Evaluation of NT-ProBNP as a marker of the volume status of neurosurgical patients developing hyponatremia and natriuresis: A pilot study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.241401
Source of Support: None, Conflict of Interest: None
Keywords: Hyponatremia, natriuresis, NT-proBNP
Hyponatremia contributes to morbidity and prolongs the hospital stay of patients undergoing neurosurgery. Some patients remain asymptomatic and are recognized only on routine laboratory testing. The main causes of hyponatremia in post-operative neurosurgical patients include: (1) Hypocortisolemia, (2) syndrome of inappropriate anti-diuretic hormone (SIADH), and (3) cerebral salt wasting (CSW). Hypocortisolemia can be easily diagnosed; it is not the same with SIADH and CSW, both of which have to be managed very differently. Patients with SIADH need fluid restriction, while those with CSW need fluid replacement.
Studies that used clinical parameters, laboratory tests or central venous pressure (CVP) show that none of these methods can correctly estimate the volume status of patients. We decided to use NT-proBNP, the precursor of brain natriuretic peptide (BNP), along with uric acid to estimate the volume status of patients who develop hyponatremia due to natriuresis.
NT-pro BNP was assessed with an automated chemiluminescent immunoassay using Siemens Immulite 2000XPi, USA. This machine has a wide range for measuring NT-proBNP (20–35,000 pg/ml). The reference range for NT-proBNP for patients less than 75 years is <125 pg/ml; and for those above 75 years, the reference range extends upto 450 pg/ml.
After obtaining approval from the Institutional Review Board, we prospectively recruited patients into the study. The study was carried out over a period of 30 months (August 2011 to February 2014). We recruited all neurosurgical patients who had not been admitted for management of traumatic injuries and who had developed hyponatremia and natriuresis following surgery. Those with underlying hypocortisolism; those on diuretics and/or mannitol; and, those with underlying congestive cardiac failure or renal disease were excluded from the study.
Hyponatremia was defined as serum sodium <130 mEq/L. Natriuresis was defined as a urine spot sodium >25 mEq/L., The sodium deficit was calculated using: 0.6 (weight in Kg) for men and 0.5 (weight in kg) for women × (desired serum sodium level – actual serum sodium level). Strict intake and output records were maintained and patients were closely monitored until discharge from the hospital.
Phase 1 (10 patients)
In the 1st phase, the volume status of the patient was assessed using CVP; this was measured via a central line passed through the antecubital or subclavian vein. Hypovolemia was defined as CVP <5 cm, normovolemia as CVP 6–10cm, and hypervolemia as CVP >11cm.
Before starting treatment, a blood sample was collected for NT- proBNP and uric acid. Patients with SIADH (CVP >5cm) were asked to restrict fluid intake to <1.5 liters per day while those with CSW (CVP <5 cm) were resuscitated with appropriate intravenous fluids. In the first 24 hours, hyponatremia was corrected at the rate of 10–12 mEq/L. Hypertonic saline was used only for patients with serum sodium <120 mEq/L and others who were symptomatic. The primary outcome was to gradually bring up serum sodium levels to >130 mEq/L. We then correlated the NT-proBNP levels with the clinical diagnosis and the response to treatment.
Phase 2 (21 patients)
In the 2nd phase, patients with NT-proBNP levels <125 pg/ml were treated as SIADH with fluid restriction while those with NT-proBNP levels >125 pg/ml were treated as CSW and resuscitated with IV fluids.
Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS Inc, Chicago, USA) version 16.0. The Fisher exact test was used to calculate the P value.
Seventy-six patients with hyponatremia were screened and only 31 could be recruited into the study; all the others failed the inclusion criteria. Those recruited included 18 (58%) male and 13 (42%) female patients; their median age was 46 years (range 28–71 years). The underlying diagnoses included: pituitary adenoma (n = 11), glioma (n = 5), suprasellar arachnoid cyst (n = 2), vestibular schwannoma (n = 2), tuberculous meningitis with hydrocephalus (n = 2). A suprasellar epithelial cyst, colloid cyst, tuberculum sella meningioma, planum sphenoidale meningioma, craniopharyngioma, aneurysm, lymphoma, intramedullary tumor, and cervicomedullary hemangioblastoma was present in one patient each, respectively.
