January 1977 The Journal o f P E D I A T R I C S

111

Inappropriate secretion of antidiuretic hormone in a premature infant Joseph A. Weinberg, M.D., Richard E. Weitzman, M.D., Shereen Zakauddin, M.D., and Rosemary D. Leake, M.D.,*

Torrance, Calif.

T . E SV N D R 0 M E o f i n a p p r o p r i a t e a n t i d i u r e t i c h o r m o n e

has been well described in both adults and children ' ~ in m a n y clinical situations. Cases have been reported in term n e w b o r n infants,-' but none has been r e p o r t e d in p r e m a ture infants. We present a case o f S I A D H , with corres p o n d i n g plasma arginine vasopressin levels, in a p r e m a ture infant following ligation o f a patent ductus arterioSUS. CASE R E P O R T Patient S. F. was an 1,100 gm male infant born to a 21-yearold, gravida 2, para 1, abortion t, Mexican-American mother at 28 weeks' gestation (by dates and by the clinical criteria of Dubowitz and associates:'). The pregnancy had been uncomplicated until spontaneous onset of premature labor. Apgar scores were 8 at 1 minute and 9 at 5 minutes, respectively. Only bulb suctioning was required in the delivery room. The infant had mild respiratory distress requiring a concentration of 28% inspired oxygen at 19 hours of age. At 29 hours of age a grade 2/6 systolic murmur was heard at the lower left sternal border, and the infant was noted to have bounding pulses and a hyperactive precordium. Chest roentgenogram revealed cardiomegaly and increased pulmonary vasculature. The infant developed progressive congestive heart failure with cardiomegaly, pulmonary edema, hepatomegaly, and episodes of apnea responding to stimulation. Treatment included fluid restriction, digitalization, diuretics, and continuous positive airway pressure. In spite of this he required intubation to control his increasingly

From the Departments of Pediatrics and Endocrinology, UCLA School of Medicine, Harbor General Hospital. Supported in part by a General Research Support Grant, National Institutes of Health. *Reprint address: Department of Pediatrics, Harbor General Hospital, 1000 W. Carson St., Torrance, Calif. 90509.

frequent apnea and acidosis. An aortogram demonstrated a massive left-to-right shunt through the ductus arteriosus. The patent ductus arteriosus, ligated at 70 hours of age, was noted to be as large as the aorta, approximately 4 mm in diameter. Fluid and electrolyte data are summarized in Table I except for serum potassium levels which were always normal and are not included. Pre- and immediate post-operative serum electrolyte concentrations were normal. The infant received 105 ml/kg/day of 10% dextrose in water for the first 17 hours postoperatively. The intravenous infusion rate was then increased to 160 ml/kg/ day with a maintenance sodium infusion of 3 mEq/kg/day. Abbreviations used SIADH: syndrome of inappropriate antidiuretic hormone AVP: arginine vasopressin DOCA: desoxycorticosterone acetate Forty-eight hours postoperatively the infant was noted to be hyponatremic with a sodium of 114 mEq/l, but he remained asymptomatic. Urine specific gravity was 1.015 to 1.020. There was no clinical evidence of dehydration or congestive heart failure and a presumptive diagnosis of SIADH was made. Fluids were restricted to 80 ml/kg/day with 3 mEq/kg/day NaCI and the serum sodium concentration slowly increased to 134 mEq/1 over the next 36 hours. When the volume of infused fluids was increased to 135 ml/kg/day, the serum sodium concentration fell to 120 mEq/l. At this time the serum osmolality was 249 mOsm/ kg and urine osmolality, 285 mOsm/kg. Urinary sodium concentration was 98 mEq/1 and potassium, 44 mEq/l. Five milliliters of isotonic saline was given intravenously over 20 minutes as a salt challenge: this increased the urinary sodium concentration to 110 mEq/l. For the remainder of the infant's course, fluid was restricted to 100 ml/kg/day and urinary sodium loss was replaced mEq for mEq every four hours with 3% sodium chloride. Repeated urinalyses demonstrated trace glycosuria only, without proteinuria.

Vol. 90, No. 1, pp. 111-114

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Weinberg et al.

