**10. Treatment of the hyponatremic patient with SIADH and RSW**

The increasing reports of significant symptoms being attributed to even mild hyponatremia not only shed light on a long unrecognized phenomenon, but introduce the need for some urgency in developing adequate treatment strategies for a condition with diverse etiologies and divergent therapeutic goals. Treatment, however, has undergone a period of uncertainty due to adverse outcomes that are related to delays in treatment and overcorrection of chronic hyponatremia. (Berl et al, 1990) The approach to methods of correction in different clinical conditions will be limited to SIADH and RSW and the reader is referred to broader reviews of treating hyponatremia. (Stern et al, 2009; Verbalis et al, 2007) As discussed earlier, foremost among the diagnostic and therapeutic dilemma is the need to

Complexity of Differentiating Cerebral-Renal Salt Wasting

administration of free water and/or intranasal dDAVP.

(Imbriano et al, 2011)

from SIADH, Emerging Importance of Determining Fractional Urate Excretion 59

symptomatic improvement in patients with SIADH. (Berl et al, 2010**;** Schrier et al, 2006**;** Verbalis et al, 2011) Patients should not be water-restricted while being treated with the vaptans except under very unusual circumstances to avoid rapid correction of hyponatremia. Serum sodium should be monitored at least within 8 hours of initiating vaptan therapy, but we recommend repeating serum sodium determinations earlier if the patient increases urine output soon after starting vaptan therapy. (Berl et al, 2010) The increase in urine output suggests that ADH receptor inhibition is occurring rapidly and the resulting increase in free water excretion would correct sodium rapidly thereafter, hence a recommendation to determine serum sodium at this time. Over-correction of hyponatremia can be avoided by closely matching the increased urine volume or if too rapid, by the

The treatment of SIADH, including RO, traditionally starts with the treatment of the associated clinical condition, fluid restriction to < 1000 ml/day, salt supplementation, occasionally diuretics, demeclocyline and ADH inhibitors. The correction of hyponatremia in SIADH by fluid restriction and/or salt supplementation has been slow and often incomplete or unsuccessful. Treatment of RO has been generally unsuccessful to the point of not recommending any treatment for these patients. The use of vaptans in SIADH can be justified by their hypervolemic state, but it is uncertain whether patients with RO are similarly volume expanded. Although an increase in volume makes intuitive sense, volume studies have not been performed in patients with RO to justify use of vaptans . Our ability to identify patients with RO by virtue of a normal FEurate will uncover this common cause of hyponatremia and test the efficacy of vaptans in this therapeutically challenging group.

In contrast to the difficulty of treating patients with SIADH or RO, the treatment of RSW is simple. Eliminating the appropriate volume stimulus for ADH secretion in this disorder with saline will allow the coexisting hypo-osmolality to inhibit ADH secretion, increase free water excretion and correct the hyponatremia. (Bitew et al, 2009; Maesaka et al, 2007) Use of vaptans is obviously contraindicated in these volume depleted patients. While the rationale for increasing salt and water intake in patients with RSW is obvious, we are again confronted with our inability to differentiate SIADH from RSW with any degree of certainty. This therapeutic dilemma has been partially resolved by the recommendation to treat hyponatremic patients with acute neurological/neurosurgical diseases with hypertonic saline to prevent the complications associated with brain edema of multiple causes. (Sterns & Silver, 2008 and et al, 2009) As discussed earlier, RSW is more common than SIADH in neurosurgical diseases and the use of hypertonic saline not only reduces brain edema but has other advantages, such as treating their volume depletion. (Sterns & Silver, 2008) Administration of hypertonic saline prevents hyponatremia from occurring so an increased FEurate would be consistent with RSW. (Youmans & Maesaka, 2011). A timely correction of an existing hyponatremia by judicious use of hypertonic saline can also differentiate SIADH from RSW, whether FEurate normalizes or remains increased, respectively, figures 3, 4.

Hyponatremic patients outside of the neurology/neurosurgical ICU, including those with nonedematous hyponatremia with or without cerebral disease, need to be evaluated for etiology of their hyponatremia, as discussed above. Following the algorithm in table 1 has been useful in our hands. Therapy will depend on the etiology of the hyponatremia. In those with increased FEurate, the diagnostic dilemma of differentiating SIADH from RSW must

differentiate SIADH from RSW in order to fulfill divergent therapeutic goals. It is well known that severe hyponatremia can cause neurologic symptoms, such as irritability, seizures and even apnea, but more subtle alterations in memory and judgment, unsteady gait and even falls have been associated with mild hyponatremia that have responded to treatment of their hyponatremia. (Berl et al, 2010; Decaux et al, 2006, 2009; Gankam Kengne et al, 2008; Renneboog et al, 2006) It is, therefore, pertinent to ask whether "asymptomatic hyponatremia exists". (Schrier, 2010) One of the most alarming outcomes has been the descriptions of a four-fold increase in falls that have been attributed to mild hyponatremia, mean serum sodium 131 mmol/L, in the elderly. (Renneboog et al, 2006; Gankam Kengne et al, 2008) There is, therefore, a movement to consider treating all hyponatremics, including the infusion of hypertonic saline to treat hyponatremic patients with brain diseases to avoid brain edema regardless of whether or not they have SIADH or RSW. (Sterns & Silver, 2008)

Table 1. New approach to hyponatremia based on FEurate. Normonatremia and FEurate without hyponatremia needs further verification, dotted line.

