**5. Assessment of extracellular volume**

It is generally agreed that the assessment of ECV by clinical criteria is fraught with inaccuracies that the term "appeared dehydrated" is not acceptable for clinical and research purposes. (Chung et al, 1987; Maesaka et al, 1999; Oh & Carroll, 1999; Singh et al, 2002) The usual criteria of tissue turgor, axillary sweat, dry mucus membranes, neck vein distention or even postural hypotension in a nonedematous patient have been collectively inaccurate in assessing ECV. Even the presence of postural hypotension must consider autonomic dysfunction as we reported in a hyponatremic patient with autonomic failure and SIADH, proven by increased blood volume by gold standard radioisotope-dilution methods and depressed plasma renin and aldosterone. (Bitew et al, 2009) The use of plasma renin and aldosterone to differentiate SIADH from RSW can be helpful under ideal circumstances. In SIADH, plasma renin and aldosterone levels should be depressed, reflecting a slightly hypervolemic state, while in RSW, both levels should be increased, reflecting volume depletion. Clinically, however, determinations of plasma renin and aldosterone are delayed. Their diagnostic value is limited by a variety of exogenous factors. They include medication like ACE inhibitors, ARBs, B-Blockers, NSAIDS, heparin, diuretics and hyperuricemia. (Mulatero et al, 2002; Eraranta et al, 2008) A/BNP has not been used to differentiate SIADH from RSW.

It appears that noninvasive methods to assess ECV have limited value. Invasive methods have also been limited by various factors. A commonly used parameter is to measure central venous pressures (CVP). CVP has a poor correlation with concomitant radioisotope dilution measurements of blood volume and is also being discarded as a guide to fluid management. (Marik et al, 2008) The use of bioimpedance to determine volume in different compartments of the body is not useful as a single determination. (Schneditz, 2006)) Pulmonary wedge pressures are limited by a failure consistently to predict ECV but also by their invasiveness. (Godje et al, 1998)

There are two credible methods that can reliably determine ECV with greater accuracy than methods discussed above. One is the gold standard radioisotope-dilution method, using radioiodinated serum albumin and/or 51Cr-tagged red blood cells, and the other, determination of total body water by deuterium and extracellular water by sodium bromide. As will be discussed below, there are a limited number of studies using radioisotope-dilution methods in SIADH and RSW and none using measurements of total and extracellular water in either of these two groups of patients.

#### **5.1 Volume studies using radioisotope-dilution and other pertinent methodologies**

As reviewed above, estimates of ECV have been made by determining chloride and thiosulfate spaces to support other criteria to establish the diagnosis of RSW and SIADH, respectively. (Cort, 1954; Schwartz et al, 1957) The gold standard for determining blood volume is by radioisotope dilution methods including radioiodinated serum albumin and/or 51Cr labeled red blood cells. A study of 12 neurosurgical hyponatremic patients with UNa ranging from 41-203 mmol/L had blood volume determined by 51Cr tagged red cells and radioiodinated serum albumin. Ten of the 12 patients had decreased blood volume and 2 had increased blood volume as compared to 6 control patients. (Nelson et al, 1981) The high UNa of 41 to 203 mmol/L suggests that 83.3% had RSW and 16.7% had SIADH. Eight patients had subarachnoid hemorrhage (SAH). In another study, plasma volume was

It is generally agreed that the assessment of ECV by clinical criteria is fraught with inaccuracies that the term "appeared dehydrated" is not acceptable for clinical and research purposes. (Chung et al, 1987; Maesaka et al, 1999; Oh & Carroll, 1999; Singh et al, 2002) The usual criteria of tissue turgor, axillary sweat, dry mucus membranes, neck vein distention or even postural hypotension in a nonedematous patient have been collectively inaccurate in assessing ECV. Even the presence of postural hypotension must consider autonomic dysfunction as we reported in a hyponatremic patient with autonomic failure and SIADH, proven by increased blood volume by gold standard radioisotope-dilution methods and depressed plasma renin and aldosterone. (Bitew et al, 2009) The use of plasma renin and aldosterone to differentiate SIADH from RSW can be helpful under ideal circumstances. In SIADH, plasma renin and aldosterone levels should be depressed, reflecting a slightly hypervolemic state, while in RSW, both levels should be increased, reflecting volume depletion. Clinically, however, determinations of plasma renin and aldosterone are delayed. Their diagnostic value is limited by a variety of exogenous factors. They include medication like ACE inhibitors, ARBs, B-Blockers, NSAIDS, heparin, diuretics and hyperuricemia. (Mulatero et al, 2002; Eraranta et al, 2008) A/BNP has not been used to differentiate SIADH

