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Propranolol in treatment of neonatal thyrotoxicosis
1046
December, 1973 The Journal of P E D I A T R I C S
Propranolol in treatment of neonatal tbyrotoxicosis Colin S. Smith, M.B., Ch.B., M.R.C.P., a n d Neville J. H o w a r d , M.B., F . R . C . P . ( C ) , ~ Toronto, Ontario, Canada
S i N c E 1 9 0 0 forty-three cases of neonatal hyperthyroidism have been reported1-2; six of the infants died as a direct result of their thyrotoxicosis. These figures d e m o n s t r a t e a significant case fatality rate, a n d indicate the need for p r o m p t initiation of effective medical m a n a g e m e n t . C u r r e n t s t a n d a r d pediatric texts advocate antithyroid t h e r a p y c o m b i n e d with sedation, digitalization, a n d supportive measures, b u t drugs a i m e d at controlling the sympathetic overstimulation of hyperthyroidism are not generally advised in neonates. T h e purpose of this r e p o r t is to describe the case of a newborn infant with thyrotoxicosis, already treated with sedation, digitalization, a n d s t a n d a r d antithyroid medications, whose recovery a p p e a r e d to relate directly to the use of the p - a d r e n e r g i c blocking agent, propranolol hydrochloride. CASE R E P O R T
The fifth pregnancy of the mother proceeded normally until the last trimester, when she developed hyperthyroidism (T4 [D] 16/~g per cent, RT3U 40 per cent). Symptoms were controlled with a combination of carbimazole, propranolol, phenobarbital, and Valium. Labor was induced
From the Division of Endocrinology, Department o[ Paediatries, The Hospital ]or Sick Children, Toronto, Ontario, Canada. ~Reprint address: Division o[ Endocrinology, 555 University Ave., Toronto, Ontario M5G IX8.
Vol. 83, No. 6, pp. 1046-1048
at 39 weeks' gestation and spontaneous vaginal delivery produced a 2,500 Gm. male child who appeared normal. The initial examination revealed a soft goiter, but the child was clinically euthyroid. Thyroid indices on the second day of life were T4 (D) 15.2 /xg per cent and RT3U 59.2 per cent. The baby remained well, although not gaining weight, until the seventh day of life when he developed, over several hours, extreme tachypnea (120 per minute) and tachycardia (200 per minute). On arrival at our hospital, the infant appeared lean and had a prominent forehead. He was restless and had a warm skin, exaggerated tendon reflexes, and a moderate soft goiter (2 cm. x 2 cm. each lobe). Exophthalmos was absent. The increased cardiac and respiratory rates were noted, and an electrocardiogram confirmed a supraventricular tachycardia with a rate of 220 per minute. A chest radiograph showed no evidence of cardiac enlargement. Despite these findings, the baby was hungry and fed readily. Laboratory data included a serum T4 (D) of 30 /~g per cent and RT3U of ~ 65 per cent with a long-acting thyroid stimulator response index in the baby of 240 per cent and in t h e mother of 200 per cent. The bone age (Greulich and Pyle a) was 6 to 9 months. Treatment was started on the day of admission with Lugol's solution, one drop every 8 hours, propylthiouracil (10 mg.), and phenobarbital (2.5 mg.) every 8 hours. After 24 hours and because of increasing tachycardia and liver enlargement, additional therapy with digoxin, 0.025 mg. intramuscularly twice a day for two
Volume 83 Number 6
Propranolol treatment o[ thyrotoxicosis
1 04 7
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Fig. 1. Clinical parameters during hospital stay. doses and then 0.0125 mg. orally each day was started. This regimen produced little clinical improvement, but the baby continued to feed well despite rapid cardiac and respiratory rates. On the eleventh day of life, when it became apparent that the tachycardia was resistant to full digitalization, the digoxin was stopped and oral propranolol 2 rag. twice a day (2 mg. per kilogram per day) was initiated. Within 24 hours there were significant reductions in cardiac and respiratory rates (Fig. 1). Improvement continued, and the baby was discharged on the twenty-fourth day of life; weight was 2,900 Gm. Satisfactory weight gain with no recurrence of symptoms occurred at home and gradual withdrawal of therapy was commenced at 4 weeks of age. Lugol's solution and propranolol were withdrawn completely by 5 weeks; the dosage of propylthiouracil was reduced at 6 weeks and withdrawn by 8 weeks. Supplemental thyroxin was added at 6 weeks because of hypothyroidism (T4 [D~ 2.8 t~g per cent and RT3U 25 per cent). This medication .was continued for 3 weeks and then gradually withdrawn. Two weeks after cessation of all therapy, the child had normal