In Phase 1, we compared the CVP measurement with the clinical diagnosis and NT-proBNP. Except in two patients (no. 7 and 9), we found that the CVP and clinical diagnosis correlated well with the NT-proBNP result [Table 1]. Those with SIADH (CVP >5cm) had NT-proBNP levels <125 pg/ml and those with CSW (CVP <5 cm) had NT-proBNP levels >125 pg/ml. NT-proBNP, thus, had 100% sensitivity and 66.7% specificity in establishing the diagnosis of these patients. The P value based on Fisher exact test was 0.07. The positive predictive value of the test was 66.7% and the negative predictive value was 100% [Table 2].
In Phase 2, we managed all the patients according to their NT-proBNP result. Those with NT- proBNP <125 pg/ml were treated with fluid restriction (SIADH) and those with NT- proBNP >125 pg/ml were treated with adequate fluid replacement (CSW). All the 11 patients who had NT-proBNP levels <125 pg/ml responded to fluid restriction, and 9 of the 10 patients with NT-proBNP levels >125 pg/ml responded to fluid resuscitation [Table 3]. The mean time for correction of hyponatremia was 2.8 ± 1.63 days.
NT-proBNP had a sensitivity of 90% and specificity 100% in predicting the diagnosis of CSW. This test had a positive predictive value of 100%, a negative predictive value of 91.67%, and a P value <0.001.
Combining the results of Phase 1 and Phase 2, in all patients with CSW, NT-proBNP could diagnose hypovolemia with a sensitivity of 87.50%, a specificity of 93.33%, and had a P value <0.001. The positive predictive value of the test was 93.33% and the negative predictive value of the test was 87.50%.
The normal range for uric acid varies from 2.5–5.6 mg/dl (in female subjects) and 3.1–7 mg/dl (in male subjects). In patients with SIADH, the uric acid levels ranged from 1.4–3.8 mg/dl (mean 2.1 ± 0.86 mg/dl) in female, and 1.2–6.3 mg/dl (mean 3.3 ± 1.59 mg/dl) in male patients. In patients with CSW, uric acid levels ranged from 1–4.3 mg/dl (mean 2.3 ± 1.1 mg/dl) in female, and 2–6.3 mg/dl (mean 3.44 ± 1.3 mg/dl) in male patients. Hence, uric acid cannot be used to differentiate between SIADH and CSW.
Urine spot sodium
In patients with SIADH, the urine spot sodium ranged from 54–229 mmol/l (mean 118 ± 46.94 mmol/l); and, in patients with CSW, the urine spot sodium ranged from 42–233 mmol/l (mean 129.18 ± 60 mmol/l).
Natriuresis contributes to hyponatremia in the postoperative period. 5] This could be the result of either SIADH or CSW. Some authors argue that the existence of CSW is overstated. They note a connection between the increased use of triple H therapy (a combination of hypertension, hypervolemia, and hemodilution used to treat cerebral vasospasm following subarachnoid hemorrhage) and CSW. They believe that large infusions of saline was causing pressure natriuresis, and hence, resulting in a negative balance of sodium, along with a contracted extracellular fluid status, which was being reported as CSW. Others reckon that the occurrence of CSW is at least as common, if not more than that of SIADH., A recent study by Sherlock et al., on 116 neurosurgical patients with hyponatremia showed that 62% had SIADH, 4.8% had CSW, and 26.7% had diuretic-induced hypovolemic hyponatremia. In our study, involving 31 post-operative neurosurgical patients, the incidence of SIADH and CSW were almost equal; 15 patients (48.4%) had SIADH and 16 patients (51.6%) had CSW.
There remains a significant delay in the diagnosis and management of patients with hyponatremia. It is not easy to differentiate SIADH and CSW due to their overlapping clinical and biochemical features. The differentiation is based on the extracellular volume status of the patient. Patients with SIADH are either normovolemic or slightly hypervolemic, while patients with CSW are always hypovolemic.,
Some authors have used physical signs like tachycardia and hypotension, while others have used laboratory markers like hematocrit, blood urea nitrogen, radioisotopes and CVP to estimate the volume status of patients. Chung et al., showed that clinical assessment can correctly identify only 47% of patients with hypovolemia and 48% of patients with normovolemia. Newer meta-analyses have cast doubts on whether or not central venous lines accurately measure blood volume and fluid responsiveness. Marik et al., analyzed 24 studies that included 803 patients. The pooled correlation coefficient between CVP and measured blood volume was 0.16 (95% confidence interval [CI], 0.03 to 0.28). There was very poor relationship between CVP and blood volume. The hemodynamic response to fluid challenge was not predicted by CVP or a change in CVP. The authors concluded that CVP should not be used to make clinical decisions regarding fluid management. Methods using a radioisotope give the most accurate measure of intravascular volume.
In a previous study from our institution, Damaraju et al., used CVP to determine the course of treatment for patients developing hyponatremia. They included 25 patients, 19 had hypovolemia (CVP <5 cm), and the others were normovolemic (CVP 6–10 cm). Hypovolemic patients were given intravenous (IV) fluids (50 ml/kg/day) and 12 g salt/day; euvolemic patients were given a lesser amount of fluids (volume not specified) along with 12 g salt/day. Nineteen of them normalized serum sodium within 72 hours, and an additional 3 responded within 108 hours, while one patient normalized serum sodium after 1 week. The patients included 3 non-responders, 2 of whom had severe dehydration. The authors concluded that CSW is more common than SIADH.
Sahay et al., recently suggested an algorithm based on a combination of multiple parameters for the diagnosis of hyponatremia. We have tried to summarize the algorithm focusing on SIADH and CSW. The process starts with a history and clinical examination of the patient to assess the volume status and rule out any endocrinological dysfunction, CNS lesion or lung lesion. At this stage, direct hemodynamic measurements can be done if available. The first step thereafter is the assessment of serum sodium to confirm hyponatremia. Then, serum osmolality is checked, wherein a low serum osmolality (<280 mosm/kg) would indicate true hyponatremia, whereas a normal serum osmolality (280–295 mosm/kg) could be due to hyperlipidemia or hyperproteinemia, and a high serum osmolality (>295 mosm/kg) would indicate hyperglycemia or mannitol as the cause. The third step is to check urine osmolality, with a value >150 mosm/kg indicating an impaired ability to excrete free water, as seen in hyponatremic patients who are salt depleted and hypovolemic indicating the presence of CSW, or euvolemic with a high urine sodium indicating the presence of SIADH. Values of urinary osmolality <150 mos/kg are seen in patients with euvolemic hyponatremia, hypovolemia, SIADH (reset osmostat variety), antidiuretic use, primary polydipsia, etc. Therefore, urine osmolality per se has a limited role in differentiating SIADH from CSW and has to be used in conjunction with the other parameters. The fourth step is to assess urine sodium. If urine sodium is >20 meq/L, it would indicate that the loss of sodium from the body is renal rather than non-renal. Both SIADH and CSW would be expected to have a urine sodium >20 meq/L. The fifth step is to assess the urine-to-serum electrolyte ratio, which is calculated by assessing the ratio of the sum of urine sodium and potassium concentrations divided by the serum sodium concentration. A ratio of <0.5 indicates that the patient requires fluid restriction and a ratio >1 indicates that the patient should not be fluid restricted. The sixth step is the assessment of fractional excretion of sodium as a surrogate marker for assessment of the volume status. In patients with normal renal function, a value of <0.1% would indicate hypovolemic hyponatremia and a value >0.1% would indicate euvolemia or hypervolemia. The seventh step is the assessment of serum uric acid and blood urea nitrogen concentrations. SIADH would have low serum levels of both uric acid and urea, while they would be normal or high in CSW. The eight step is the evaluation of acid base and potassium balance, with SIADH having a normal acid base and potassium balance, and CSW having a normal acid base balance with hyperkalemia. In case of any doubt, as a final step, a 0.9% saline infusion can be given with serial serum sodium measurement. CSW would improve with saline infusion, while SIADH would not improve or could worsen with this step.
