Volume 94 Number 3

B r i e f clinical and laboratory observations

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Brief clinical and laboratory observations Nephrogenic diabetes insipidus in transplacental lithium intoxication Eli M. Mizrahi, M.D., Jean F. Hohbs, M.D., and David I. Goldsmith, M.D.,* Bronx, N. Y.

THE PHARMACOLOGIC a n d toxic effects o f lithium carbonate, a m o o d stabilizer used in the t r e a t m e n t o f manic-depressive illnesses, h a v e b e e n extensively studied in adults? Only in the current decade, reports a p p e a r e d c o n c e r n i n g the effects o f lithium ion ( L P ) in utero. ~ This report identify transient n e p h r o g e n i c diabetes complication o f fetal Li + exposure.

however, h a v e exposure to the is the first to insipidus as a

CASE REPORT A 38-year-old woman with a manic-depressive psychosis was treated throughout her pregnancy with 1,800 rag/day of lithium carbonate and 50 to 100 mg/day of chlorpromazine. The pregnancy was complicated by gestational diabetes detected in the thirty-fourth week. Ultrasonography demonstrated a large-fordates infant and polyhydramnios. Following the spontaneous onset of labor, the child was delivered vaginally at 35 weeks' gestation, and weighed 3,510 gm. The Apgar scores were 2 and 6 at 1 and 5 minutes, respectively. Physical examination on admission to the Neonatal Unit revealed a large-for-dates male with lethargy, poor Moro and suck reflexes, nonparalytic hypotonia, mild respiratory distress, and an enlarged thyroid gland. Shortly after birth the serum glucose concentration was less than 25 mg/dl. The hypoglycemia was rapidly corrected by intravenous administration of glucose. Persistent tachypnea prompted evaluation for sepsis and treatment with kanamycin (15 mg/kg/day) and ampicillin (100 mg/kg/day) for 5 and 7 days, respectively. No organisms were grown from any of the cultures. Laboratory and clinical studies performed during hospitalization, including serum electrolytes and creatinine, thyroid function tests, chest radiograph, electrocardiogram, and electroencephalogram, were normal. The Li+ concentration in cord serum (1 mEq/l) was similar to that in maternal serum (0.9 mEq/l), and on five subsequent occasions the Li+ concentration in the neonate From the Department of Pediatrics, Bronx Municipal Hospital Center, and the Rose F. Kennedy Center, Albert Einstein College of Medicine. *Reprint address: Division of Pediatric Nephrology, Rose 1L Kennedy Center-Rm. 721, 1410 Pelham Parkway South, Bronx, N.Y. 10461.

0022-3476/79/300493 +03500.30/0 9 1979 The C. V. Mosby Co.

was never within the range previously described as toxic. ~ Following an exchange transfusion performed for hyperbilirubinemia due to ABO incompatibility and hemolytic anemia, a marked reduction in the LP concentration was noted. LP could not be detected in the infant's urine at any time. Abbreviation used AMP: adenosine monophosphate Polyuna was noted within the first hours of life. The urinary volume on the first day was 87 ml/kg while 90 ml/kg were provided intravenously as 10% dextrose in water (Figure). Results of the urinalysis, urine culture, and Addis count were normal. During the second day of life 150 ml/kg of a commercially available electrolyte solution (D 5 E 48, Cutter Laboratories, Inc., Berkeley, Calif.) were infused and the urinary output (153 ml/kg) exceeded this volume. During the remainder of the first week the daily intake of fluids (more than 200 ml/kg/24 hours) exceeded the urinary output but the difference approximated the usual estimates of insensible loss. The body weight decreased by 12.5% in the first seven days of life. By the tenth day of life all fluids were taken orally and consisted of 150 ml/kg/day of Similac (20 calories/ounce) and supplemental water feedings on demand. The creatinine clearance measured on the third day of life was 4.8 ml/minute and by one month of age had increased to 10.0 ml/minute. The renal concentrating ability was tested on days 5, 18, and 33 by intravenous administration of aqueous vasopressin (50 milliunits/m0. The results are shown in the Table. On each occasion, administration of aqueous vasopressin failed to result in concentration of the urine. During this period of time, fluid restriction resulted in dehydration rather than an increase in urinary osmolality. By 2 months of age the mother noted that the infant began to void less frequently and to drink smaller amounts of the supplemental water feedings. At 86 days of age, the infant tolerated a six-hour period of water deprivation without a serious weight loss, and the urinary osmolality was found to be 580 mOsm/kg while the plasma osmolality was 279 mOsm/kg. Further stimulation of the concentrating mechanism by exogenous vasopressin administration was felt to be unwarranted. At 5 days of age the urinary concentrations of cyclic AMP were 0.7 nmol/ml before and 0.8 nmol/ml after vasopressin stimula-

