It is suggested that natriuretic factors such as ANP, brain natriuretic peptide (BNP), C type natriuretic peptide and dendroaspis natriuretic peptide may be responsible for CSW, although BNP is regarded as the most important cause of CSWS. Natriuretic peptides released from the hypothalamus after traumatic brain injuries can directly act on the renal medullary collecting duct and inhibit the secretion of renin and aldosterone, thereby increasing the excretion of urinary sodium. It can also directly inhibit nerve impulse down-transmission from the brainstem level and participate in the regulation of the nervous system on the kidney, so as to resist the increase of intracranial pressure and protect the brain tissue (7). Thus, increased intracranial pressure may provide a signal for brain BNP release, and previous studies had found a linear correlation between intracranial pressure and natriuretic peptide concentration in cerebrospinal fluid in patients with subarachnoid hemorrhage. Since ANP may inhibit mineralocorticoid secretion in patients with CSWS, the application of agents with mineralocorticoid activities, such as fludrocortisone, has been shown to be effective in normalizing the serum sodium levels (3). In this case, BNP gradually increased since 17th January, and reached a peak concentration of 4909 pg/mL on 23th January. At the same time, urine output consequently increased progressively, and diabetes insipidus appeared.
Besides, it has been found that the BNP levels in epilepsy children were higher than that in the control group 12 hours after seizures, suggesting that ANP and BNP secretion may be caused by epileptic stimulation (8). Therefore, clinicians should pay more attention to CSWS in children with epilepsy and carry out safe and effective treatment immediately.
This patient was admitted to our hospital because of diarrhea and vomiting for 1 month. Although his serum potassium and sodium levels were slightly lower on admission, the serum potassium and sodium returned normal on 18th and 19th January with potassium and sodium supplementation. On 20th January, serum sodium dramatically decreased to 118 mmol/L while BNP increased to 2139 pg/mL, hence, a diagnose of CSWS was considered. A sharp decrease in serum sodium (120–125 mmol/L) can lead to severe cerebral edema, cerebral hernia, and even death. It can leave sequelae of the central nervous system without treatment in time (9). Therefore, the treatment of CSWS is mainly to correct hypovolemia and hyponatremia, and the difficulty is to evaluate blood volume and blood sodium during the treatment. Infusion of large amount of normal saline is the preferred treatment of CSWS (10). Children with CSWS have polyuria, increased urinary sodium loss, contraction of extracellular fluid, hypotension and even shock. This patient also had hypotension and was treated with fluid, sodium, and vasopressors. High-volume therapy can aggravate myocardial stress and increase BNP secretion. Besides, it was very challenging to administer such a large amount of salt intravenously to a young patient, so fludrocortisone was added.
Hydrocortisone is a natural glucocorticoid, which has a certain sodium and water retention effect of mineralocorticoid. It has a significant effect on reducing urinary sodium excretion and urine output in the treatment of CSWS. It has been reported that a leukemia child with CSWS was not respond to conventional sodium supplementation, but his blood sodium level returned to 130mmol/L on the fifth day of treatment with hydrocortisone (2mg/kg, bid, ivgtt) (11). Another study which reviewed 12 patients with CSWS recommended oral hydrocortisone 0.1–0.4 mg/d to increase renal tubular reabsorption of sodium (12). After the diagnose of cerebral salt wasting syndrome was made, he was immediately treated with fluid and sodium supplementation, and hydrocortisone was given to maintain sodium and water. After 3 days of hydrocortisone monotherapy, the serum sodium level returned to normal, but BNP was 4909 pg/mL, and then fludrocortisone was given. The next day, his serum sodium level was 137.6 mmol/L and the urine output decreased to 1770 mL, consequently, hydrocortisone was discontinued. However, three days after discontinuation of hydrocortisone, serum sodium decreased to 124.3 mmol/L and urine output increased to 4984 mL. Fludrocortisone combined with hydrocortisone were immediately administered.
Corticosteroids are used for substitution therapy in the management of primary adrenal insufficiency both in non-septic and septic shock patients. The physiological replacement is best achieved with a combination of hydrocortisone and fludrocortisone (13). Fludrocortisone, a 9 alpha-fluorinated derivative of hydrocortisone, has strong mineralocorticoid activity, was initially used to replace aldosterone hormones that were reduced due to adrenal insufficiency. In addition, it is also used in severe infection and acute inflammatory reaction, organ transplant rejection, autoimmune and allergic diseases, shock and blood diseases. Fludrocortisone mainly acts as a mineralocorticoid, although it has some glucocorticoid activity, but the commonly used doses have no significant glucocorticoid activity. Fludrocortisone is very effective when added to CSWS fluid therapy. The mechanism of fludrocortisone is reducing renal sodium excretion and increasing renal reabsorption of sodium, results in reduction of sodium excretion and urine volume. However, it worth noting that long-term use of fludrocortisone can lead to water and sodium retention, hypokalemia and hypertension (7). A single-center randomized controlled trial that investigated the efficacy and safety of fludrocortisone in the treatment of CSWS with tuberculous encephalopathy revealed that fludrocortisone could normalize serum sodium levels earlier than saline alone, but this did not influence the outcomes of 6 months (14).
At present, the application of fludrocortisone in the treatment of CSWS in children has not been fully explored, with only a few case reports. Nagendra Chaudhary et al. (15) reported a case of a 17-month-old female infant with CSWS caused by craniocerebral injury. Despite the infusion of normal saline, polyuria was remained. Therefore, oral fludrocortisone (0.1 mg/d in two divided doses) was administered on the 13th day, and then, the dosage of fludrocortisone was raised to 0.2 mg/d 2 days later. Her urine output gradually decreased and polyuria disappeared finally and fludrocortisone was tapered and discontinued on the 20th day. Sibel Tulgar Kinik et al. (16) reported a case of an 11-year-old boy who developed hyponatremic seizures after resection of an intracranial tumor and subsequently developed CSWS. Despite intensive fluid and salt therapy, his urine output was not reduced. So, fludrocortisone was administered, and the patient's urine output and sodium excretion decreased, with the serum sodium level normalized. Shilpa Gurnurkar et al.(17) reported a two-year-old boy who suffered CSWS after subtotal resection of low-grade juvenile pilocytic astrocytoma and was successfully treated with fludrocortisone for refractory hyponatremia and reduced the need for large oral sodium supplements. Patel Zeeshan Jameel et al. (18) reported a case of a child undergoing craniotomy who developed central diabetes insipidus complicated with CSWS after surgery, and the symptoms were relieved after 7 days of fludrocortisone treatment. CSWS can be caused by any form of central nerves system (CNS) injury and result in hyponatremia. Fludrocortisone may be a safe and effective treatment for children with refractory hyponatremia when routine sodium supplementation and rehydration are sub-effective.
Hydrocortisone is another adrenal cortical hormone used in the treatment of CSWS. It is a natural glucocorticoid and also has certain sodium and water retention effects of mineralocorticoid. Hydrocortisone is effective in reducing urinary sodium excretion and urine output in the treatment of CSWS.
Infants with CSWS need more mineralocorticoids, the fludrocortisone doses of 0.05 to 0.1 mg twice daily are recommended, and can be increased to 0.4 mg once daily if necessary, along with 1–3 g sodium chloride. The fludrocortisone doses of 0.05–0.10 mg daily are recommended to elder children, increasing appropriately (6). This patient was 5 years old. Oral fludrocortisone (0.05 mg, bid), was started on 23th January, and on the same day, hydrocortisone discontinued. Daily urine output gradually decreased from that day on, but BNP remained high above the normal range. On 27th January, his urine output increased to 4984 mL, and serum sodium was dropped to 124.3 mmol/ L. Therefore, hydrocortisone (100mg, q8h) was continued, and the dose of fludrocortisone was increased to 0.075mg, bid. After the combination of the two drugs, serum sodium returned to normal and urine output gradually decreased. In order to avoid corticosteroid withdrawal syndrome, the dose of fludrocortisone was reduced to 0.05mg, bid on 3rd February, while hydrocortisone was reduced to 100mg, q12h. Serum sodium, urine sodium and urine output were normal after dose reduction, and no adverse reactions were observed. On 7th February, BNP returned to normal, and no additional fluid was needed for sodium supply. On 9th February, fludrocortisone was further reduced to 0.025mg, bid, while hydrocortisone was reduced to 100mg, qd. On 13th February, hydrocortisone and fludrocortisone were discontinued. The process of dosage reduction and withdrawal of the two agents was stable, and the patient could tolerate it without recurrence of the disorder. At the same time, there were no adverse reactions.
CSWS can be caused by any form of CNS injury, including epilepsy. We present a case of a child with epileptic encephalopathy who suffered from cerebral salt-wasting syndrome, treating with fludrocortisone and hydrocortisone, and his prognosis was favorable. During the therapy, the clinical pharmacist participated in the whole process. No serious adverse reactions were observed during the hospitalization. Fludrocortisone may be a safe and effective agent for children with CSWS, but it should be noted that long-term use of fludrocortisone may lead to water and sodium retention, hypokalemia, and hypertension.