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Clinical Medicine

Corridor Consult —What Is Cerebral Wasting?

Jasminder Momi, MD Christopher M Tang, MD Antoine C Abcar, MD minute. His intake and outtake Dean A Kujubu, MD Abstract John J Sim, MD documentation reveals that his urine Background: Hyponatremia is a common imbalance in hos- output has been 2 to 4 L/d despite pitalized patients. It is associated with significant morbidity and mortality, a fluid restriction of <1.5 L/d that especially if the underlying cause is incorrectly diagnosed and not treated was initiated two days earlier. His appropriately. Often, the hospitalist is faced with a clinical dilemma when level has continued to de- a patient presents with hyponatremia of an unclear etiology and with cline after the fluid restriction. The uncertain volume status. Syndrome of inappropriate antidiuretic hormone working diagnosis is syndrome of (SIADH) is frequently diagnosed in this clinical setting, but cerebral salt inappropriate antidiuretic hormone wasting (CSW) is an important diagnosis to consider. (SIADH). Objective: We wanted to describe the diagnosis, treatment, and history of CSW to provide clinicians with a better understanding of the differential Background diagnosis for hyponatremia. Hyponatremia (sodium level of Conclusion: CSW is a process of extracellular volume depletion due to <136mEq/L) has been associated a tubular defect in sodium transport. Two postulated mechanisms for CSW with confusion, lethargy, seizures, are the excess secretion of natriuretic peptides and the loss of sympathetic coma, and even death.1 The differ- stimulation to the . Making the distinction between CSW and SIADH ential diagnosis for hyponatremia is important because the treatment for the two conditions is very different. is broad and includes hormone disorders (eg, thyroid and adrenal Case Presentation hyponatremia workup reveals a low insufficiency), medications, and A man, age 43 years, is evaluated serum osmolarity of 256 mOsm/kg, volume-related problems. In the for hyponatremia. He was admitted a normal serum creatinine level of acute-care setting, hyponatremia to the hospital six days earlier for 0.6 mg/dL, a urine sodium level of has been reported to occur in up an intracranial hemorrhage that re- 89 mmol/L, and an inappropriately to 30% of patients with subarach- quired emergency evacuation. The high urine osmolarity of 588 mOsm/ noid hemorrhage (SAH).2,3 The patient was later extubated when kg. His urinalysis reveals a specific physician often faces a clinical his neurologic status improved. gravity of 1.030, with no or dilemma when hyponatremia has His medical history includes poorly protein. His levels of serum thyroid- an unclear etiology and volume controlled hypertension and rheu- stimulating hormone and random status is uncertain. Early and ac- matoid arthritis. cortisol are within normal limits. His curate diagnosis of the etiology of On hospital day 6, his serum brain natriuretic peptide (BNP) and the hyponatremia is important in sodium level is noted to be 121 fractional excretion of uric acid are order to institute proper therapy. mEq/L. He has been receiving elevated, at 686 pg/mL and 83.8%, An incorrect diagnosis can cause 0.9% normal saline since admis- respectively. significant morbidity and mortality. sion, and his sodium level has The patient appears euvolemic, SIADH is a frequent diagnosis in been gradually decreasing from with a blood pressure of 115/70 a patient with hyponatremia and 141mEq/L, the level at admission. A mm Hg and pulse of 90 beats per a concurrent intracranial process.4

Jasminder Momi, MD, is a Fellow at the Los Angeles Medical Center in CA. E-mail: [email protected]. Christopher M Tang, MD, is an Internist at the Los Angeles Medical Center in CA. E-mail: [email protected]. Antoine C Abcar, MD, is a Nephrologist at the Los Angeles Medical Center in CA. E-mail: [email protected] Dean A Kujubu, MD, is the Director of the Nephrology Fellowship program at the Los Angeles Medical Center in CA. E-mail: dean.a.kujubu.kp.org. John J Sim, MD, is a Nephrologist at the Los Angeles Medical Center in CA. E-mail: [email protected].

62 The Permanente Journal/ Summer 2010/ Volume 14 No. 2 Clinical Medicine Hyponatremia—What Is Cerebral Salt Wasting?

However, cerebral salt wasting (CSW) ent with low serum osmolality, high resorption in the proximal tubule is an important diagnosis to consider urine osmolality, and a high urine may be decreased because of an and differentiate from SIADH. sodium level. The fundamental dif- expanded ECFV, which can lead CSW was first described by Peters ference between the two processes to less uric acid absorption and et al in 19505 when they reported is the volume increased uric acid loss in the urine. the cases of three patients with an (ECFV) status. CSW is defined by Another contributing mechanism in intracranial process who exhibited the renal loss of salt with con- SIADH, proposed by Decaux et al,12 renal salt wasting, but the existence comitant extracellular fluid loss.2,3,8-10 involves the stimulation of the V1 of CSW was questioned after the Consequently, patients with CSW receptor by antidiuretic hormone, identification of SIADH in 1957 have hypovolemia compared with which enhances excretion of uric by Schwartz et al.6 For years after- patients with SIADH, who have acid in the renal tubules. The ex- ward, CSW was considered either euvolemic or mild ECFV expansion. act mechanism of uric acid loss in a condition that was an element of The clinical history and assessment CSW has not been well defined. It SIADH or one that did not exist. findings may be helpful if postural is generally believed to be part of CSW now is again being recognized blood pressure changes, tachycar- the solute diuresis that occurs in as a separate entity altogether. A dia, or poor skin turgor are present. CSW with impaired urate transport retrospective review of data for 316 Unfortunately, this difference is in the proximal tubules.4,8 The key patients who presented with SAH not always clinically apparent. In differentiation is that patients with and hyponatremia found that the a study conducted by Chung et a11 SIADH have a serum uric acid level diagnosis was SIADH in 69% and to evaluate the clinical assessment and fractional excretion of uric acid was CSW in 6.5%.7 Both conditions of the ECFV status in 58 patients that normalize after correction of have been reported to occur in the without edema and hyponatremia, the serum sodium level, whereas setting of head trauma, intracranial only 47% of those with hypovolemia the uric acid level remains low and or metastatic neoplasm, carcinoma- and 48% of those with euvolemia uric acid excretion remains elevated tous or infectious meningitis, SAH, were accurately classified. in patients with CSW, despite cor- and surgery.8 Uric acid excretion may be one rection of hyponatremia.2,4,8,9 The distinction between these two measure for differentiating between Response to fluid therapy is also conditions is important because CSW and SIADH. Initially, both a key distinction between SIADH their treatments are different. conditions are associated with a and CSW. The treatment of choice low serum uric acid level and a for SIADH is free water restriction Diagnosis high fractional excretion of uric when increased fluid intake will CSW and SIADH share many acid.4,8,9 Uric acid is normally re- worsen the hyponatremia. In con- similar laboratory and clinical find- sorbed in the proximal tubule along trast, CSW is a volume-depleted and ings (Table 1). Both conditions pres- with sodium. In SIADH, sodium sodium-wasting state requiring fluid

Table 1. Biochemical markers: comparison of SIADH and CSW Biochemical marker SIADH CSW Extracellular fluid volume Normal to high Low Urinary sodium level >40 mEq/L >40 mEq/L Serum uric acid level Low Low Initial fractional excretion of urate High High Fractional excretion of urate after correction Normal High Urinary osmolality High High Serum osmolality Low Low Blood urea nitrogen/creatinine level Low to normal High Serum level Normal Normal to high Central venous pressure Normal to high Low Pulmonary capillary wedge pressure Normal to high Low Brain natriuretic peptide level Normal High Treatment Water restriction Fluids and/or mineralocorticoids CSW = cerebral salt wasting; SIADH = syndrome of inappropriate antidiuretic hormone.

The Permanente Journal/ Summer 2010/ Volume 14 No. 2 63 Clinical Medicine Hyponatremia—What Is Cerebral Salt Wasting?

