PEDIATRICS Vol. 118 No. 6 December 2006, pp. e1904-e1908 (doi:10.1542/10.1542/peds.2006-0702)
EXPERIENCE & REASON |
Fludrocortisone Therapy in Cerebral Salt Wasting
Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
ABSTRACT
Cerebral salt wasting is an increasingly recognized condition in pediatrics and is characterized by inappropriate natriuresis and volume contraction in the presence of cerebral pathology. Diagnosis can be difficult and therapy challenging. A few single case reports of the successful use of fludrocortisone exist. We report 4 patients with cerebral salt wasting, all of whom presented with hyponatremia in the presence of known intracerebral pathology. All had clinically significant hyponatremia, and 3 had hyponatremic seizures. Two of the patients also satisfied clinical criteria for diabetes insipidus. They all were treated with regimens using increased sodium and fluid administration but experienced ongoing salt wasting. Fludrocortisone was instituted in all 4 patients and in 3 resulted in rapid improvement in net sodium balance, enabling the weaning of hypertonic fluids and stabilization of serum electrolytes. In 3 patients, fludrocortisone treatment was complicated by hypokalemia, and in 1 patient by hypertension, which necessitated a dose reduction or brief cessation of therapy. Duration of therapy was 4 to 125 days. Cerebral salt wasting presents considerable management challenges; however, fludrocortisone therapy can be an effective adjunct to treatment.
Key Words: cerebral salt wasting • hyponatremia • fludrocortisone
Abbreviations: SIADH, syndrome of inappropriate antidiuretic hormone secretion • CSW, cerebral salt wasting • DI, diabetes insipidus • ADH, antidiuretic hormone
Disturbances in salt and water balance are relatively common in children managed in tertiary institutions for intracranial pathologies such as tumors and head injuries and present significant complexities in diagnosis and management. Although hypernatremia associated with diabetes insipidus (DI) is a commonly encountered entity, hyponatremia is also frequently encountered.
The major differential diagnoses in this situation are the syndrome of inappropriate antidiuretic hormone secretion (SIADH), marked by inappropriate retention of free water, and cerebral salt wasting (CSW), characterized by excessive urinary loss of sodium and resulting in polyuria and extracellular volume contraction. Diagnosis can be difficult, especially because other conditions such as central DI can precede or coexist.1
Reports of the existence of the CSW syndrome in the pediatric population first appeared in the 1980s and early 1990s,2,3 and the use of the mineralocorticoid fludrocortisone to treat cases of CSW has only been reported in isolated pediatric cases.4,5 Here we present our experience with 4 cases of CSW and the use of fludrocortisone in these patients.
CASE REPORTS
Patient 1.
A 10-year-old girl was diagnosed with a hypothalamic-chiasmatic pilocytic astrocytoma and underwent resection of the tumor in another country with preservation of the pituitary stalk. She was not on pituitary-hormone replacement. Three years later she underwent further resection for tumor recurrence with placement of an extraventricular drain. On day 7 postoperatively, she had a generalized tonic-clonic seizure, and her serum sodium level was found to be 129 mmol/L, having fallen from 137 mmol/L over the previous 72 hours despite negative fluid balance (–2 L) and a weight decrease of 0.8 kg. In the 24 hours before the seizure, calculated negative sodium balance was 95 mmol (2.6 mmol/kg). Despite administration of hypertonic saline, her serum sodium level decreased further to 124 mmol/L over the next 24 hours, and calculations showed continuing negative sodium balance. Fludrocortisone therapy was instituted at 0.1 mg twice daily. After 24 hours her serum sodium level was 136 mmol/L and urinary sodium concentration had decreased from 269 to 105 mmol/L. Mild hypokalemia prompted a reduction in fludrocortisone to 0.05 mg twice daily, and we were able to cease use of fludrocortisone after 4 days, with her electrolyte levels remaining normal.
Patient 2.
A 5-month-old girl presented with poor feeding, increasing head circumference, and nystagmus and was subsequently diagnosed with a pilocytic astrocytoma. Debulking was performed. On postoperative day 4, she had a generalized seizure. Testing of her electrolyte levels showed a serum sodium level of 127 mmol/L. Urine output was 2 to 3 mL/kg per hour; it had been 5 to 6 mL/kg per hour the previous day. Her urinary sodium level was 67 mmol/L, and urine osmolality was 264 mmol/kg. Fluid status was difficult to assess, and the child had gained 10% of her admission weight. Over the next 24 hours her serum sodium concentration continued to decrease and reached a nadir of 116 mmol/L. Urine output remained at >2 mL/kg per hour, and a diagnosis of CSW was made. Sodium replacement was instituted with hypertonic saline and liberalization of fluids. Within 48 hours, her serum sodium level had returned to 131 mmol/L.
Ongoing treatment was required with high amounts of sodium supplementation up to 25 mmol/kg per day; however, her serum sodium level continued to decrease below 134 mmol/L with high urinary salt losses. Plasma aldosterone (<40 pmol/L [reference range: 80–1040 pmol/L]) and renin activity (<32 fM/L per second [reference range: 1070–2930 fM/L per second]) were suppressed. Before commencing fludrocortisone, the patient had a net sodium balance of –5 mmol/kg per day at a time of ongoing hyponatremia. In the first 24-hour period after starting fludrocortisone, her absolute sodium balance became +11 mmol/kg per day, suggesting a dramatic and rapid effect on renal reabsorption of sodium. Her serum sodium level increased to 145 mmol/L; however, fludrocortisone was temporarily ceased because of hypokalemia (potassium: 2.4 mmol/L) before being restarted at a lower dose. The patient was eventually stabilized on 25 µg twice daily, and therapy was required for 21 days.
Patient 3.
A 12-year-old girl presented with decreased visual acuity and headache; MRI showed a 3 x 3 x 2.5-cm lesion in the pituitary fossa with suprasellar extension. Biopsy revealed craniopharyngioma.
Four weeks later she underwent a resection via craniotomy. Early DI was treated with intravenous aqueous vasopressin and then oral desmopressin. She was discharged from intensive care on postoperative day 4 with normal electrolyte levels.
On day 5 she was hypotensive. Urine output was consistently above 6 mL/kg per hour. Her serum sodium level decreased to133 mmol/L, and her serum bicarbonate level had risen to 30 mmol/L. She was managed with intravenous 0.9% saline. The following day she had a generalized seizure; her serum sodium level at this time was 121 mmol/L. Absolute sodium balance showed a net deficit of 7.4 mmol/kg of sodium on the day before her hyponatremic seizure.
Her salt-wasting state persisted for several weeks, and her plasma aldosterone (<40 pmol/L) and renin activity (<32 fM/L per second) levels were suppressed. Attempts at weaning the concentration and rate of hypertonic saline replacement were thwarted by hyponatremia and polyuria of up to 7 L per day (166 mL/kg day).
Before commencing fludrocortisone, her serum sodium level was 131 mmol/L, urine output was 131 mL/kg per day, urine sodium was 330 mmol/L, and net sodium balance was –6 mmol/kg per day. Three days after commencing fludrocortisone, her serum sodium had normalized, and urinary sodium concentration was 54 mmol/L. Hypertonic fluids were weaned, and oral salt supplementation commenced. She was discharged from the hospital 19 days after commencing fludrocortisone. Fludrocortisone was continued at a dose of 0.1 mg twice daily for another 4 months and then ceased with maintenance of normal electrolyte levels.
Patient 4.
A 10-month-old girl presented with a hypothalamic tumor filling the third ventricle and suprasellar region that proved to be a pilocytic astrocytoma. This was initially debulked, and 9 days later she underwent a bifrontal craniotomy resection. Both optic nerves had to be divided, but the pituitary stalk was thought to be spared.
Early DI responded to vasopressin with a reduction in urine volume. On days 2 and 3, the patient was hyponatremic with a serum sodium level of 123 and 124 mmol/L, respectively. Urinary sodium concentration was 200 mmol/L with polyuria (7 mL/kg per hour). Sodium chloride (0.9%) was used to replace urine losses. The ratio of urine to serum osmolality was >1.
This pattern continued for several weeks with persistent and progressive polyuria of 4 to 6 L/day (21–32 mL/kg per hour) despite a frequently titrated aqueous vasopressin infusion. Her serum sodium levels were maintained in the range of 132 to 145 mmol/L using 0.9% to 3% saline infusions, replacing urine output on an hourly basis. Urine sodium concentrations remained elevated, between 150 and 230 mmol/L. Attempts to wean the saline-replacement fluids were thwarted by rapid development of hyponatremia and persistently elevated urinary sodium concentration.
On postoperative day 12, fludrocortisone was commenced at a dose of 0.1 mg three times daily. On a typical day before commencement of fludrocortisone, the patient excreted 110 to 120 mmol/kg per day of sodium. Accurate net sodium deficit was difficult to calculate, because the patient was feeding orally by this time. Her serum sodium level rose mildly after the commencement of fludrocortisone; however, total sodium excretion remained essentially unchanged. Other investigations performed showed a suppressed aldosterone level of <40 pmol/L (reference range: 80–1040 pmol/L) and plasma renin activity of 34 fM/L per second (reference range: 1070–2930 fM/L per second). Subsequently, brain natriuretic peptide collected at the time was shown to be elevated at 25.4 pM/L (reference range: <12.6 pM/L in adults). An increase in fludrocortisone to 0.1 mg four times daily had no measurable effect on urine output or sodium excretion.
A clinical decision was made on day 27 to slowly wean both vasopressin and the intravenous replacement fluids. Forty-eight hours later the patient developed severe polyuria, passing 15 to 19 L of urine per day (100 mL/kg per hour). Urine sodium concentration was unchanged, and daily sodium excretion calculated was 365 mmol/kg per day. Fludrocortisone was weaned because of hypokalemia and hypertension.
Indomethacin was added in an attempt to reduce the glomerular filtration rate. Subsequently, urine output stabilized and decreased from these extraordinary heights to 4 mL/kg per hour over the next week. On day 43, the urinary sodium concentration was 23 mmol/L, serum sodium level was 140 mmol/L, and urine output was 3 to 4 mL/kg per hour. On day 47 the patient was discharged from the ICU and discharged from the hospital on day 55 with normal electrolyte levels and urine output. Fludrocortisone and indomethacin were ceased before discharge, but the pituitary-hormone replacement was continued with hydrocortisone, thyroxine, and intranasal desmopressin.
DISCUSSION
The management of salt and water balance in pediatric patients with intracranial pathology can be complex. Clinical assessment of hydration status is an inexact science,5,6 yet it is critical for differentiating SIADH from CSW. Most patients with CSW will, in fact, meet laboratory criteria for SIADH.7 As at least 1 of our cases illustrates, diagnostic uncertainty can occur. The picture can also be clouded by preceding or coexisting DI. The importance of regularly reviewing the clinical picture, hydration status, urine output, and sodium balance and the effect of any instituted treatment is highlighted.
Opinion on how common CSW is varies. Some authors argue that its existence is overstated,8 whereas others report that it is at least as common, if not more so, than SIADH.9 Information on its prevalence in childhood is even more scant, with mostly isolated case reports2,3,6 and 1 small series.10
The key feature of CSW is negative sodium balance. Increased excretion of salt necessarily leads to increased water excretion, giving rise to the most clinically significant features of increased urine output and extracellular volume contraction. Hyponatremia, although almost universally reported in CSW and often the initial marker that leads to the diagnosis, is a secondary event8 and can be prevented by matching sodium and water input to output in the first instance. It is important to note also that spot urinary electrolyte levels can be misleading, because urinary sodium concentration will be elevated in both CSW and SIADH. The critical calculation to make is absolute sodium excretion. Caution should also be used when interpreting ADH levels to differentiate CSW from SIADH, because CSW can be associated with a rise in ADH, which is mediated both centrally and by the contracted extracellular volume.8 As demonstrated in our cases, aldosterone levels are typically suppressed in CSW and normal or high in SIADH, with plasma renin suppressed in both.3
The use of fludrocortisone to treat CSW was first reported in the 1980s in adults with head injury,11 and single case reports of its use in pediatrics have appeared sporadically.3–5 It has been reported in isolated case reports that mineralocorticoid can effectively control natriuresis.5 In 3 of the 4 patients presented here, mineralocorticoid clearly reversed the negative sodium balance, with 1 patient experiencing a net change in absolute sodium balance of +16 mmol/kg per 24 hours on commencing fludrocortisone. This mediated a return to normal sodium values via a reduction in natriuresis. In 2 of our patients, the fludrocortisone was able to be ceased soon afterward, whereas in the others the treatment was continued for several weeks or months, suggesting that CSW has a variable time course.
Patient 4's case represented a complex diagnostic and management problem. She showed evidence of DI on day 1, as is often seen in the classical triphasic response to pituitary fossa trauma. However, hyponatremia developed on day 2. It is possible that this could have been the onset of SIADH; however, her urine output was excessive, which would not fit with this diagnosis on its own. In addition, her urinary sodium concentration was significantly elevated and urine osmolality was above that of plasma, suggesting that any contributing component of DI to her polyuria was controlled. Her serum osmolality was low (252 mmol/L), and thus it is possible that both SIADH and CSW coexisted at this stage. Nevertheless, the pattern became one of excessive natriuresis and polyuria, which was apparently unresponsive to mineralocorticoid. It is unclear why this was the case, although we postulate that the prevailing conditions favoring excessive salt excretion were unable to be overcome by the administered doses of fludrocortisone without clinically significant adverse effects (hypokalemia and hypertension). It is also possible that in some patients, continued administration of isotonic or hypertonic saline for CSW eventually "drives" ongoing natriuresis. Careful and slow weaning of replacement fluids may be instituted if this is suspected, while observing for dehydration and hyponatremia.
There are 4 recognized natriuretic peptides.12,13 Atrial natriuretic peptide has been shown to be elevated in CSW,2,14 whereas B-type natriuretic peptide is elevated in hyponatremic patients after subarachnoid hemorrhage,15 even in those who remain euvolemic with therapy. Both atrial and B-type natriuretic peptides were shown to be elevated 8 days after cerebral infarction when compared with controls,6 and both peptides paralleled sodium and water excretion, eventually waning 2 weeks after the cerebral insult. This finding correlates with at least 3 of the cases reported here in which CSW was not an immediate postoperative phenomenon.
Data suggest that natriuretic peptides exert potent natriuretic and diuretic effects by acting directly at the site of the renal tubule, opposing the action of ADH, increasing the glomerular filtration rate, and suppressing the renin-aldosterone axis. They also can act centrally by inhibiting thirst. These mechanisms of action offer the opportunity to supplement the drive for salt retention and override the natriuretic properties of these potent peptides with the administration of synthetic mineralocorticoid. The rapid response to fludrocortisone in 3 of our patients suggests that the majority of the action of the natriuretic peptides is at the site of the renal tubule and may be overcome.
First-line management for CSW should be accurate replacement of salt and fluid. On the basis of our relatively small sample, it is difficult to put an exact time frame on when fludrocortisone should be commenced. However, we suggest that this be considered after several days when the diagnosis is clear and management by replacement of salt and fluids is not readily achieved or is causing practical difficulties.
The doses of fludrocortisone used in our series varied but are mostly in line with single case reports in which doses of 0.05 to 0.1 mg twice daily were reported. In 2 published case reports, the authors were able to wean and stop fludrocortisone after 4 days.4,5 In neither of these reports was hypokalemia noted as an adverse effect of mineralocorticoid therapy, as it was in 3 of our cases. Also, we have shown that doses as low as 0.025 mg twice daily can be effective in children with CSW. Potassium supplements may be added if weaning or stopping fludrocortisone is unsuccessful. Prolonged courses of fludrocortisone may also be associated with hypertension, as in one of the patients in our series.
CONCLUSIONS
We have reported a case series of fludrocortisone therapy for CSW in a pediatric population. Fludrocortisone may offer a rapid and effective treatment that targets the major site of action of the natriuretic peptides known to be associated with CSW and was effective in 3 of the 4 patients in our series.
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FOOTNOTES
Accepted Jun 29, 2006.
Address correspondence to Geoffrey Ambler, MD, The Children's Hospital at Westmead, Institute of Endocrinology and Diabetes, Locked Bag 4001, Westmead 2145, New South Wales, Australia. E-mail: geoffa{at}chw.edu.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
- Kurtoglu S, Atabek ME, Keskin M, Patiroglu T, Kumandas S, Topaloglu N. Rhabdomyosarcoma with coexistent diabetes insipidus and cerebral salt wasting as postoperative complication. Pediatr Int. 2006;48 :79 –81[CrossRef][Web of Science][Medline]
- Ganong CA, Kappy MS. Cerebral salt wasting in children: the need for recognition and treatment [published correction appears in Am J Dis Child. 1993;147:369].
Am J Dis Child. 1993;147
:167
–169
[Abstract/Free Full Text] - Kappy MS, Ganong CA. Cerebral salt wasting in children: the role of atrial natriuretic hormone. Adv Pediatr. 1996;43 :271 –308[Medline]
- Kinik ST, Kandemir N, Baykan A, Akalan N, Yordam N. Fludrocortisone treatment in a child with severe cerebral salt wasting. Pediatr Neurosurg. 2001;35 :216 –219[CrossRef][Web of Science][Medline]
- Sakarcan A, Bocchini J Jr. The role of fludrocortisone in a child with cerebral salt wasting. Pediatr Nephrol. 1998;12 :769 –771[CrossRef][Web of Science][Medline]
- Berger TM, Kistler W, Berendes E, Raufhake C, Walter M. Hyponatremia in a pediatric stroke patient: syndrome of inappropriate antidiuretic hormone secretion or cerebral salt wasting? Crit Care Med. 2002;30 :792 –795[CrossRef][Web of Science][Medline]
- Rabinstein AA, Wijdicks EF. Hyponatremia in critically ill neurological patients. Neurologist. 2003;9 :290 –300[CrossRef][Web of Science][Medline]
- Singh S, Bohn D, Carlotti AP, Cusimano M, Rutka JT, Halperin ML. Cerebral salt wasting: truths, fallacies, theories, and challenges. Crit Care Med. 2002;30 :2575 –2579[CrossRef][Web of Science][Medline]
- Nelson PB, Seif SM, Maroon JC, Robinson AG. Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Neurosurg. 1981;55 :938 –941[Web of Science][Medline]
- Berkenbosch JW, Lentz CW, Jimenez DF, Tobias JD. Cerebral salt wasting syndrome following brain injury in three pediatric patients: suggestions for rapid diagnosis and therapy. Pediatr Neurosurg. 2002;36 :75 –79[CrossRef][Web of Science][Medline]
- Ishikawa SE, Saito T, Kaneko K, Okada K, Kuzuya T. Hyponatremia responsive to fludrocortisone acetate in elderly patients after head injury.
Ann Intern Med. 1987;106
:187
–191
[Abstract/Free Full Text] - Levin ER, Gardner DG, Samson WK. Natriuretic peptides.
N Engl J Med. 1998;339
:321
–328
[Free Full Text] - Lisy O, Lainchbury JG, Leskinen H, Burnett JC Jr. Therapeutic actions of a new synthetic vasoactive and natriuretic peptide, dendroaspis natriuretic peptide, in experimental severe congestive heart failure.
Hypertension. 2001;37
:1089
–1094
[Abstract/Free Full Text] - Wijdicks EF, Ropper AH, Hunnicutt EJ, Richardson GS, Nathanson JA. Atrial natriuretic factor and salt wasting after aneurysmal subarachnoid hemorrhage.
Stroke. 1991;22
:1519
–1524
[Abstract/Free Full Text] - McGirt MJ, Blessing R, Nimjee SM, et al. Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage. Neurosurgery. 2004;54 :1369 –1373; discussion 1373–1374[CrossRef][Web of Science][Medline]
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