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© Freund Publishing House Ltd., London                 Journal of Pediatric Endocrinology & Metabolism, 23, 153-158 (2010)...
154                                         H. YAGASAKI ET AL.

therapy and LCD is unclear. Therefore, we report        ...
LATE-ONSET CIRCULATORY DYSFUNCTION                                          157

stable circulatory and respiratory condi...
158                                                H. YAGASAKI ET AL.

     Society. Update of newborn screening and the...
Late-Onset Circulatory Dysfunction After Thyroid Hormone ...
Late-Onset Circulatory Dysfunction After Thyroid Hormone ...
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  1. 1. © Freund Publishing House Ltd., London Journal of Pediatric Endocrinology & Metabolism, 23, 153-158 (2010) Late-Onset Circulatory Dysfunction After Thyroid Hormone Treatment in an Extremely Low Birth Weight Infant Hideaki Yagasaki1, Kisho Kobayashi2, Atsushi Nemoto1, Atsushi Naito1, Kanji Sugita2, and Kenji Ohyama2 1 Division of Neonatology, Perinatal Center, Yamanashi Prefectural Central Hospital and 2 Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan ABSTRACT KEY WORDS Late-onset circulatory dysfunction (LCD) is late-onset circulatory dysfunction, hypothyroid- a phenomenon specific to premature infants ism, extremely low birth weight infant, adrenal and is characterized by sudden onset of hypo- insufficiency natremia, hypotension, oliguria and non- physiological weight gain, without an obvious INTRODUCTION cause, in premature infants after stabilization of circulation and respiration. The cause of Premature infants often have poor pituitary LCD is not clear, but adrenal insufficiency in function and hormone synthesis, and often deve- premature infants is a severe syndrome lop relative hormone insufficiency. In Japan, a because steroid replacement therapy is often number of premature infants with late-onset essential to treat the symptoms. We report a circulatory dysfunction (LCD; or late-onset rare case of a premature infant who developed circulatory collapse) have been reported1. This an LCD crisis the day after thyroxine replace- syndrome is classified as adrenal insufficiency of ment therapy. The female infant was born at prematurity (AOP) when steroids need to be 25 weeks of gestational age, weighing 672 g, administered to overcome impaired adrenal and appeared to have hypothyroidism, with function. LCD is usually characterized by sudden free T4 of 0.19 ng/dl and elevated TSH levels onset of hyponatremia, hypotension, oliguria, of 26.3 μIU/ml at Day 14. She developed an and non-physiological weight gain, without an LCD crisis the day after starting thyroxine obvious cause, in infants after stabilization of treatment. She received steroid replacement circulation and respiration. Some LCD cases are therapy for 4 weeks and her adrenal function considered to show relative adrenal insufficiency progressively recovered. She also needed thy- because volume expanders (physiological saline roxine supplementation for 13 weeks, which or plasma albumin agents) and inotropic agents maintained her thyroid function as euthyroid. are often ineffective, whereas steroid replacement Because she exhibited cortisol insufficiency therapy is usually effective2. On the other hand, and thyroid hormone insufficiency, the ante- hypothyroxinemia is often reported in premature cedent thyroid hormone replacement may be infants3, and many trials of thyroxine replacement responsible for the onset of LCD. We must therapy (predominantly levothyroxine) have been consider monitoring adrenal function when reported4. However, it is unclear whether thy- starting thyroxine therapy in premature roxine replacement is effective in terms of neuro- infants with hypothyroxinemia. developmental outcome in premature infants. Some cases of premature infants who developed Reprint address: LCD after receiving thyroxine treatment for Hideaki Yagasaki M.D. hypothyroxinemia have recently been Department of Pediatrics Yamanashi Prefectural Central Hospital experienced in Japanese neonatal intensive care 1-1-1 Fujimi, Kofu units (NICU). These cases have not been reported Yamanashi 400-8506, Japan yet, and the relationship between thyroxine e-mail: VOLUME 23, NO. 1-2, 2010 153
