Hyponatremia and polyuria in children with central diabetes insipidus: Challenges in diagnosis and management

Hyponatremia and polyuria in children with central diabetes insipidus: Challenges in diagnosis and management Robert J. Ferry, Jr, MD, Vatsala Kesavulu, MD, Andrea Kelly MD, Lorraine E. Levitt Katz, MD, and Thomas Moshang, Jr, MD Five patients with well-controlled, long-standing, central diabetes insipidus had acute development of dehydration, hyponatremia, and inappropriate natriuresis in the setting of polyuria resistant to exogenous antidiuretic hormone. Hyponatremia and dehydration worsened with fluid restriction or use of exogenous antidiuretic hormone. We discuss the challenges in diagnosis and management of probable salt wasting in children with central diabetes insipidus. (J Pediatr 2001;138:744-7)

Central diabetes insipidus is a common consequence of acute intracranial diseases such as brain tumors, hemorrhage, or trauma. Inappropriate natriFrom the Divisions of Endocrinology & Diabetes and Critical Care Medicine, Department of Pediatrics, Mattel Children’s Hospital at The University of California, Los Angeles; and the Division of Endocrinology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

Supported in part by The Lawson Wilkins Pediatric Endocrine Society Postdoctoral Research Fellowship (Pharmacia & Upjohn Award to Dr Ferry; Eli Lilly & Co. Award to Dr Kelly) and grants from the National Institutes of Health (F32 DK09985 to Dr Ferry, T32 DK07314 to Dr Kelly, and the Clinical Associate Physician Award to Dr Katz). Presented in part at The Year 2000 Pediatric Academic Societies and American Academy of Pediatrics Joint Meeting, Boston, Massachusetts, May 12-16, 2000. Submitted for publication Apr 17, 2000; revisions received July 21, 2000, and Oct 11, 2000; accepted Oct 27, 2000. Reprint requests: Thomas Moshang, Jr, MD, Division of Endocrinology & Diabetes, The Children’s Hospital of Philadelphia, 34th St & Civic Center Blvd, Philadelphia, PA 191044399. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/112651 doi:10.1067/mpd.2001.112651

744

uresis in the face of hyponatremia and intracranial disease was described as “cerebral” salt wasting more than 50 years ago.1,2 Polyuria caused by diabetes insipidus can obscure polyuria as a result of salt wasting, yet unrecognized salt wasting can be fatal.3 Moreover, many clinicians continue to favor the syndrome of inappropriate antidiuretic hormone secretion to lead the differential diagnosis of hyponatremia in patients with acute illness.4 Therapies for salt wasting and SIADH differ greatly. We describe a series of children exhibiting simultaneous CDI and hyponatremia with polyuria (presumptive salt wasting) and discuss difficulties in recognition and management of natriuresis in patients with CDI.

CASE REPORTS Patient 1 was a 12-year-old with panhypopituitarism and CDI caused by suprasellar germinoma treated with lthyroxine, hydrocortisone, and deamino8-D-arginine vasopressin (desmopressin) replacement. The serum sodium concentration on admission was 136 mEq/L,

with serum osmolality of 260 mOsm/ kg. After therapeutic irradiation was performed, she had acute development of thirst and polyuria refractory to additional intranasal DDAVP (urinary output exceeded 3 mL/kg/h). Eight hours later, she had a generalized seizure associated with hyponatremia (126 mEq/L). Despite her chronic ADH deficiency, her caretakers restricted fluids empirically, treating her as though she had SIADH. Polyuria persisted, and her serum sodium concentration fell further to 120 to 122 mEq/L, with a simultaneous serum creatinine levelDecember 26, 2000 of 0.3 mg/dL. Administration of 3% saline solution (4 mL/kg) raised her serum sodium level, and supraphysiologic saline solution and fluid supplementation (>6 mEq Na/kg/d and 2200 mL/m2/d) restored eunatremia over the subsequent 24-hour period. ADH ANP CDI

Antidiuretic hormone Atrial natriuretic peptide Central (neurogenic) diabetes insipidus CSW Cerebral salt wasting DDAVP Deamino-8-D-arginine vasopressin (desmopressin) SIADH Syndrome of inappropriate antidiuretic hormone secretion UOP Urinary output

Patient 2 (Fig 1) was a 25-year-old man with panhypopituitarism (caused by craniopharyngioma partially resected and irradiated 9 years earlier) treated with l-thyroxine, hydrocortisone, and DDAVP. Several days before admission, he experienced acute visual loss with enlargement of his tumor.

FERRY ET AL

THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 5 Dexamethasone (6 mg) was administered every 6 hours. Forty-eight hours later, he became acutely agitated and thirsty. UOP ranged from 5 to 21 mL/kg/h despite multiple doses of intranasal DDAVP administered at home and in the clinic over the 12-hour period before admission (Fig 1). At presentation, he had tachycardia (107 beats/min) and a 4-kg weight loss compared with his weight of 85 kg 1 week earlier. Serum sodium concentration was 115 mEq/L with a serum creatinine level of 0.6 mg/dL and serum osmolality of 224 mOsm/kg, which, in the face of dehydration and polyuria, indicated tremendous natriuresis and diuresis. Urinary sodium concentration was 34 mEq/L, and the plasma atrial natriuretic peptide concentration was 110 pg/mL (normal range, 25 to 77 pg/mL; Quest Diagnostics; Horsham, Pa), both inappropriately elevated in the setting of hyponatremia with dehydration.5 DDAVP was withheld, and supraphysiologic saline solution replacement restored eunatremia (Fig 1). UOP subsequently increased, but in association with hypernatremia (Fig 1), suggesting the salt wasting had probably resolved, and CDI had become the primary disorder. Intravenous vasopressin (0.0005 to 0.008 U/kg/h) with isotonic fluids restored eunatremia (Fig 1). Patient 3 (Fig 2) was a 4-year-old boy with holoprosencephaly and congenital CDI who underwent elective Nissen fundoplication. Fluid intake was discontinued for 8 hours before pentothal and pancuronium induction and intubation. The night before surgery, his serum sodium concentration was 155 mEq/L, and he received 740 mL of water with simultaneous urinary production of 82 mL (specific gravity 1.028). During surgery and recovery, he received 490 mL of 5% dextrose and 730 mL of 0.9% NaCl in association with 241 mL of UOP and minimal blood loss. During recovery he received 10 U of vasopressin intramuscularly when his serum sodium

Fig 1. Clinical course of patient 2, starting at presentation to oncology clinic. Arrows indicate repeated 10-µg doses of intranasal DDAVP, self-administered in clinic. Resuscitation with sodium, 9.8 to 22 mEq/kg/d, over the initial 11 hours restored eunatremia. Circles represent serum sodium concentration; squares represent urinary output (UOP).

level was 143 mEq/L, serum osmolality 291 mOsm/kg, and hemoglobin 16.8 g/dL (vs 12.6 g/dL before surgery). UOP remained high at 5 to 8 mL/kg/h despite additional ADH (Fig 2). He had acute dehydration with a 1.3-kg weight loss from his preoperative weight of 14 kg and tachycardia (108 to 140 beats/min), and he displayed hypotension (60/30 mm Hg at radial artery while supine). When his serum sodium level dropped to 130 mEq/L, his serum creatinine level was 0.3 mg/dL. His urine sodium level was high throughout this period of hyponatremia, ranging from 192 mEq/L to 367 mEq/L. Supraphysiologic saline solution supplementation restored eunatremia. Within 36 hours of surgery, natriuresis resolved, and his uncomplicated CDI resumed as before surgery. Patient 4 (Fig 3) was a 28-month-old girl with CDI and panhypopituitarism caused by sellar retinoblastoma. She was admitted for her third cycle of induction chemotherapy. She received intravenous hydrocortisone 100 mg/m2/d, and DDAVP was withheld. When UOP exceeded 5 mL/kg/h, signaling liberation from DDAVP, she received routine prechemotherapy hydration at

twice her maintenance rate and received, in order, intravenous vincristine (0.05 mg/kg), etoposide (2.5 mg/kg), cyclophosphamide (56.6 mg/kg), cis-platin (3.6 mg/kg), and mannitol (36 mg/kg). Six hours later she became nauseated, displayed tachycardia (144 beats/min), and was hyponatremic (125 mEq/L). Her serum sodium concentration remained at 125 mEq/L during 8 hours of saline solution resuscitation (6.6 mEq Na/kg/h). Fractional urinary excretion of sodium was >1%, inappropriately elevated given her hyponatremia (Fig 3). An attempt to wean the sodium infusion at 33 hours resulted in hyponatremia, suggesting ongoing natriuresis (Fig 3). Serum creatinine levels ranged from 0.3 to 0.4 mg/dL throughout her entire hospital course. Five days later she returned to her baseline CDI, and DDAVP was reinstituted. Patient 5 was a blind, severely developmentally delayed 14-year-old boy with CDI related to intracerebral hemorrhage that had occurred 10 years earlier during partial resection of hypothalamic astrocytoma. Without any apparent illness or ill contacts, he had persistent polyuria despite a fourfold 745