replacement with isotonic solutions. nial process and compared them matching the urinary output with The renal wasting of sodium with study control participants. volume repletion. in CSW is poorly understood. Sixty patients were divided into Fludrocortisone, a potent miner- Two postulated mechanisms are three groups. Group 1 included 10 alocorticoid, has also been used for disruption of sympathetic neural patients with SAH who underwent the treatment of CSW at doses of input to the kidney and natriuresis clipping of ruptured aneurysms 0.1 to 1 mg/d. It exerts its effects by induced by natriuretic peptides. within 24 hours, group 2 included stimulating reabsorption of sodium Both mechanisms can lead to 10 patients with intracranial tu- and water in the distal tubule, lead- downstream inhibition of the renin- mors who underwent craniotomy, ing to expansion of the ECFV. When angiotensin-aldosterone system.2,4,8,9 and group 3 included 40 healthy fludrocortisone therapy was used in Sympathetic stimulation normally individuals. Natriuretic peptides patients with SAH, less natriuresis CSW is a causes proximal tubule absorption (ANP, BNP), aldosterone, renin, and occurred and sodium balance was volume- of sodium. Depression of this sym- antidiuretic hormone levels were as- achieved more frequently.14,15 Thus, depleted state pathetic input to the kidney results sessed before surgery and at 1 hour, volume depletion and hyponatre- treated with in less sodium resorption in the 4 hours, 12 hours, and daily for 7 mia are preventable in patients intravenous proximal tubule and an increase days after surgery. Patients with treated with fludrocortisone. The administration in sodium delivery to the distal SAH had elevated baseline BNP most common adverse effect as- of isotonic or tubule. This leads to a decrease levels but normal ANP levels when sociated with fludrocortisone was hypertonic in the effective arterial blood vol- compared with healthy individuals. , which was observed fluids … ume, triggering the baroreceptors Urine output and urinary excretion in up to 73% of patients.15 to release antidiuretic hormone to of sodium were greater in the SAH The length of therapy depends help maintain intravascular volume. group than in the other groups. on the clinical course of the hypo- A depressed sympathetic drive Aldosterone levels were also lower natremia and the underlying pathol- has also been associated with a in this group. BNP appeared to ogy associated with CSW (Table 2). decrease in renin and aldosterone be the primary natriuretic peptide Once the underlying pathology is levels, further inhibiting sodium that caused salt wasting in patients corrected, CSW is usually a transient retention.2,4,8,9 with SAH. condition that resolves within three Elevated natriuretic peptides lev- to four weeks. Hence, long-term els have been described with CSW.13 Treatment therapy is usually not needed.9 Atrial natriuretic peptide (ANP) and Early appropriate therapy of hy- BNP have both been studied in ponatremia is important to prevent Table 2. Causes of cerebral patients with intracranial pathology complications. CSW is a volume- salt wasting and hyponatremia. Although both depleted state treated with intrave- • ANP and BNP have been described nous administration of isotonic or • Head trauma to be elevated for up to two weeks, hypertonic fluids to obtain positive • Intracranial neoplasm BNP elevation is more consistent. and correct volume • Metastatic neoplasm BNP is primarily released by the depletion. Depending on the acu- • Infections or carcinomatous cardiac ventricles in response to the ity and clinical manifestation of the meningitis increased ECFV but can also be se- hyponatremia, isotonic or hyper- • Encephalitis creted by the brain.13 The natriuretic tonic solutions would be indicated. • Central nervous system surgery peptides have been described as Additionally, sodium tablets can causing direct tubular inhibition of be combined with the intravenous Case Outcome sodium resorption and inhibition of fluids. Doses of sodium of up to 12 The case presented here illus- intramedullary collecting-duct so- g/d may be used.2 Rapid correc- trates the dilemma that clinicians dium absorption.8,9,13 They are also tion of the serum sodium by more face. The patient’s condition did believed to cause direct inhibition than 12 mmol/d should be avoided not respond to fluid restriction, of renin and aldosterone release because of the risk of osmotic although his laboratory test results from the juxtaglomerular cells and demyelination.1 Once euvolemia and presentation appeared to sug- the adrenal gland, respectively.8,9,13 is achieved, the goal of therapy is gest SIADH. However, the fact that Berendes et al13 studied BNP to maintain a positive salt balance his hyponatremia continued to levels in patients with an intracra- and to prevent volume depletion by worsen with fluid restriction raised

64 The Permanente Journal/ Summer 2010/ Volume 14 No. 2 Clinical Medicine Hyponatremia—What Is Cerebral Salt Wasting?

some questions. In addition, his A correct and timely diagnosis is 8. Palmer BF. Hyponatremia in patients fractional excretion of uric acid was important in order to obtain a good with central nervous system disease: SIADH versus CSW. Trends Endocri- persistently elevated. The patient outcome, because the two condi- nol Metab 2003;14(4):182–7. v also continued to have a high urine tions are treated very differently. 9. Palmer BF. Hyponatraemia in a output. He was immediately given neurosurgical patient: syndrome of isotonic saline, keeping his net fluid Disclosure Statement inappropriate antidiuretic hormone balance positive. The serum sodium The author(s) have no conflicts of secretion versus cerebral salt wast- interest to disclose. level started to improve, but he ing. Nephrol Dial Transplant 2000 Feb;15(2):262–8. continued to require 3 L to 4 L of Acknowledgment 10. Singh S, Bohn D, Carlotti AP, isotonic saline daily to keep his fluid Katharine O’Moore-Klopf, ELS, of KOK Cusimano M, Rutka JT, Halperin ML. balance between even and posi- Edit provided editorial assistance. Cerebral salt wasting: truths, falla- tive. Although there is no absolute cies, theories, and challenges. Crit certainty in a diagnosis of a clinical References Care Med 2002 Nov;30(11):2575–9. syndrome, the patient’s condition 1. Adrogué HJ, Madias NE. Hypona- 11. Chung HM, Kluge R, Schrier RW, tremia. N Engl J Med 2000 May Anderson RJ. Clinical assessment was diagnosed as probable CSW. 25;342(21):1581–9. of extracellular fluid volume in He was eventually discharged with 2. Betjes MG. Hyponatremia in acute hyponatremia. Am J Med 1987 a serum sodium level of 140 mEq/L. brain disease: the cerebral salt wast- Nov;83(5):905–8. ing syndrome. Eur J Intern Med 2002 12. Decaux G, Namias B, Gulbis B, Conclusion Feb;13(1):9–14. Soupart A. Evidence in hyponatremia related to inappropriate secretion of Hyponatremia in the setting of a 3. Harrigan MR. Cerebral salt wasting syndrome: a review. Neurosurgery ADH that V1 receptor stimulation central nervous system event is a 1996 Jan;38(1)152–60. contributes to the increase in renal diagnostic challenge to physicians. 4. Maesaka JK, Gupta S, Fishbane S. uric acid clearance. J Am Soc Nephrol Both SIADH and CSW are likely Cerebral salt-wasting syndrome: 1996 May;7(5):805–10. etiologies, as they present with very does it exist? Nephron 1999 13. Berendes E, Walter M, Cullen P, et similar biochemical profiles. Levels Jun;82(2):100–9. al. Secretion of brain natriuretic peptide in patients with aneurysmal of natriuretic peptides and changes 5. Peters JP, Welt LG, Sims EA, Orloff J, Neeham J. A salt-wasting subarachnoid haemorrhage. Lancet in fractional excretion of uric acid syndrome associated with cerebral 1997 Jan 25;349(9047):245–9. may help differentiate between the disease. Trans Assoc Am Physicians 14. Hasan D, Lindsay KW, Wijdicks two conditions. The key difference 1950;63:57-64. EF, et al. Effect of fludrocortisone is that SIADH is a euvolemic to 6. Schwartz WB, Bennett W, Curelop acetate in patients with subarach- mildly hypervolumic state, whereas S, Bartter FC. A syndrome of renal noid hemorrhage. Stroke 1989 sodium loss and hyponatremia prob- Sep;20(9):1156–61. CSW is a volume-depleted state. ably resulting from inappropriate 15. Mori T, Katayama Y, Kawamata T, Unfortunately, the volume status secretion of antidiuretic hormone. Hirayama T. Improved efficiency of is not always clinically apparent in Am J Med 1957 Oct;23(4):529-42. hypervolemic therapy with inhibition every patient. It is important to con- 7. Sherlock M, O’Sullivan E, Agha A, et of natriuresis by fludrocortisone in sider CSW in addition to SIADH in al. The incidence and pathophysiolo- patients with aneurysmal subarach- noid hemorrhage. J Neurosurg 1999 patients who present with hypona- gy of hyponatraemia after subarach- noid haemorrhage. Clin Endocrinol Dec;91(6):947–52. tremia and an intracranial process. (Oxf) 2006 Mar;64(3):250–4.

Chemistry is a deadly poison gas employed on European battlefields in World War I. Sodium is a corrosive metal, which burns upon contact with water. Together they make a placid and unpoisonous material, table salt. Why each of these substances has the properties it does is a subject called chemistry. — Broca’s Brain, Carl Sagan, 1934-1996, American astronomer, astrophysicist, author, and cosmologist

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