  2. 2. 154 H. YAGASAKI ET AL. therapy and LCD is unclear. Therefore, we report was very low (2.0 μg/dl), relative adrenal here an extremely low birth weight infant who insufficiency was suspected. developed LCD after thyroxine treatment. Based on these findings, we diagnosed LCD and started steroid therapy (hydrocortisone, 1 mg/dose, twice per day), and continued thyroxine PATIENT REPORT therapy. Her blood pressure and urine volume improved within 24 hours, she was able to A female infant was born at the gestational continue milk feeding, and showed weight gain. age of 25 weeks and 1 day, with a birth weight of The clinical course after steroid therapy is shown 672 g and height of 31.5 cm. She was the first in Figure 2. Her steroid therapy was continued for child of healthy parents of Brazilian nationality. 40 days after the first administration. Thyroxine Her mother was admitted to our hospital due to therapy was set to 5.0 μg/day between Days 15 premature rupture of the membranes, and her and 116. On Day 116, her body weight had laboratory data were WBC 13,000/μl and CRP increased to 1,700 g and thyroxine was dis- 0.56 mg/dl. Therefore, continuation of pregnancy continued. Her thyroid hormone status was was difficult and an emergency Cesarean section maintained as euthyroid and, 1 month later, her was performed. Antenatal steroids were not TSH, free T3 and free T4 levels were 2.58 administered because of the emergency delivery. μIU/ml, 3.68 pg/ml and 1.28 ng/dl, respectively. The infant had a 1-min Apgar score of 5 and a 5- On day 160, we performed a CRH loading test to min score of 7. Therefore, she was intubated assess her adrenal function, and the results are while in the delivery room for positive pressure shown in Figure 3. The CRH loading test ventilation and she was then admitted to our revealed normal adrenal function, although a NICU. TRH administration test was not performed at The clinical course of the emergency period is that time. The patient was discharged on Day 165 shown in Figure 1. She was treated with intra- weighing 3,586 g and continued treatment at an tracheal surfactant due to respiratory distress outpatient department. At this time, she had syndrome; antibiotics, gamma-globulin and granu- chronic lung disease (CLD) and mild deafness, locyte-colony stimulating factor due to infection; without periventricular leukomalacia (a major and inotropic agent (dopamine) and indomethacin complication associated with LCD). because of the presence of patent ductus arteriosus. After stabilizing her respiratory and circulatory status, breast-milk feeding was started DISCUSSION at day 5 and her body weight increased slightly. Fourteen days after birth, her laboratory Here, we have reported a rare case of an examination revealed hypothyroidism; her serum extremely low birth weight infant who had free T3 concentration was 1.65 pg/ml, free T4 cortisol insufficiency and thyroid hormone was 0.19 ng/dl and TSH was 26.3 μIU/ml. insufficiency. We considered that it would be Therefore, thyroxine therapy (5.0 μg/day) was dangerous to treat hypothyroidism in a premature commenced. The next day (Day 15), she suddenly infant, and it was difficult to assess the associ- developed hyponatremia (serum Na: 129 mEq/l), ation between LCD and thyroxine therapy. hypotension (blood pressure: 45/24 mm Hg; The underlying pathogenesis of LCD is <80% of the mean for the previous day), oliguria obscure although it seems to represent adrenal (urine volume: 0.9 ml/kg/h), and non-physio- dysfunction because intravenous steroids are logical weight gain with severe edema. We effective in some cases. Relative adrenal in- performed blood examinations, culture and ultra- sufficiency occurs when an infant’s cortisol sonography; sepsis, PDA and intraventricular response is inadequate for the degree of illness or hemorrhage (IVH) were excluded as possible stress5. The diagnostic criteria for LCD are now causes of hypotension. Thyroid function on Day considered to include the sudden development of 14 and emergency data on Day 15 are shown in hypotension or oliguria requiring treatment, Table 1. Because her serum cortisol concentration without obvious cause, in preterm infants with JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM
  3. 3. LATE-ONSET CIRCULATORY DYSFUNCTION 157 stable circulatory and respiratory conditions for hormone affects the onset of LCD, and there are several days. Hypotension is defined as a blood no clear reports describing such events in the pressure <80% of the mean value before the literature. Another report suggested that some episode, and oliguria is defined as at least one of cases of LCD may occur in premature infants the following: (1) passed less than 50% of the with hypothyroxinemia and elevated TSH10. urine volume before the episode over 8 hours; (2) Therefore, thyroxine therapy should be started passed <1 ml/kg/h over 8 hours; or (3) anuria carefully in infants with immature adrenal func- lasting 4 hours6. We believe our patient met these tion. In patients with complex hypopituitarism, criteria, but steroid therapy was not completely glucocorticoids should be administered before successful because she developed steroid depen- starting thyroid hormone replacement, because dence and steroid replacement therapy could not thyroid hormone administration in hypothyroid be withdrawn for 40 days, while the mean steroid patients increases the requirement for gluco- therapy period reported is within 8 days. The corticoids during stress11. Our patient exhibited concomitant thyroxine therapy likely affected her adrenal insufficiency and low cortisol production steroid dependence. At the onset of LCD, her and, because thyroid hormone activates cortisol serum cortisol was low (2.0 μg/dl), which was metabolism, she was unable to compensate for considered to be due to adrenal immaturity, hypotension and was dependent on steroids for which was considered to be insufficient to one month. Therefore, assessment of adrenal maintain homeostasis during acute stress or function (e.g., serum cortisol concentration) is clinical syndromes such as hypotension. Thus, the important when starting thyroxine therapy. best therapeutic plan was considered to be to Further studies are needed to clarify the patho- maintain observation until her adrenal function physiology of LCD and the association between had matured. In fact, her adrenal function, as LCD and hypothyroidism. determined by the CRH stimulation test on Day 160, was nearly normal. REFERENCES In preterm infants, thyroxine (T4) and triiodothyronine (T3) levels are lower than those 1. Kusuda S, Fujimura M, Sakuma I, Aotani H, Kabe K, in term infants, and thyroid function in premature Nishida H, et al. Morbidity and mortality of infants with very low birth weight in Japan: center variation. infants is characterized by decreased serum free Pediatrics 2006; 118: 1130-1138. T4 and TSH levels during the first 2-4 postnatal 2. Masumoto K, Kusuda S, Aoyagi H, Tamura Y, weeks of life, a condition known as transient Obonai T, Kobayashi Y, et al. Comparison of serum hypothyroxinemia of prematurity7. On the other cortisol concentrations in preterm infants with or hand, hypothyroxinemia with elevated TSH without late-onset circulatory collapse due to adrenal levels is suspected to represent congenital insufficiency of prematurity. Pediatr Res 2008; 63: 686-690. hypothyroidism and the administration of thyroid 3. LaFranchi S. Thyroid function in the preterm infant. hormone should be started immediately8. Thyroid Thyroid 1999; 9: 71-78. function in the present infant on Day 14 revealed 4. Osborn DA, Hunt RW. Postnatal thyroid hormones hypothyroidism with elevated TSH levels; for preterm infants with transient hypothyroxinaemia. therefore, we did not hesitate to commence Cochrane Database Syst Rev 2007; (1): CD005945. thyroid hormone replacement. However, she was 5. Fernandez EF, Watterberg KL. Relative adrenal in- sufficiency in the preterm and term infant. J Perinatol successfully withdrawn from thyroid hormone 2009; 29: 44-49. replacement, and we believe this case represents 6. Kawai M, Kusuda S. Late-onset circulatory dys- transient hypothyroidism. function. In: Handbook of Neonatal Endocrinology In Japan, some cases of LCD after thyroxine [in Japanese]. Osaka: Medicus Shuppan Publisher therapy have been experienced. The incidence of Co. Ltd., 2008; 39-47. LCD is 11.6% in extremely low birth weight 7. Fisher DA. Thyroid system immaturities in very low birth weight premature infants. Semin Perinatol infants (birth weight below 1,000 g), and 9.3% of 2008; 32: 387-397. all cases of LCD occurred after thyroxine 8. American Academy of Pediatrics, American Thyroid therapy9. However, it is unclear whether thyroid Association, Lawson Wilkins Pediatric Endocrine VOLUME 23, NO. 1-2, 2010
  4. 4. 158 H. YAGASAKI ET AL. Society. Update of newborn screening and therapy 10. Hattori T. Three cases of extremely low birth weight for congenital hypothyroidism. Pediatrics 2006; 117: infants, who developed circulatory dysfunction after 2290-2303. l-T4 therapy. J Jpn Soc Premature Newborn Med 9. Kawai M. Questionnaire of late-onset circulatory 2008; 20: 66 (Abst). dysfunction cases after levothyroxine administration. 11. Kronenberg HM, Melmed S, Polonsky KS, Larsen 43rd Japanese Society for Pediatric Endocrinology, PR. Williams’ Textbook of Endocrinology, 11th Ed. 2009, Utsunomiya, Japan. OR-18. Philadelphia, PA: WB Sanders, 2007; 240-241. JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM