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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 5  |  Page : 1389-1391

Role of NT-ProBNP to differentiate syndrome of inappropriate antidiuretic hormone secretion and cerebral salt wasting syndrome: The conundrum

1 Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication17-Sep-2018

Correspondence Address:
Dr. Pinaki Dutta
Department of Endocrinology, PGIMER, Chandigarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.241372

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How to cite this article:
Pal R, Rai A, Dhandapani S, Dutta P. Role of NT-ProBNP to differentiate syndrome of inappropriate antidiuretic hormone secretion and cerebral salt wasting syndrome: The conundrum. Neurol India 2018;66:1389-91

How to cite this URL:
Pal R, Rai A, Dhandapani S, Dutta P. Role of NT-ProBNP to differentiate syndrome of inappropriate antidiuretic hormone secretion and cerebral salt wasting syndrome: The conundrum. Neurol India [serial online] 2018 [cited 2019 Feb 16];66:1389-91. Available from:

Sellar-suprasellar tumors constitute a major challenge not merely because of the surgical difficulty required in excising them but also due to the post-operative electrolyte disturbances that may occur.[1],[2],[3] The incidence of hyponatremia in such a setting may occur in as high as 50% of the cases. Hyponatremia following neurosurgical procedures tends to develop rapidly over a period of 2-4 days, hence it is more likely to lead to cerebral edema.[3] Consequently, hyponatremia contributes significantly to the morbidity and mortality in hospitalized patients, with one study showing that serum sodium levels of less than 130 mEq/L were associated with a 60-fold increase in fatality.[4] Herein lies the importance of prompt identification and correction of any underlying hyponatremia in neurosurgical patients.

Hyponatremia in postoperative neurosurgical patients could be attributed to multiple causes, namely, an overzealous fluid administration during the pre- and intra-operative period, relative adrenal insufficiency, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting (CSW). The real challenge to a physician is in differentiating SIADH from CSW, as these two entities have an entirely dissimilar pathophysiological origin and need to be managed differently.

SIADH is characterized by an excess and an ‘inappropriate' antidiuretic hormone (ADH) release. ADH causes water retention in the renal tubules leading to volume expansion and dilutional hyponatremia. This leads to activation of the natriuretic mechanisms that causes sodium and water loss, restoring the euvolemic state. However, the term ‘euvolemia' is relative, as the extracellular fluid volume is normal while the intracellular fluid volume is expanded.[5]

CSW, on the other hand, primarily results from reduced urinary sodium reabsorption and the subsequent loss of sodium and water in urine. CSW disrupts the central sympathetic outflow to the kidney and promotes the release of natriuretic peptides, notably the atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP). Decreased renal sympathetic input impairs reabsorption of sodium from the proximal convoluted tubules. Also, decreased sympathetic tone reduces renin release; hence, the renin-angiotensin-aldosterone axis fails to get activated, further contributing to natriuresis without associated kaliuresis, in spite of increased delivery of sodium to the distal segments of the nephron. The role of natriuretic peptides in causing salt wasting is multipronged: a direct inhibition of central sympathetic outflow, a direct inhibition of renin release, an increase in glomerular filtration rate and a direct inhibition of sodium reabsorption in the inner medullary collecting duct. Natriuresis and the consequent diuresis lead to a reduction in the effective arterial blood volume and cause hypovolemia. This, in turn, sets in homeostatic mechanisms including the release of ADH as an ‘appropriate' response to hypovolemia, unlike the situation in SIADH, where ADH is released even amidst euvolemia. The renin-angiotensin-aldosterone axis does ultimately get activated in response to hypovolemia. The activation, however, is not to the same extent as would be expected in a hypovolemic subject without CSW. As all these homeostatic countermeasures set in, the patient enters into a new state of equilibrium where the sodium input matches its output.

Whatever may be the underlying pathophysiology, accurately labeling a patient with hyponatremia as having either SIADH or CSW has always been a physician's nightmare. The two entities are almost indistinguishable biochemically; both present with normal adrenal and thyroid functions, hyponatremia, hypouricemia, and a concentrated urine with the urinary sodium concentration (UNa) usually being >20 mmol/l. Euvolemia in SIADH and hypovolemia in CSW are the only variables that guide a physician at the patient's bedside. Hence, an accurate assessment of the volume status is expected to resolve this dilemma. Clinicians often resort to the assessment of clinical signs, like tachycardia, postural hypotension, a dry mucous membrane, lack of pedal edema, flat neck veins and weight loss, to determine the presence of hypovolemia. Measuring central venous pressure (CVP) is an alternative minimally invasive method of gauging the volume status of an individual. However, the clinical as well as the CVP-based estimation of volume status are not foolproof methods, and cannot reliably estimate the extracellular fluid volume.[6] The radioisotope dilution techniques with 51 Cr-tagged red blood cells or 131 I-labelled albumin remain the gold standard techniques for measuring the volume status of an individual, although, these methods are not applicable in day-to-day clinical practice. Similarly, laboratory findings that may suggest hemoconcentration (as seen in CSW syndrome), like an increased hematocrit, raised serum albumin and pre-renal azotemia are more of historical importance and cannot be relied upon. In fact, unlike other causes of hypovolemia, CSW does not lead to a pre-renal azotemia, as absorption of urea from the renal tubule is also impaired.[7] On the contrary, an increased fractional excretion of phosphate, and the persistence of hypouricemia and the elevated fractional excretion of urate despite correction of serum sodium, are the two features that can reliably distinguish CSW from SIADH.[8] The help that these methods will provide in clinching an etiological diagnosis following the correction of serum sodium is still doubtful. Hence, we, as bedside clinicians, need more robust and practical methods to help differentiate CSW from SIADH, as the treatment options required for these two entities are entirely different; namely, the administration of intravenous fluids for CSW, and fluid restriction for SIADH.

Measurement of serum levels of the natriuretic peptides, especially the brain natriuretic peptide (BNP), has been proposed as an effective means of differentiating CSW from SIADH, as serum levels of this peptide are elevated in CSW while they remain normal in SIADH.[8] N-terminal pro BNP (NT-proBNP), the precursor of BNP, too has been shown to be elevated in patients with CSW.[9] To the best of our knowledge, however, till date, no definite cut-off value has been put forward for BNP or NT-proBNP that would help clinicians differentiate between CSW and SIADH.

In the present issue of this journal, Tobin et al.,[10] have proposed the use of serum level of NT-proBNP as an indirect marker of volume status in neurosurgical patients with CSW or SIADH. The authors have correlated the volume status of the patients (assessed using CVP) with the NT-proBNP levels, with the final diagnosis of CSW or SIADH being based on the treatment response. They have proposed that an NT-proBNP cut-off of 125 pg/ml would distinguish between CSW and SIADH, with a sensitivity of 87.50% and a specificity of 93.33%. Such a finding would be of help to clinicians in dealing with neurosurgical patients in tertiary care settings, where facilities for estimating NT-proBNP levels are available. This study is fraught with some flaws. The author should have done a pilot study to find out the prevalence of these two disorders in a heterogeneous sub-group of neurosurgical patients, namely those who have suffered from a sub-arachnoid hemorrhage (SAH), meningitis with hydrocephalus, traumatic brain injury (TBI), or are harboring a type of sellar supra-sellar mass. Secondly, the cut-off values for NT-proBNP should have been found out from the receiver operating charcteristic curve in neurosurgical patients, in other surgical patients, and in normal age-matched controls. CWS is an uncommon disorder but it does not appear to be so in the authors' series. The article in focus is silent regarding whether or not the presence of hypothyroidism and/or hypocortisolism was excluded, as well as the mode of treatment of both these conditions and the duration of therapy administered. They have also not mentioned the body weight as well as the urine and plasma osmolality measurements in such critically ill patients. The authors are silent regarding the appropriate type of intravenous (IV) fluid administered, the duration of therapy given, and the extent of recovery of patients suffering from CWS. The methodology of sodium estimation, and how many times it was reconfirmed, has not been mentioned by the authors. Though TBI, SAH, and chronic meningitis are more often associated with CWS, this fact is not reflected in the paper. Therefore, there is a significant amount of selection bias. Similarly, the percentage of patients harboring a craniopharyngioma is surprisingly low as compared to the percentage of patients harbouring a pituitary adenoma. The use of acetazolamide, mannitol, and dexamethasone further complicates the issue. In these types of patients, both measured and calculated osmolality should be estimated. Clinically, central DI (CDI) is also a great mimicker of CWS. Therefore, CWS is often referred to as a combined form of DI-SIADH. Both are associated with hypovolemia and a low CVP, but CDI is associated with hypernatremia and a low urine osmolality. NT-proBNP is highly non-specific, but given the clinical scenario, it is useful. However, an overzealous treatment of hyponatremia may lead to volume overload, seizures, and rarely, pontine and extra-pontine myelinolysis.