Currently there is no reliable method to correctly differentiate SIADH and CSW. We chose to use NT-proBNP and uric acid as these tests are quick and easy to perform.
The natriuretic peptides are a family of molecules consisting of several structurally related hormones. At present, the natriuretic peptide family includes atrial natriuretic peptide (ANP), B-type (or brain) natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and dendroaspis natriuretic peptide (DNP). In humans, the largest concentration of NT-proBNP and BNP are found within the myocardium of the left ventricle. These peptides are also found within the hypothalamus.
BNP circulates in the bloodstream as a biologically active compound and is actively cleared from circulation by neutral endopeptidases and natriuretic peptide receptors. It has a short half-life of <20 minutes making routine testing impractical. NT-proBNP, the precursor of BNP, is more stable with a half-life of about 120 minutes and can be stored in glass tubes for more than 72 hours.
BNP causes CSW by: (1) Increasing glomerular filtration rate, (2) inhibiting sodium reabsorption, (3) inhibiting action of vasopressin, and (4) inhibiting mineralocorticoid synthesis. The mechanisms by which CNS insult causes release of natriuretic peptides and causes CSW include: (1) Direct damage to cortical and subcortical structures leading to the release of BNP into the circulation, or via central nervous system injury mediated sympathetic surges which release BNP from the myocardium. (2) Loss of sympathetic activation of the kidney leading to reduced sodium reabsorption within the renal tubules causing natriuresis. (3) Inhibition of the renin-aldosterone system, which further compounds the renal loss of sodium.
Studies show an increase in serum BNP levels after subarachnoid hemorrhage., All the 10 patients with subarachnoid hemorrhage reported by Berendes et al., had elevated BNP levels.
Bunnag and Pattanasombatsakul  looked at the relationship between NT-proBNP and extracellular water status. Using bioimpedance analysis, the patients were categorized into the hypovolemic and euvolemic groups. NT-proBNP levels were measured at three stages: (1) At the beginning of treatment, (2) at half correction, and (3) at the end of treatment. They found that patients with hypovolemia had lower NT-proBNP values as compared to those with euvolemia. Although bioimpedance analysis measures extracellular volume reasonably well, it is not an accurate measure of intravascular volume. It is known that extracellular volume and intravascular volume do not always share a linear correlation.
In our study, in Phase 1, we found that NT-proBNP predicts hypovolemia with 100% sensitivity of and 66.7% specificity. A NT-proBNP cutoff of 125pg/ml will distinguish CSW and SIADH with 87.50% sensitivity and 93.33% specificity.
Beck proposed that the coexistence of hyponatremia and hypouricemia differentiates SIADH from other causes of hyponatremia. He observed that 16 of 17 patients with SIADH had serum uric acid levels ≤4 mg/dl. In our study, we found that the serum uric acid levels overlap and they cannot be used to differentiate SIADH and CSW. Our findings are similar to those described by Maesaka  who looked at the rate of correction of hypouricemia and the fractional excretion of uric acid in patients with SIADH and CSW.