growth and development for his 3 months of age. The goiter which had gradually become smaller during treatment was no longer palpable. Thyroid indices were T4 (D) 10.6/zg per cent and RT3U 29 per cent, with a bone age of 6 months. DISCUSSION Neonatal hyperthyroidism m a y be due to transplacental passage of maternal long-acting thyroid stimulator? T h e usual threemonth course of the condition supports this concept. However, recent data ~ indicate that the problem is not always transient and symptoms m a y persist long past the postulated half-life of long-acting thyroid stimulator. The appearance of symptoms in the newborn child is often delayed for several days if the mother is receiving antithyroid medication at the time of delivery. The symptoms may develop with surprising rapidity, 6 and treatment should be instituted without delay. O u r infant had many of the accepted features of neonatal thyrotoxicosis, namely, a goiter at birth, a latent period before the
10 4 8
S m i t h and H o w a r d
onset of overt thyrotoxicosis, a n elevated long-acting thyroid stimulator response index, and an a d v a n c e d bone age. P r o m p t treatm e n t with antithyroid drugs a n d sedation was insufficient to control the h y p e r m e t a b o l i c features, and digitalization was instituted because of i m p e n d i n g h e a r t failure, b u t this was ineffective. fl-adrenergic blockade with p r o p r a n o l o l has been used with considerable benefit in a d u l t thyrotoxicosis T to control the effects of sympathetic overstimulation, i n c l u d i n g the tachycardia. T h e a d d i t i o n of p r o p r a n o l o l to the t h e r a p y of our b a b y p r o d u c e d a beneficial response within 24 hours as j u d g e d by cardiac and respiratory rates. I n a d e q u a t e treatm e n t of thyrotoxicosis can result in a fatal outcome due to excessive c a r d i o s y m p a t h e t i c stimulation. Since this c o m p l i c a t i o n responds readily to /?-adrenergic blocking ,drugs, it is a d v o c a t e d that in a d d i t i o n to thyroid "blockade," propranolol in a dosage of 2 mg. p e r kilogram per d a y be used as s t a n d a r d t h e r a p y for the m a n a g e m e n t of neonatal thyrotoxieosis. ADDENDUM
Recently we have managed a second male infant, born of a euthyroid mother whose Graves' disease was treated with iodine 131 nine months before delivery. The baby weighed 1,980 Gm. after 36 weeks' gestation and had a T4 (D) > 18.4 /~g per cent and RT3U 86.2 per cent on
The ]ournal o/ Pediatrics December 1973
Day 5. The bone age was advanced to 2 months. Treatment with Lugol's solution, started on the sixth day, did not suppress the baby's tachycardia, tachypnea, weight loss, or diarrhea. On the fifteenth day he was transferred to us and started on propylthiouracil I0 mg. three times daily, and propranolol 2 mg. twice daily. Lugo.l's solution was continued. His pulse and respiratory rates were reduced from 180 to t49 per minute and 82 to 60 per minute, respectively, within 24 hours. His diarrhea resolved within 4 days followed by a mean weight gain of 80 Gm. per day until discharge from hospital. REFERENCES
1. Par6, C., and Demers, P. P.: HyperthyroMie n6onatale, insuffisance cardiaque et L. A. T., Union Med. Can. 101: 1307, 1972. 2. Riopel, D. A., and Mullins, C. E.: Congenital thyrotoxicosis: paroxysmal atrial tachycardia, Pediatrics 50: 140, 1972. 3. Greulich, W. W., and Pyle, S. I.: Radiographic atlas of skeletal development of hand and wrist, Stanford, Calif., 1959, Stanford University Press. 4. Adams, D. D., Lord, J. M., and Stevely, H. A. A.: Congenital thyrotoxicosis, Lancet 2: 497, 1964. 5. HolIingsworth, D. R., Mabry, C. C., and Eckerd, J. M.: Hereditary aspects of Graves disease in infancy and childhood, J. PEDIATR. 81: 446; 1972. 6. Huhble, D.: Diseases of the thyroid gland in paediatric endocrinology, Oxford, 1969, Blackwell Scientific Publications, p. 147. 7. Shanks, R. G., Hadden, D. R., Lowe, D. C., McDevitt, D. G., and Montgomery, D.: Controlled trial of propranolol in thyrotoxicosis, Lancet 1: 993, 1969.