It appears that noninvasive methods to assess ECV have limited value. Invasive methods have also been limited by various factors. A commonly used parameter is to measure central venous pressures (CVP). CVP has a poor correlation with concomitant radioisotope dilution measurements of blood volume and is also being discarded as a guide to fluid management. (Marik et al, 2008) The use of bioimpedance to determine volume in different compartments of the body is not useful as a single determination. (Schneditz, 2006)) Pulmonary wedge pressures are limited by a failure consistently to predict ECV but also by their invasiveness.

There are two credible methods that can reliably determine ECV with greater accuracy than methods discussed above. One is the gold standard radioisotope-dilution method, using radioiodinated serum albumin and/or 51Cr-tagged red blood cells, and the other, determination of total body water by deuterium and extracellular water by sodium bromide. As will be discussed below, there are a limited number of studies using radioisotope-dilution methods in SIADH and RSW and none using measurements of total

**5.1 Volume studies using radioisotope-dilution and other pertinent methodologies** 

As reviewed above, estimates of ECV have been made by determining chloride and thiosulfate spaces to support other criteria to establish the diagnosis of RSW and SIADH, respectively. (Cort, 1954; Schwartz et al, 1957) The gold standard for determining blood volume is by radioisotope dilution methods including radioiodinated serum albumin and/or 51Cr labeled red blood cells. A study of 12 neurosurgical hyponatremic patients with UNa ranging from 41-203 mmol/L had blood volume determined by 51Cr tagged red cells and radioiodinated serum albumin. Ten of the 12 patients had decreased blood volume and 2 had increased blood volume as compared to 6 control patients. (Nelson et al, 1981) The high UNa of 41 to 203 mmol/L suggests that 83.3% had RSW and 16.7% had SIADH. Eight patients had subarachnoid hemorrhage (SAH). In another study, plasma volume was

and extracellular water in either of these two groups of patients.

**5. Assessment of extracellular volume** 

from RSW.

(Godje et al, 1998)

determined by radioiodinated serum albumin in 21 patients on the first day of admission within 48 hours after SAH and on the 6th day after SAH. Comparisons between the first and second volume determination revealed blood volume to decrease in 8 of 9 hyponatremic patients, suggesting that 88.9% had RSW and 11.1% had SIADH. UNa values were not reported. (Wijdicks et al, 1985) Interestingly, plasma volume was decreased in 8, 66.7%, and increased in 4, 33.3%, of 12 nonhyponatremic patients with SAH, suggesting that RSW can occur in nonhyponatremic patients. Moreover, all 8 hyponatremic and 8 of 12 nonhyponatremic patients with decreased blood volume were in negative sodium balance. The increased blood volume in the 4 patients with normonatremia raises the question of whether or not SIADH can occur with normonatremia. In a separate study, Water restriction in volume depleted patients with SAH increased morbidity and mortality, probably due to decreased perfusion of brain and extension of ischemia in an already compromised circulation. (Wijdicks et al, 1985)

Another study used 51Cr tagged red cells and CVP measurements in 18 hyponatremic patients of various etiologies with UNa of 43-210 mmol/L. (Sivakumar et al, 1994) Seventeen of 18 patients had decreased blood volumes, 18 of 18 patients had decreased CVP and all 18 patients corrected their hyponatremia within 72 hours after initiating saline infusion. The high UNa, decreased blood volume and correction of hyponatremia within 72 hours after initiating saline therapy argue strongly for RSW. We demonstrated a similar correction of hyponatremia within 48 hours after initiation of saline therapy in two patients with RSW and failure of saline therapy to correct the hyponatremia in two patients with SIADH. (Bitew et al, 2009; Maesaka et al, 2007) The three neurosurgical studies demonstrate by acceptable methods of determining ECV, that RSW is much more common than SIADH in neurosurgical patients, especially SAH.

