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
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
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
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
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