494

Brief clinical and laboratory observations

The Journal of Pediatrics March 1979

i-~'-IINTRAVENOUS FLU;D VOLUME [~'//~ URINA RY VOLUME

250

ORAL INTAKE

200

N

~

I00

0 >

5O

1

2

4

3

.AGE (Days) Figure. Daily intake and urinary volume measured on the first 5 days of life. The weight of the baby at birth and on day 7 was 3,120 gm. The renal concentrating capacity was first measured on day 5. Table

Before vasopressin

After vasopressin

Plasma I Urine Age Plasma I Urine (days) (mOsm/kg) I (mOsm/kg) (mOsm/kg) (mOsm/kg) 5 lg 33 86

293 278 282 279

87 70 58 594*

287 288 287

156 258 219

*Following6 hours of dehydration;vasopressinnot given. tion. When adjusted for flow rate, the excretion of cyclic AMP/minute was found to be unchanged by administration of vasopressin. DISCUSSION The patient presented in this report illustrates several rather typical aspects of Li + intoxication. The disappearance rate of Li § from the child's serum, until altered by an exchange transfusion, was similar to that noted in another case report? The euthyroid goiter found in both mother and infant presumably results from a decrease in thyroxine and re-establishment of the euthyroid state following an increase in thyroid mass.' The marked hypotonia, which resolved spontaneously, has also been previously reported.' Both gestational diabetes and maternal lithium use may have contributed to the infant's hypoglycemia. Infants who are large for gestational age and have hypoglycemia are usually associated with maternal diabetes; however, the activity of Li" on carbohydrate and

lipid metabolism is similar to that of insulin, and may thus produce hypoglycemia) This is the first report of diabetes insipidus in a child born to a mother on chronic Li* therapy. The defect was shown to be nephrogenic and persisted for two months, although the concentration of Li* in the serum was undetectable after the fourth day of life. Lithium-induced nephrogenic diabetes insipidus is well recognized in adults and experimental animals? The condition is dose dependent, occurs months after the onset of treatment, and resolves spontaneously within weeks of the termination of the drug. ~ The patients have constant thirst, are unable to concentrate urine following either water deprivation or exogenous vasopressin administration, and, like other patients with nephrogenic diabetes insipidus, improve their concentrating capacity when given chlorothiazide? The underlying mechanisms responsible for the nephrogenic diabetes insipidus remain controversial. Some studies have suggested that Li; may affect renal concentrating ability by the inhibition of vasopressin-stimulated adenylate cyclase? That this phenomenon occurs has been demonstrated in the renal medulla of rats ~ and in preparations of renal medullary tissues of human beings. ~ Our measurements of cyclic AMP excretion support this proposed mechanism. However, urinary cAMP excretion is not dependent solely upon vasopressin stimulation, and data obtained from studies in experimental animals have shown that the concentrating defect associated with lithium ingestion cannot be corrected by administration of dibutyl cAMP, ~ suggesting that the site of action may be distal to cAMP formation. Finally, Li+-induced polydipsia may contribute to the observed water diuresis. This abnormality usually precedes the onset of polyuria and may be due to a direct effect on the thirst centers; it does not occur in rats with lateral hypothalamic lesions) ~ The number of neonates with Li*-induced nephrogenic diabetes is likely to increase with the more common use of this medication by women of child-bearing age. If it is not recognized and appropriate fluids provided, life-threatening dehydration may ensue. The authors are indebted to Dr. Detlef Schlondorff for the assay of urinary cyclic AMP concentration. We also thank Drs. A. Eidelman, L. Gartner, and A. Spitzer for their aid in the preparation of this manuscript, as well as Ms. V. Mimnaugh and Ms. M. Baudy for their secretarial assistance. REFERENCES 1. Singer I, and Rotenberg D: Mechanisms of lithium, N Engl J Med 289:254, 1973.

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Brief clinical and laboratory observations

2. Woody JN, London WL, and Wilbanks GD: Lithium toxicity in a newborn, Pediatrics 47:94, 1971. 3. Rane A, Tomson G, and Bjarke B: Effects of maternal lithium therapy in a newborn infant, J PrDIATR 93:296, 1978. 4. Stothers JK, Wilson DW, and Royston N: Lithium toxicity in the newborn, Br Med J 3:233, 1973. 5. Forrest JN, Cohen AD, and Toretti J: On the mechanisms of lithium induced diabetes insipidus in man and rat, J Clin Invest $3:1115, 1974. 6. Baldessarin RJ, and Lipinski JF: Lithium salts: 1970 to 1975, Ann Intern Med 83:527, 1975.