Therefore, the study needs some retrospection. The serum NT-proBNP cut off of 125 pg/ml is only applicable to individuals below 75 years of age, and hence, the results of this study cannot be generalized to the elderly population (those aged above 75 years). Moreover, even the NT-proBNP cut-off value of 125 pg/ml, although proposed by many manufacturers for individuals below 75 years of age, is rather arbitrary. Normal NT-proBNP levels are age and sex-based, with levels rising with age and being higher in female than in male subjects.[11] A more scientific and statistically robust approach would have been to derive NT-proBNP cut-off values based on receiver operating characteristic curve analysis that would have unequivocally differentiated between CSW and SIADH. Moreover, all NT-proBNP assays have an inherent inter-individual coefficient of variation (CV) that can be as high as 10%. The CV of the specific assay used in the present study has not been revealed.

The authors have not mentioned whether conditions other than congestive heart failure and renal disease that are known to falsely elevate serum NT-proBNP levels, had been excluded before the inclusion of patients in the study. Such conditions include septic and other non-cardiac varieties of shock as well as anemia that can commonly be encountered in postoperative neurosurgical patients. Hence, the estimation of serum NT-proBNP levels in critically ill patients with hyponatremia loses its value. Finally, although most studies have correlated CSW with high NT-proBNP levels, some studies have failed to demonstrate any significant association between them.[12]

Lastly, the volume status of patients in the study was assessed using the CVP measurement, which, as has already been highlighted, is no way completely reliable.[6] Estimating the volume status of the subjects using a ‘gold-standard' method like the radioisotope dilution technique, and then correlating it with the serum NT-proBNP levels would have been more systematic and precise.

Thus, although this pioneering study provides a useful and a novel tool to the clinicians in helping differentiate between CSW and SIADH, the data put forward needs to be accepted with some skepticism. Assays for NT-proBNP are not available universally in all neurosurgical care units and other than point-of-care assays. Most NT-proBNP assays have a significant turn-over time; deciding the patients' management solely on the basis of NT-proBNP levels can unnecessarily delay the initiation of treatment. Thus, in routine clinical practice, we would advise physicians to initiate prompt treatment based on the clinically judged volume status of the patient. In patients not responding to the empirical treatment, an estimation of the serum NT-proBNP levels may be considered, with unequivocally elevated NT-proBNP levels (in the absence of shock, congestive cardiac failure, and renal disease) favoring the diagnosis of CSW over SIADH.

  References Top

Dutta P, Gyurmey T, Bansal R, Pathak A, Dhandapani S, Rai A, et al. Visual outcome in 2000 eyes following microscopic transsphenoidal surgery for pituitary adenomas: Protracted blindness should not be a deterrent. Neurol India 2016;64:1247-53.  Back to cited text no. 1
[PUBMED]  [Full text]  
Turgut M. Visual outcome following microscopic transsphenoidal surgery for pituitary adenomas: A few concerns. Neurol India 2018;66:287-8.  Back to cited text no. 2
[PUBMED]  [Full text]  
Hannon M, Thompson C. Neurosurgical hyponatremia. J Clin Med 2014;3:1084-104.  Back to cited text no. 3
Rahman M, Friedman WA. Hyponatremia in neurosurgical patients. Neurosurgery 2009;65:925-36.  Back to cited text no. 4
Unnikrishnan AG, Pillai BP, Pavithran PV. Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder. Indian J Endocrinol Metab 2011;15:208-15.  Back to cited text no. 5
Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest 2008;134:172-8.  Back to cited text no. 6
Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E. Is it cerebral or renal salt wasting? Kidney Int. 2009;76:934-8.  Back to cited text no. 7
Dholke H, Campos A, Reddy C, Panigrahi M. Cerebral salt wasting syndrome. J Neuroanaesth Crit Care. 2016;03:205-10.  Back to cited text no. 8
Spatenkova V, Kazda A, Skrabalek P, Suchomel P. N-terminal B-type natriuretic peptide and renal function parameters in cerebral salt wasting syndrome. Crit Care. 2008;12(Suppl 2):P446.  Back to cited text no. 9
Tobin G, Chacko AG, Simon R. Evaluation of NT-ProBNP as a marker of the volume status of neurosurgical patients developing hyponatremia and natriuresis: A pilot study. Neurol India 2018;66:1383-88.  Back to cited text no. 10
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Galasko GIW, Lahiri A, Barnes SC, Collinson P, Senior R. What is the normal range for N-terminal pro-brain natriuretic peptide? How well does this normal range screen for cardiovascular disease? Eur Heart J 2005;26:2269-76.  Back to cited text no. 11
Costa KN, Nakamura HM, Cruz LR da, Miranda LSVF de, Santos-Neto RC dos, Cosme S de L, et al. Hyponatremia and brain injury: Absence of alterations of serum brain natriuretic peptide and vasopressin. Arq Neuropsiquiatr 2009;67:1037-44.  Back to cited text no. 12


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