The standard approach to treating hyponatremia depends on the etiology of the hyponatremia. Patients with edematous causes of hyponatremia such as heart failure, cirrhosis or nephrosis are treated with a combination of water-restriction, low salt diet, diuretics and the ADH inhibitors or vaptans. Vaptans are clearly indicated in edematous states and are contraindicated in hypovolemic patients. Of the available vaptans, conivaptan inhibits the V1A and V2 receptor for ADH and tolvaptan the V2 receptor. Conivaptan is administered only intravenously and inhibits CYP3A4 so its administration must consider other agents that might be metabolized by this pathway and potentially increase blood levels of conivaptan. (Sterns et al, 2009) Because conivaptan inhibits the V1A receptor, which has vasopressive activity, it is not indicated for treatment of hyponatremic cirrhotics. (Sterns et al, 2009) SIADH and RO are treated by water-restriction with salt supplementation and hypertonic saline in patients with brain disease, but the vaptans appear to be promising for both conditions. Vaptans have been shown to increase serum sodium successfully and improve symptoms attributed to non hypovolemic hyponatremia, including better

differentiate SIADH from RSW in order to fulfill divergent therapeutic goals. It is well known that severe hyponatremia can cause neurologic symptoms, such as irritability, seizures and even apnea, but more subtle alterations in memory and judgment, unsteady gait and even falls have been associated with mild hyponatremia that have responded to treatment of their hyponatremia. (Berl et al, 2010; Decaux et al, 2006, 2009; Gankam Kengne et al, 2008; Renneboog et al, 2006) It is, therefore, pertinent to ask whether "asymptomatic hyponatremia exists". (Schrier, 2010) One of the most alarming outcomes has been the descriptions of a four-fold increase in falls that have been attributed to mild hyponatremia, mean serum sodium 131 mmol/L, in the elderly. (Renneboog et al, 2006; Gankam Kengne et al, 2008) There is, therefore, a movement to consider treating all hyponatremics, including the infusion of hypertonic saline to treat hyponatremic patients with brain diseases to avoid brain edema regardless of whether or not they have SIADH or RSW. (Sterns & Silver, 2008)

Table 1. New approach to hyponatremia based on FEurate. Normonatremia and FEurate

The standard approach to treating hyponatremia depends on the etiology of the hyponatremia. Patients with edematous causes of hyponatremia such as heart failure, cirrhosis or nephrosis are treated with a combination of water-restriction, low salt diet, diuretics and the ADH inhibitors or vaptans. Vaptans are clearly indicated in edematous states and are contraindicated in hypovolemic patients. Of the available vaptans, conivaptan inhibits the V1A and V2 receptor for ADH and tolvaptan the V2 receptor. Conivaptan is administered only intravenously and inhibits CYP3A4 so its administration must consider other agents that might be metabolized by this pathway and potentially increase blood levels of conivaptan. (Sterns et al, 2009) Because conivaptan inhibits the V1A receptor, which has vasopressive activity, it is not indicated for treatment of hyponatremic cirrhotics. (Sterns et al, 2009) SIADH and RO are treated by water-restriction with salt supplementation and hypertonic saline in patients with brain disease, but the vaptans appear to be promising for both conditions. Vaptans have been shown to increase serum sodium successfully and improve symptoms attributed to non hypovolemic hyponatremia, including better

without hyponatremia needs further verification, dotted line.

symptomatic improvement in patients with SIADH. (Berl et al, 2010**;** Schrier et al, 2006**;** Verbalis et al, 2011) Patients should not be water-restricted while being treated with the vaptans except under very unusual circumstances to avoid rapid correction of hyponatremia. Serum sodium should be monitored at least within 8 hours of initiating vaptan therapy, but we recommend repeating serum sodium determinations earlier if the patient increases urine output soon after starting vaptan therapy. (Berl et al, 2010) The increase in urine output suggests that ADH receptor inhibition is occurring rapidly and the resulting increase in free water excretion would correct sodium rapidly thereafter, hence a recommendation to determine serum sodium at this time. Over-correction of hyponatremia can be avoided by closely matching the increased urine volume or if too rapid, by the administration of free water and/or intranasal dDAVP.