The Journal of" Pediatrics January 1977

Table I. Fluid a n d electrolyte data for a n i n f a n t with S I A D H

Time 2 hr pre-operatively POD 1 POD2 POD 4 POD 5AM POD5PM POD 6 3-11PM POD 6 I1-7pM POD 7 7-3AM

Fluid intake (ml/ kg /day)

Serum sodium (mEq/l)

Serum Chloride (mEq/I)

141 143 114 134 120 126 122

102 99 90 96 96

745

90 105 160 100 135 140 90

760

90

137

Weight (gin.) 900 900 840 875 875

POD 7 3-11PM POD 7 ll-7PM POD 8 7-3AM POD 8 3-11PM POD 8 I1-7PM POD 9 7-3

Osmolality serum / urine (m Osm / kg)

Urine sodium (mEq/I)

249/285 245/362

98 89 98-112

88

112 118 DOCA 0.5 mg IM

740

96

132

730

105

143

93 DOCA 0.5 mg IM IV rate increased by 1/3 109

130 112 112 112 136 136

POD = Post operative day; ADH = antidiuretic hormone: GFR = glomerular filtration rate; DOCA = desoxycorticosteroneacetate.

The infant still required assisted ventilation on the third postoperative day. A chest roentgenogram showed bronchopulmonary dysplasia, a normal-sized heart, and persistent elevation of the left hemidiaphragm. The serum sodium concentration slowly rose to 137 mEq/l by the seventh postoperative day. At this time he was given hydrocortisone, 20 mg intravenously, every 12 hours in an effort to improve his chronic pulmonary insufficiency. DOCA, 0.5 mg intramuscularly, was given on successive days without changing the urinary sodium and potassium concentrations. Fluids were increased to 150 ml/kg/day on the ninth postoperative day at which time the child's respiratory status was improving. That evening the child sustained an intracranial hemorrhage. He died on the tenth postoperative day. The infant weighed 740 gm at the time of death and the serum electrolyte concentrations were normal. An autopsy revealed cerebral hemorrhage and focal pneumonitis. The adrenal glands, thyroid gland, and kidneys were grossly and histologically normal. Special studies. The plasma arginine vasopressin level measured by the radioimmunoassay method of Skowsky and associates~ was 2.57 ~tlU/ml when the serum sodium concentration was 120 mEq/1. On the ninth postoperative day, following the intracranial hemorrhage, the AVP level had dropped to 0.97 ~IU/ml and the serum sodium concentration was normal. Renal function tests were performed on the fifth postoperative day with the infant receiving 140 ml/kg/day. Glomerular filtration rate, measured by the constant inulin infusion method,' was 0.89 ml/minute, normal for gestational and postnatal age." Total sodium reabsorption was 96%. At that time the serum sodium concentration was 126 mEq/L serum osmolality 245 mOsm/kg,

urine sodium 89 mEq/l, and urine osmolality 362 mOsm/kg. Urine and serum osmolalities were measured by freezing point depression.* Table I shows the sodium and potassium excretion data during the period of salt replacement and steroid supplementation. In addition the infant received small amounts of sodium from flushing the arterial catheter with 0.45% isotonic saline. DISCUSSION The cardinal features of S I A D H include:: (1) hyponatremia with corresponding hypo-osmolality o f the serum a n d extracellular fluid: (2) continued renal excretion of sodium; (3) absence o f clinical evidence o f fluid volume depletion; (4) osmolality o f the urine greater t h a n that appropriate for the c o n c o m i t a n t tonicity of the plasma, that is, urine less than maximally dilute; (5) n o r m a l renal function; (6) n o r m a l adrenal function: a n d (7) n o r m a l thyroid function. The infant was h y p o n a t r e m i c with a hypertonic urine, hypotonic serum, a n d decreased sodium reabsorption. Plasma A V P level was not strikingly elevated. Most patients with S I A D H have had m a r k e d l y elevated A V P levels although levels as low as 1.2 / f l U / m l have been r e p o r t e d . ' ~ R o b e r t s o n a n d associates" have shown excellent correlation between plasma osmolality and AVP *Advanced Digimatic Osmometer, Model 3D, Advanced Instrument, Inc.. Needham Heights, Mass.