Recently, two new biomarkers, namely, copeptin and fractional excretion of uric acid have generated considerable interest. Copeptin is the C-terminal segment of the arginine vasopressin (AVP) precursor peptide. Both copeptin and ADH are synthesised from the same precursor molecule pro-AVP. Both have similar responses to osmotic, hemodynamic, and stress-related stimuli. As compared to ADH, copeptin has more ex vivo stability and can be measured readily and quickly. Fenske et al., in a prospective observational study involving 106 patients with various types of hyponatremia showed that copeptin levels were significantly higher in all patients with hyponatremia as compared to healthy controls, irrespective of their volume status. Thus, copeptin alone was not of much use in distinguishing SIADH and CSW. However, when they used the ratio of copeptin to urinary sodium, they were able to distinguish between SIADH and CSW with a sensitivity of 85% and a specificity of 87%. Boursier et al., in a prospective observational study of 131 patients with hyposmolar hyponatremia, found copeptin levels to be higher in patients with hypovolemia. Nigro et al., in a prospective observational study on 298 patients with hyponatremia found that copeptin levels >84 pmol/L could identify patients with hypovolemic hyponatremia with a specificity of 90% and a sensitivity of 23%. They concluded that copeptin alone had limited use in distinguishing various aetiologies of hyponatremia. When copeptin values were combined with the results of physical examination, they could identify more patients with hypovolemia than they did with physical examination alone. They also found that copeptin/urinary sodium ratio was lower in patients with SIADH and a cut off of 0.3 could identify patients with a sensitivity of 61% and a specificity of 60%.
Mees et al., first reported that SIADH was associated with hypouricemia and increased urinary excretion of uric acid. Beck too found increased fractional excretion of uric acid in all his seventeen patients with SIADH. The mechanism through which this happens is still unknown. However, this biomarker did not receive adequate attention until recently when Fenske et al., in a prospective observational cohort study on 86 patients with hyponatremia, found that fractional excretion of uric acid was higher in patients with SIADH when compared to those with hypovolemic and diuretic-induced hyponatremia. A cut off value of >12% could distinguish all the 31 patients with SIADH from the 55 patients with non-SIADH hyponatremia (which included patients with CSW, hypervolemia, and diuretic induced hyponatremia). Fractional excretion of uric acid had a sensitivity of 86% and a specificity of 100% for identifying SIADH among patients on diuretics, and a sensitivity of 63% and specificity of 87% for identifying patients not on diuretics. They also looked at the fractional excretion of urea and found that patients with SIADH had a higher rate of excretion of urea when compared to patients with hypovolemia or those on diuretics. When a cut off of >55% was used, this biomarker had a sensitivity of 46% and a specificity of 68% for identifying SIADH among patients on diuretics, and a sensitivity of 96% and a specificity of 94% for identifying patients not on diuretics. Nigro et al., found that a cut off value of >12% for fractional excretion of uric acid could identify SIADH with a sensitivity of 66% and a specificity of 77%. They also found that fractional excretion of urea >55% had a sensitivity of 21% and specificity of 96% in identifying SIADH. The diuretic use did not influence the sensitivity or specificity of these biomarkers.
Maesaka et al., have suggested that while hypouricemia and increased fractional excretion of uric acid are seen in both SIADH and CSW, both hypouricemia and fractional excretion of uric acid normalise in SIADH once the hyponatremia is corrected but will persist in CSW. This is thought to be due to inhibition of urate transport at the proximal tubule in the kidney by a natriuretic factor in patients with CSW. However, this method would require validation with larger studies before it can be used. Attempts are now being made to identify this natriuretic factor and use it as a biomarker for CSW.
In acutely ill patients, it is important to correctly make the diagnosis of SIADH and CSW as the treatment of these two conditions is radically different. This NT-proBNP assay is commonly used by the intensive care unit physicians to differentiate cardiac and pulmonary causes of dyspnea. Its use can be extended for post-operative neurosurgery patients who develop hyponatremia. NT-proBNP levels <125 pg/ml suggest underlying SIADH, while its levels >125pg/ml suggest CSW.
The main limitation of this study is the small sample size. A larger study will define the cut-off level more accurately and improve the positive predictive value of this assay.
We thank Dr. Joe Fleming, Department of Biochemistry, Christian Medical College, Vellore for helping us with the biochemical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]