secretion shortly after birth.' Basal total serum thyroid (T,) and tri-iodo-thyronine (T~) levels were significantly lower in premature than in term infants during the first week of life? One reason for this is lower serum concentrations of thyroid hormone-binding globulin (TBG), prealbumin, and albumin in premature infants compared with those of term infants? Calculations of ratios between thyroid hormone and thyroid hormone-binding protein serum concentrations indicated a less pronounced saturation of the hormone-binding proteins in premature infants compared with that of term infants. ~ This is probably not due to a decreased thyroid hormone secretion in premature infants, since TSH stimulation of the thyroid gland (after TRH injection) induces similar increases in serum thyroid hormone concentrations in term, small-for-gestational age, and premature newborn infants. 4 Increased utilization of the thyroid hormones in healthy premature infants compared to that in term infants might be another cause of the different thyroid hormone levels. Uhrmann et al ~ observed low serum TSH, low thyroid hormone concentrations, and decreases in serum T, and T:, levels during the acute stage of idiopathic respiratory distress syndrome