The treatment of SIADH, including RO, traditionally starts with the treatment of the associated clinical condition, fluid restriction to < 1000 ml/day, salt supplementation, occasionally diuretics, demeclocyline and ADH inhibitors. The correction of hyponatremia in SIADH by fluid restriction and/or salt supplementation has been slow and often incomplete or unsuccessful. Treatment of RO has been generally unsuccessful to the point of not recommending any treatment for these patients. The use of vaptans in SIADH can be justified by their hypervolemic state, but it is uncertain whether patients with RO are similarly volume expanded. Although an increase in volume makes intuitive sense, volume studies have not been performed in patients with RO to justify use of vaptans . Our ability to identify patients with RO by virtue of a normal FEurate will uncover this common cause of hyponatremia and test the efficacy of vaptans in this therapeutically challenging group. (Imbriano et al, 2011)

In contrast to the difficulty of treating patients with SIADH or RO, the treatment of RSW is simple. Eliminating the appropriate volume stimulus for ADH secretion in this disorder with saline will allow the coexisting hypo-osmolality to inhibit ADH secretion, increase free water excretion and correct the hyponatremia. (Bitew et al, 2009; Maesaka et al, 2007) Use of vaptans is obviously contraindicated in these volume depleted patients. While the rationale for increasing salt and water intake in patients with RSW is obvious, we are again confronted with our inability to differentiate SIADH from RSW with any degree of certainty. This therapeutic dilemma has been partially resolved by the recommendation to treat hyponatremic patients with acute neurological/neurosurgical diseases with hypertonic saline to prevent the complications associated with brain edema of multiple causes. (Sterns & Silver, 2008 and et al, 2009) As discussed earlier, RSW is more common than SIADH in neurosurgical diseases and the use of hypertonic saline not only reduces brain edema but has other advantages, such as treating their volume depletion. (Sterns & Silver, 2008) Administration of hypertonic saline prevents hyponatremia from occurring so an increased FEurate would be consistent with RSW. (Youmans & Maesaka, 2011). A timely correction of an existing hyponatremia by judicious use of hypertonic saline can also differentiate SIADH from RSW, whether FEurate normalizes or remains increased, respectively, figures 3, 4.

Hyponatremic patients outside of the neurology/neurosurgical ICU, including those with nonedematous hyponatremia with or without cerebral disease, need to be evaluated for etiology of their hyponatremia, as discussed above. Following the algorithm in table 1 has been useful in our hands. Therapy will depend on the etiology of the hyponatremia. In those with increased FEurate, the diagnostic dilemma of differentiating SIADH from RSW must

Complexity of Differentiating Cerebral-Renal Salt Wasting

evaluating patients with hyponatremia.

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*(Baltimore)*,55(2),pp.121-129.

37(3),pp.1006-1018.

*Nephol*,4:309-315

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hyponatremia*. J Am Soc Nephrol*,21(4),pp.705-712

hyponatremia. *J Am Soc Nephrol*, 21,pp.705-712

hormone secretion. *Intensive Care Med,*34,pp.125-131

fluid volume in hyponatremia. *Am J Med*,83,pp.905-908

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hypertensive man. *Circulation,*41,pp.97-108..

Cort JH. (1954) Cerebral salt wasting. *Lancet*(1),pp.752-754

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from SIADH, Emerging Importance of Determining Fractional Urate Excretion 61

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neurological patients: cerebral salt wasting versus inappropriate antidiuretic

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upon the fractional reabsorption of urate and other ions in normal and

be extended to those without clinical cerebral disease. This diagnostic and dependent therapeutic dilemma will persist until we have a mindset to consider RSW in these patients and develop a better diagnostic approach to solving this dilemma. Recommendations to determine FEurate in normonatremic patients have not been resolved except to include it as a routine measurement in any patient with acute brain disease and demented patients with AD.

In patients with symptomatic hyponatremia such as muscular irritability, altered mental status or seizures, the patient should be treated with hypertonic saline to increase serum sodium by 4-6 mmol/l over 4 hours and then slowly thereafter. (Sterns & Silver, 2008) Although it is safe to increase serum sodium to normal values in conditions such as in acute and documented water intake, marathon runners, that cause acute hyponatremia, we recommend gradual improvement in all patients with hyponatremia to avoid any contributions rapid correction might add to circumstances in which osmotic demyelination might occur irrespective of their sodium, such as in malnourished patients or those with liver disease. (Almond et al, 2005, Sterns & Silver, 2008) We favor a conservative approach to the correction of chronic hyponatremia by increasing serum sodium <10 mmol/l/24 hrs with slower rates for patients with severe malnutrition and cirrhosis to avoid osmotic demyelination.