A study in neurosurgical patients determined blood volume by 51Cr labeled red cells in 20 hyponatremic and 20 nonhyponatremic "control" patients. Patients with evidence of "dehydration or hypovolemia" were excluded. All met criteria for SIADH. (Brimioulle et al, 2008) The exclusion of dehydrated or hypovolemic patients might have excluded patients with RSW and meeting the criteria for SIADH would include patients with RSW. Blood volumes were found to be comparable in the "control" and hyponatremic groups, suggesting that the hyponatremic group was entirely SIADH. Interestingly both the "control" and experimental groups were hypouricemic, mean serum urate 2.7 and 1.3 mg/dL and had high mean FEurate of 19% and 32% (normal 5-10%), respectively. There is ample evidence to suggest that the high FEurate in the hyponatremic group was consistent with both SIADH and RSW, while the nonhyponatremic group with increased FEurate would be consistent with RSW or normal controls depending on whether the FEurate was high or normal, respectively, figures 3, 4, table 1. (Maesaka et al, 1996, 1998, 1999, 2009) Based on these diagnostic possibilities, this study suffers first from a protocol-based elimination of patients with evidence of volume depletion as in RSW and failure to select the proper "control" and hyponatremic groups.

Ten patients with acquired immune deficiency syndrome with saline-responsive postural hypotension had CVP of 0 cm water, increased renin and aldosterone, hyponatremia, hypouricemia, elevated FEurate and UNa >40 mmol/l, which collectively support the diagnosis of RSW. (Cusano et al, 1990; Maesaka et al, 1990)

Complexity of Differentiating Cerebral-Renal Salt Wasting

(Maesaka et al, 2007).

from SIADH, Emerging Importance of Determining Fractional Urate Excretion 51

Interestingly, the baseline FEurate of 29.6% increased further to a peak of 63% and 48% at the time of correction of the hyponatremia at 138 mmol/L, figure 2. The effect of saline on FEurate has been amply shown to be minimal. This persistently increased FEurate after correction of hyponatremia is consistent with RSW and not SIADH, to be discussed later.

Fig. 2. Relationship between serum urate, serum sodium and FEurate during volume repletion with saline for 48 hours. Note that persistence of increased FEurate after correction of hyponatremia contrasts this to SIADH. Saline has been amply shown to have a meager

In our view, this very instructive case followed predicted physiologic parameters for RSW and proved unequivocally the existence of RSW by collectively demonstrating the critical decrease in blood volume, increased plasma renin and aldosterone, low normal plasma ANP, appropriately increased plasma ADH, which was inhibited by the combination of volume repletion and hypo-osmolality, increased free water excretion, and timely correction of hyponatremia. These compelling data proved that RSW can occur without evidence of clinical cerebral disease and that a low sodium intake will be associated with a low UNa in a

Determination of serum urate in SIADH was first reported in 1971. Patients with SIADH had hypouricemia and increased FEurate, which normalized after correction of the hyponatremia. (Dorhout Mees et al, 1971) In 1979 Beck duplicated these findings, but compared serum urate in SIADH with other causes of hyponatremia. Except for only one overlapping value, there was complete separation of serum urate in SIADH from other causes of hyponatremia. (Beck, 1979) Correcting the hyponatremia by water restriction was accompanied by an increase in serum urate with normalization of a previously increased FEurate, figures 3, 4. (Beck, 1979) Beck concluded that the coexistence of hyponatremia and hypouricemia differentiated SIADH from most other causes of hyponatremia. This apparent simple method of differentiating SIADH from other causes of hyponatremia stimulated

effect on FEurate. (reproduced with permission from publisher)

patient with RSW. (Maesaka et al, 2007)

**7. Emerging value of determining FEurate** 

#### **5.2 Other pertinent studies**

In a retrospective study of 319 patients with SAH, 179 were hyponatremic and met criteria for SIADH and CSW. They found that 69.2% had SIADH, 6.5% CSW and 4.8% a combination of SIADH and CSW. The volume status was determined by CVP measurements, presence of hypotension and undefined parameters. This report suffers by its retrospective design, paucity of data to support their diagnoses and reliance on CVP measurements that have little value in assessing ECV. (Sherlock et al, 2006) In a similar retrospective study that included a variety of intracranial diseases, they found 62% of patients to have SIADH, 26.7% hypovolemic, 16.6% drug-related, 4.8% CSW, 3.7% related to IV fluids and 2.7% a combination of CSW and SIADH. In both studies, the combination of SIADH and CSW in 4.8% and 2.7% of patients lacked supportive data to justify such a difficult and improbable diagnostic combination, especially in a retrospective study. (Sherlock et al, 2006, 2009)