December, 1973 The Journal of P E D I A T R I C S
Propranolol in treatment of neonatal tbyrotoxicosis Colin S. Smith, M.B., Ch.B., M.R.C.P., a n d Neville J. H o w a r d , M.B., F . R . C . P . ( C ) , ~ Toronto, Ontario, Canada
S i N c E 1 9 0 0 forty-three cases of neonatal hyperthyroidism have been reported1-2; six of the infants died as a direct result of their thyrotoxicosis. These figures d e m o n s t r a t e a significant case fatality rate, a n d indicate the need for p r o m p t initiation of effective medical m a n a g e m e n t . C u r r e n t s t a n d a r d pediatric texts advocate antithyroid t h e r a p y c o m b i n e d with sedation, digitalization, a n d supportive measures, b u t drugs a i m e d at controlling the sympathetic overstimulation of hyperthyroidism are not generally advised in neonates. T h e purpose of this r e p o r t is to describe the case of a newborn infant with thyrotoxicosis, already treated with sedation, digitalization, a n d s t a n d a r d antithyroid medications, whose recovery a p p e a r e d to relate directly to the use of the p - a d r e n e r g i c blocking agent, propranolol hydrochloride. CASE R E P O R T
The fifth pregnancy of the mother proceeded normally until the last trimester, when she developed hyperthyroidism (T4 [D] 16/~g per cent, RT3U 40 per cent). Symptoms were controlled with a combination of carbimazole, propranolol, phenobarbital, and Valium. Labor was induced
From the Division of Endocrinology, Department o[ Paediatries, The Hospital ]or Sick Children, Toronto, Ontario, Canada. ~Reprint address: Division o[ Endocrinology, 555 University Ave., Toronto, Ontario M5G IX8.
Vol. 83, No. 6, pp. 1046-1048
at 39 weeks' gestation and spontaneous vaginal delivery produced a 2,500 Gm. male child who appeared normal. The initial examination revealed a soft goiter, but the child was clinically euthyroid. Thyroid indices on the second day of life were T4 (D) 15.2 /xg per cent and RT3U 59.2 per cent. The baby remained well, although not gaining weight, until the seventh day of life when he developed, over several hours, extreme tachypnea (120 per minute) and tachycardia (200 per minute). On arrival at our hospital, the infant appeared lean and had a prominent forehead. He was restless and had a warm skin, exaggerated tendon reflexes, and a moderate soft goiter (2 cm. x 2 cm. each lobe). Exophthalmos was absent. The increased cardiac and respiratory rates were noted, and an electrocardiogram confirmed a supraventricular tachycardia with a rate of 220 per minute. A chest radiograph showed no evidence of cardiac enlargement. Despite these findings, the baby was hungry and fed readily. Laboratory data included a serum T4 (D) of 30 /~g per cent and RT3U of ~ 65 per cent with a long-acting thyroid stimulator response index in the baby of 240 per cent and in t h e mother of 200 per cent. The bone age (Greulich and Pyle a) was 6 to 9 months. Treatment was started on the day of admission with Lugol's solution, one drop every 8 hours, propylthiouracil (10 mg.), and phenobarbital (2.5 mg.) every 8 hours. After 24 hours and because of increasing tachycardia and liver enlargement, additional therapy with digoxin, 0.025 mg. intramuscularly twice a day for two
Volume 83 Number 6
Propranolol treatment o[ thyrotoxicosis
1 04 7
AGEINDAYS aooo
-17
]
i~
isI
~s I
~zI
2800
~9I
~I
2~I
~ ' /
2600 ~.--.-- ~...../~....~'J 2400D
BODY
WE IG H T IN G RA MS
200 --
180~ HEA~RT s 110 5070 RESPIRATORY RATE
* ~ ~
40
Fig. 1. Clinical parameters during hospital stay. doses and then 0.0125 mg. orally each day was started. This regimen produced little clinical improvement, but the baby continued to feed well despite rapid cardiac and respiratory rates. On the eleventh day of life, when it became apparent that the tachycardia was resistant to full digitalization, the digoxin was stopped and oral propranolol 2 rag. twice a day (2 mg. per kilogram per day) was initiated. Within 24 hours there were significant reductions in cardiac and respiratory rates (Fig. 1). Improvement continued, and the baby was discharged on the twenty-fourth day of life; weight was 2,900 Gm. Satisfactory weight gain with no recurrence of symptoms occurred at home and gradual withdrawal of therapy was commenced at 4 weeks of age. Lugol's solution and propranolol were withdrawn completely by 5 weeks; the dosage of propylthiouracil was reduced at 6 weeks and withdrawn by 8 weeks. Supplemental thyroxin was added at 6 weeks because of hypothyroidism (T4 [D~ 2.8 t~g per cent and RT3U 25 per cent). This medication .was continued for 3 weeks and then gradually withdrawn. Two weeks after cessation of all therapy, the child had normal