FERRY ET AL

THE JOURNAL OF PEDIATRICS MAY 2001

A

B Fig 2. Clinical course of patient 3, starting at recovery from anesthesia. Urinary output (UOP) increased and hyponatremia developed during the initial hours after surgery (A). Polyuria did not respond to repeated doses of subcutaneous ADH. He required administration of fluids, at least 5 mL/kg/h, over the initial 22 hours to restore hydration (vs usual maintenance of 3.3 mL/kg/h). Fluid restriction at 22 to 24 hours was associated with lowering of serum sodium concentration and high urinary sodium losses (B). Supraphysiologic NaCl replacement (>9.4 mEq Na/kg/d) restored eunatremia by 32 hours; thereafter, vasopressin was infused to control CDI.

increase in his oral DDAVP dose. He was lethargic, had decreased skin turgor, and had a 1-kg weight loss over the previous week. Serum sodium level measured 116 mEq/L. His mother refused admission and treated him at home with supraphysiologic oral saline solution (>10 mEq Na/kg/d) while withholding DDAVP. His serum sodium level was corrected to 136 mEq/L within 24 hours. When polyuria continued in her now hydrated child, the mother restored DDAVP therapy, and her son remained eunatremic. 746

DISCUSSION These patients demonstrate that profound hyponatremia and polyuria can occur in the presence of CDI. Our series reflects our own learning curve as we progressed from under-recognition of this combination to its outpatient management. Although we do not have urinary sodium values for all of our patients, we infer from their shared clinical presentations (hyponatremia, ADH-unresponsive polyuria, and dehydration) that each patient manifest-

ed increased urinary sodium losses. It is difficult to recognize polyuria caused by natriuresis in the face of polyuria resulting from diabetes insipidus. These patients illustrate that salt wasting should be considered when a patient with CDI displays polyuria that becomes abruptly unresponsive to exogenous ADH. Salt wasting can be primarily renal, as illustrated by patient 4, for whom cis-platin or mannitol could have been the cause of natriuresis. Cerebral salt wasting refers to natriuresis occurring in association with intracranial disease in a patient with otherwise normal renal function. CSW most often occurs in association with subarachnoid hemorrhage, neurosurgery, or intracranial neoplasms.6 Because these disorders and their treatment can also result in CDI, the clinician should suspect CSW in patients with brain disorders when they have acute polyuria or when their chronic polyuria becomes unresponsive to ADH. Immediate assessment of serum and urinary electrolyte composition is indicated in these situations. Patients 3 and 5 had salt wasting without an acute intracranial injury; however, both patients had chronic brain disease. Patient 3 was recovering from general anesthesia which, by definition, acutely alters brain function. We are not aware of other reports of CSW associated with general anesthesia. The courses of patients 3 and 5 suggest that development of salt wasting in the absence of an acute neurologic disorder should prompt a search for an acute intracranial process. Alternatively, because both patients had chronic brain disorders, it is possible that an underlying chronic brain disorder makes patients more susceptible to development of CSW. Although mild electrolyte wasting can be observed with SIADH or diabetes insipidus,7 SIADH can be excluded as the cause of hyponatremia in our patients with chronic ADH deficiency. Our patients who had intact

FERRY ET AL

THE JOURNAL OF PEDIATRICS VOLUME 138, NUMBER 5 thirst mechanisms reported thirst while hyponatremic, and fluid restriction worsened hyponatremia, both findings atypical for patients with SIADH. All 5 patients were hypovolemic and polyuric, which is also inconsistent with SIADH. The clinical diagnosis of hypovolemia is difficult to make without resorting to invasive procedures such as central venous pressure, pulmonary wedge pressure, or determination of blood volume. Orthostatic hypotension (in the absence of autonomic failure) or acute weight loss is consistent with hypovolemia. Urinary sodium, plasma ADH, and plasma ANP concentrations are not necessary to diagnose CSW. Although low plasma ANP levels are consistent with hypovolemia, ANP concentration can be elevated in CSW or SIADH and so is not useful to distinguish these 2 conditions.8 Baseline determinations of plasma renin and aldosterone can help distinguish CSW from SIADH, because patients with salt wasting have increased renin and aldosterone levels, but these tend to be low-normal or low in SIADH. Hyponatremia is the feature that distinguishes natriuresis from diabetes insipidus. The danger of empiric treatment of hyponatremia with fluid restriction, presuming SIADH as the cause of hyponatremia, was illustrated in the only other report to date, in 2 adults, of coexistent CDI and CSW.3 One of these patients died after water restriction resulted in profound hyponatremia and dehydration.3 Frequent monitoring of serum sodium levels and UOP is key to early detection of CSW in patients at high risk for salt wasting such as those with subarachnoid hemorrhage or those who have undergone neurosurgery.9 Although we can instinctively accept the diagnosis of CSW, and the physiology of various natriuretic peptides has been extensively studied,7 the cause of CSW remains unknown. One attractive mechanism for CSW is the inappropriate release of brain natriuretic peptides in the setting of acute brain

Fig 3. Clinical course of patient 4 after chemotherapy. Urinary output (UOP) exceeded 5 mL/kg/h throughout the time line shown. She developed acute hyponatremia and dehydration while polyuric over the initial 16 hours. Supraphysiologic NaCl replacement (8-20 mEq/kg/d) restored eunatremia by 20 hours. An attempt to wean her sodium infusion at 33 to 35 hours was associated with relapse to hyponatremia. She remained eukalemic throughout this time with physiologic potassium supplementation.

dysfunction. Alternatively, chronic brain disease may predispose to CSW by impairment of regulatory pathways for natriuretic peptides. We think the safest, most effective therapy for natriuresis in the setting of CDI is saline solution administration directed by serial assessment of serum sodium concentrations, UOP, and hydration status. Exogenous ADH must be withheld, because ADH will retain free water and exacerbate hyponatremia. Fludrocortisone has been used to treat patients with CSW10; however, stress doses of mineralocorticoid did not prevent natriuresis in our patients. Patients with salt wasting and CDI can require tremendous amounts of salt and water replacement, and their natriuresis may cease abruptly. Thus vigilance is essential for rapid response to dynamic fluid and electrolyte imbalances in such children.

4.

5.

6.

7.

8.

9.

REFERENCES 1. Peters JP, Welt LG, Sims EAH, Orloff J, Needham J. A salt wasting syndrome associated with cerebral disease. Trans Assoc Am Physicians 1950; 63:57-64. 2. Cort JH. Cerebral salt wasting. Lancet 1954;1:752-4. 3. Laredo S, Yuen K, Sonnenberg B,

10.

Halperin ML. Coexistence of central diabetes insipidus and salt wasting: the difficulties in diagnosis, changes in natremia, and treatment. J Am Soc Nephrol 1996;7:2527-32. Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;529-42. Rodriguez-Soriano J, Vallo A. Salt-losing nephropathy associated with inappropriate secretion of atrial natriuretic peptide: a new clinical syndrome. Pediatr Nephrol 1997;11:565-72. Harrigan MR. Cerebral salt wasting syndrome: a review. Neurosurgery 1996;38:152-60. Kappy MS, Ganong CA. Cerebral salt wasting in children: the role of atrial natriuretic hormone. Adv Pediatr 1996;43:271-308. Cogan E, Debieve MF, Philipart I, Pepersack T, Abramow M. High plasma levels of atrial natriuretic factor in SIADH. N Engl J Med 1986;314: 1258-9. Lehrnbecher T, Muller-Scholden J, Danhauser-Leistner I, Sorensen N, von Stockhausen HB. Perioperative fluid and electrolyte management in children undergoing surgery for craniopharyngioma. A 10-year experience in a single institution. Childs Nerv Syst 1998;14:276-9. Sakarcan A, Bocchini J Jr. The role of fludrocortisone in a child with cerebral salt wasting. Pediatr Nephrol 1998;12: 769-71. 747