495

7. Baylis PH, and Heath DA: Water disturbances in patients treated with oral lithium carbonate, Ann Intern Med 118:607, 1978. 8. Doussa TP, and Hechter O: The effect of NaC1 and LiC1 on vasopressin-sensitive adenyl cyclase, Life Sci 9:765, 1970. 9. Doussa TP: Interaction of lithium with vasopressin-sensitive cyclic AMP system of human renal medulla, Endocrinology 95:1359, 1974. 10. Smith DF, Balagura S, and Lubran M: Antidotal thirst and lithium excretion in rats with hypothalamic lesions, Physiol Behav 6:209, 1971.

Acute hexachlorophene poisoning by mouth in a neonate Joel Herskowitz, M.D., and N. Paul Rosman, M.D.,* Boston, Mass.

H E X A C H L O R O P H E N E poisoning by mouth in the neonate is an exceedingly rare event; we have been able to find only one fully documented case, and that with only a six-month follow-up) Because of continuing concern about short- and long-term effects of H C P exposure, ~ we present our experience with a neonate accidentally fed a 3% H C P solution w h o m we have followed for 2V2 years.

Trousseau signs were absent, and serum electrolyte values were normal. Jitteriness and excitability increased over the first 12 to 18 hours, were notably diminished by day three, and disappeared entirely by the time of discharge at age 14 days, when the neurologic examination was normal. Plasma samples obtained at 24 and 48 hours after ingestion, analyzed for HCP by the Sterling-Winthrop Research Institute, New York, N.Y., had levels of 88 and 50/.tg/ml, respectively.

CASE REPORT An 8-day-old male Puerto Rican infant weighing 2,800 gm was inadvertently fed a 3% solution of HCP (pHisoHex) given to his Spanish-speaking mother in a milk container labeled in English to indicate its use for bathing only. The baby ingested an estimated l0 to 15 ml of pHisoHex (nearly 100 mg/kg of HCP) and spit up milky fluid immediately. He had three watery bowel movements within an hour and was brought to the Boston City Hospital, where he vomited again. The vomitus consisted of 3 ml of creamy white material. Another 3 ml were aspirated by nasogastric tube. Three washings with isotonic saline were required before clear fluid was obtained. Activated charcoal was then administered by nasogastric tube and left in the stomach. Over the first eight hours of hospitalization, the infant continued to vomit and pass diarrheal stools, leading to a state of 3 to 5% dehydration, Vital signs were normal. The anterior fontanel was slightly depressed. Six hours after ingestion, the infant was lethargic and poorly responsive to painful stimulation. Two hours later, left facial twitching, accentuated blinking, and exaggerated startle responses were seen. Tone was increased in all extremities, and deep tendon reflexes were abnormally brisk. Chvostek and

From the Departments of Pediatrics and Neurology (Pediatric Neurology), Boston University School of Medicine, Boston City Hospital. *Reprint address: Pediatric Neurology, Boston City Hospital, 818 Harrison Ave,, Boston, MA 02118.

0022-3476/79/300495 +02500.20/0 9 1979 The C. V. Mosby Co.

Abbreviation used HCP: hexachlorophene Evaluated at 2~h years of age, the patient was a cheerful, intelligent child speaking in sentences in Spanish. Growth measures, which approximated the third percentile, were commensurate with previous values and with those of his parents. He preferred the right hand for scribbling and throwing; he performed the latter in an overhanded fashion with unusual skill for age. Gait, muscle tone, and strength were normal, as were deep tendon reflexes. DISCUSSION The first case of H C P poisoning by mouth in childhood was reported in 1963 by Lustig? He described a 6-year-old mentally retarded girl who died nine hours after ingesting an estimated 120 to 150 ml of a 3% H C P solution, about 250 mg of H C P / k g . Despite gastric lavage within 15 minutes of ingestion, the child was comatose by one hour. Shock and a single convulsion preceded her death. In 1966 Pilapil reported a 17-day-old infant who over a one-week period of time received regular doses of pHisoHex that had been placed in a container labeled "Gantrisin. TM Vomiting followed the first administration. Fussiness and a single episode of opisthotonic posturing were