growth and development for his 3 months of age. The goiter which had gradually become smaller during treatment was no longer palpable. Thyroid indices were T4 (D) 10.6/zg per cent and RT3U 29 per cent, with a bone age of 6 months. DISCUSSION Neonatal hyperthyroidism m a y be due to transplacental passage of maternal long-acting thyroid stimulator? T h e usual threemonth course of the condition supports this concept. However, recent data ~ indicate that the problem is not always transient and symptoms m a y persist long past the postulated half-life of long-acting thyroid stimulator. The appearance of symptoms in the newborn child is often delayed for several days if the mother is receiving antithyroid medication at the time of delivery. The symptoms may develop with surprising rapidity, 6 and treatment should be instituted without delay. O u r infant had many of the accepted features of neonatal thyrotoxicosis, namely, a goiter at birth, a latent period before the
10 4 8
S m i t h and H o w a r d
onset of overt thyrotoxicosis, a n elevated long-acting thyroid stimulator response index, and an a d v a n c e d bone age. P r o m p t treatm e n t with antithyroid drugs a n d sedation was insufficient to control the h y p e r m e t a b o l i c features, and digitalization was instituted because of i m p e n d i n g h e a r t failure, b u t this was ineffective. fl-adrenergic blockade with p r o p r a n o l o l has been used with considerable benefit in a d u l t thyrotoxicosis T to control the effects of sympathetic overstimulation, i n c l u d i n g the tachycardia. T h e a d d i t i o n of p r o p r a n o l o l to the t h e r a p y of our b a b y p r o d u c e d a beneficial response within 24 hours as j u d g e d by cardiac and respiratory rates. I n a d e q u a t e treatm e n t of thyrotoxicosis can result in a fatal outcome due to excessive c a r d i o s y m p a t h e t i c stimulation. Since this c o m p l i c a t i o n responds readily to /?-adrenergic blocking ,drugs, it is a d v o c a t e d that in a d d i t i o n to thyroid "blockade," propranolol in a dosage of 2 mg. p e r kilogram per d a y be used as s t a n d a r d t h e r a p y for the m a n a g e m e n t of neonatal thyrotoxieosis. ADDENDUM
Recently we have managed a second male infant, born of a euthyroid mother whose Graves' disease was treated with iodine 131 nine months before delivery. The baby weighed 1,980 Gm. after 36 weeks' gestation and had a T4 (D) > 18.4 /~g per cent and RT3U 86.2 per cent on
The ]ournal o/ Pediatrics December 1973
Day 5. The bone age was advanced to 2 months. Treatment with Lugol's solution, started on the sixth day, did not suppress the baby's tachycardia, tachypnea, weight loss, or diarrhea. On the fifteenth day he was transferred to us and started on propylthiouracil I0 mg. three times daily, and propranolol 2 mg. twice daily. Lugo.l's solution was continued. His pulse and respiratory rates were reduced from 180 to t49 per minute and 82 to 60 per minute, respectively, within 24 hours. His diarrhea resolved within 4 days followed by a mean weight gain of 80 Gm. per day until discharge from hospital. REFERENCES
1. Par6, C., and Demers, P. P.: HyperthyroMie n6onatale, insuffisance cardiaque et L. A. T., Union Med. Can. 101: 1307, 1972. 2. Riopel, D. A., and Mullins, C. E.: Congenital thyrotoxicosis: paroxysmal atrial tachycardia, Pediatrics 50: 140, 1972. 3. Greulich, W. W., and Pyle, S. I.: Radiographic atlas of skeletal development of hand and wrist, Stanford, Calif., 1959, Stanford University Press. 4. Adams, D. D., Lord, J. M., and Stevely, H. A. A.: Congenital thyrotoxicosis, Lancet 2: 497, 1964. 5. HolIingsworth, D. R., Mabry, C. C., and Eckerd, J. M.: Hereditary aspects of Graves disease in infancy and childhood, J. PEDIATR. 81: 446; 1972. 6. Huhble, D.: Diseases of the thyroid gland in paediatric endocrinology, Oxford, 1969, Blackwell Scientific Publications, p. 147. 7. Shanks, R. G., Hadden, D. R., Lowe, D. C., McDevitt, D. G., and Montgomery, D.: Controlled trial of propranolol in thyrotoxicosis, Lancet 1: 993, 1969.