Volume 90 Number 1

Net sodium excretion (mEq)

A ntidiuretic hormone secretion

Sodium

Potassium

excretion

excretion

(mEq/1. 73 m V hr)

(mEq)

Blood urea nitrogen (mg/dl)

17 17 6 5 9 -0.35

2.82

0.46

6

+0.12 + 0.01

2.82 4.08

0.46 0.56

11

-0.36

4.94

0.46

+ 1.29 +0.70 -0.48

2.55 1.7 4.25

0.29 0.18 0.46

-2.3 +0.37

10.9 8.8

levels in adults. They found plasma AVP levels of 0.5 to 1.5 pg/ml (0.2-0.6/~IU/ml) when the osmolality decreased below 280 mOsm/kg. There are no comparable data for infants. Hoppenstein and associates? ~ using a sensitive bioassay, reported blood ADH levels of 1.3 t~U/ml in infants 22 to 100 days of age and 3.6/~U/ml in infants 100 hours to three months of age. No comparisons with osmolality were made. In our nursery a series of nine premature infants, weighing 1,800 to 2,500 gm and recovering from the respiratory distress syndrome, had plasma AVP levels of 0.57 _+ 0.26 ~IU/ml (range 0.38-1.05/.dU/ ml) (unpublished data). A plasma AVP level of 2.57/dU/ ml with a concurrent serum osmolality of 249 mOsm/kg and a serum sodium concentration of 120 mEq/1 would be inappropriately elevated by known criteria and is consistent with levels previously reported in SIADH. The high concentration of urine sodium in the face of marked hyponatremia eliminates several causes of dilutional hyponatremia such as congestive heart failure, ascites, and positive pressure ventilation." The infant had no signs of congestive heart failure postoperatively and blood pressure and urine output were maintained within normal limits throughout his course. Salt depletion is unlikely in the absence of dehydration and with the high urinary sodium concentration unless the infant's kidneys were not capable of normal sodium reabsorption. Adrenal insufficiency is unlikely. The adrenal glands

1 13

Clinical correlation

In congestive heart failure, intubated No dehydration ADH = 2.57 ulU/ml GFR = 0.89 ml/min Saline challenge increases urine sodium loss: urine sodium replaced with 3% NaCL Hydrocortisone, DOCA given without decrease in urine sodium concentration

14

20

ADH = 0.97 utU/ml

were normal at autopsy. The serum potassium concentration was never elevated. The initial hyponatremia responded to fluid restriction without corticosteroid supplementation or increased sodium intake. Fluid and salt restriction should worsen the clinical condition of a patient with adrenal insufficiency. Saline infusion and DOCA administration should decrease urinary sodium and increase urinary potassium in salt-depleted subjects. Table I shows that while urinary sodium excretion appeared to decrease after the first dose of DOCA, potassium excretion did not increase and urinary electrolyte concentrations were unchanged. Thus the correction of the serum electrolyte concentrations during this period was most likely due to fluid restriction. There is no way to determine definitely that the infant had normal renal function. The glomerular filtration rate as determined by inulin clearance was normal. There was a trace of glycosuria, but this is commonly found in premature infants receiving dextrose infusions at high rates. There was no proteinuria, and urine acidification and concentrating ability were normal. Thus there was no evidence for generalized renal tubular dysfunction. Selective salt loss is possible. Prior to the increase in the intravenous infusion rate on postoperative Day 8, the rate of sodium excretion was equivalent to that reported in healthy premature infants by Aperia and associates"-' and by Nicolopoulas. ':~ Table I shows that the infant was

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Weinberg et al.

actually in positive sodium balance for many periods. Moreover sodium excretion markedly increased with increased fluid intake on postoperative Day 8 as would be expected with SIADH. '~ A similar response to fluid challenge had been previously demonstrated with decreased sodium reabsorption on Day 5. Thyroid function was not assessed but the gland was normal at autopsy. Continued weight loss can be explained by malnutrition, fluid restriction, and debilitations Serum sodium concentration increased with fluid restriction and decreased with fluid expansion. S I A D H appears to be the most consistent diagnosis in this patient. The syndrome of inappropriate antidiuretic hormone has been reported in infancy in the following clinical situations: meningitis5 asphyxia neonatorum,':' hypoplasia of the anterior pituitary,'" pneumonia, ~; and idiopathic vasopressin secretion. '* There are many possible reasons for this infant's SIADH, including central nervous system dysfunction, pulmonary disease, hypoxia, stress, and surgery, any one of which may be associated with SIADH. 1 Another possibility we considered is that the decrease in left atrial pressure following the ligation of the ductus arteriosus contributed to the increased levels of AVP as has been described following mitral commissurotomy. Although the etiology of this infant's S I A D H is unclear, premature infants can manifest the syndrome, and it should be considered in the differential diagnosis of hyponatremia in this age group.

The Journal of Pediatrics January 1977

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