Wim Musch

Clinical Laboratory Evaluation of the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a frequent cause of hypotonicity. Although the differential diagnosis with other causes of hypotonicity such as salt depletion is sometimes challenging, some simple and readily available biologic parameters can be helpful in the diagnosis of SIADH. In SIADH, urea is typically low; this is less specific for elderly patients, for whom lower clearance of urea accounts for higher values. Low levels of uric acid are more often seen in SIADH (70%) compared with salt-depleted patients (40%). Typically, patients with SIADH will show a lower anion gap with nearly normal total CO2 and serum potassium, this despite dilution. In patients with hyponatremia secondary to hypocorticism, total CO2 is usually lower than in nonendocrine SIADH despite low urea and uric acid levels. Urine biology can also be helpful in diagnosis of SIADH because patients with SIADH have high urine sodium (Na; >30 mEq/L), and most of them will have a high fractional excretion of Na (>0.5% in 70% of cases), reflecting salt intake. Conversely, low urine Na in patients with SIADH and poor alimentation is not rare. Finally, measurement of urine osmolality is useful for the diagnosis of polydipsia and reset osmostat and could further help in the choice of therapeutic strategy because patients with low urine osmolality will benefit from water restriction or urea, whereas those with high urine osmolality (>600 mOsm/kg) would be good candidates for V2 antagonist.

Combined fractional excretion of sodium and urea better predicts response to saline in hyponatremia than do usual clinical and biochemical parameters.

BACKGROUND The treatment of hyponatremic patients requires physicians to make a therapeutic choice between saline infusion and water restriction. Therefore, they need readily available and reliable parameters to facilitate making that choice. This study was designed to determine whether the use of clearance ratios can help clinicians recognize saline-responding hyponatremic patients. PATIENTS AND METHODS Thirty-five nonedematous, hospitalized, hyponatremic patients were classified according to their history and saline response into four groups: diuretic-taking patients, polydipsic patients, saline responders, and saline nonresponders. Within these four groups, clinical and biochemical volume-related parameters, including clearance ratios, were prospectively evaluated before infusion of 2 L isotonic saline. Clearance ratios as well as usual clinical and biochemical parameters were tested for their accuracy in predicting saline responsiveness. RESULTS Both positive (70%) and negative (54.5%) predictive values for hypovolemia were unsatisfactory; clinical prediction of hypovolemia was also characterized by low sensitivity (41.1%), but acceptable specificity (80%). In the polydipsia and saline-nonresponder groups, plasma urea and uric acid values tended to be lower than in the diuretic and saline-responder groups. However, the usefulness of these parameters was limited by too large an overlap among the different groups. In both polydipsic patients and saline responders, urinary sodium concentration was low. The combined amount of urinary sodium and potassium in relation to plasma sodium did not discriminate among the different groups. Most helpful in distinguishing among the groups was a combination of several clearance ratios (fractional excretions of sodium, potassium, urea, and uric acid), since the predictive use of each parameter on its own was restricted. The best indicator of saline responsiveness was a low fractional excretion of filtered sodium (< 0.5%) combined with a low fractional excretion of urea (< 55%). CONCLUSION The accuracy of clinical evaluation for predicting the state of extracellular fluid volume in hyponatremia is low. The combination of low fractional sodium excretion (< 0.5%) and low fractional urea excretion (< 55%) is the best biochemical way to predict saline response, whereas high fractional potassium excretion (> 20%) indicates diuretic intake.

Age-Related Increase in Plasma Urea Level and Decrease in Fractional Urea Excretion: Clinical Application in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

This study confirms in humans an age-related increase in plasma urea levels (r = 0.62; P < 0.001; y = 0.229x + 18.26) and no correlation between plasma creatinine and age (r = 0.06; NS). Fractional urea excretion (FE urea) decreases with age (r = -0.41; P < 0.001; y = -0.226x + 55). Comparing urea and creatinine clearances, measured in 19 young and in 15 old women, a larger decrease of urea clearance (-56%) compared with the creatinine clearance (-43%) was observed as expected, explaining the lower FE urea in the elderly. In old women, the daily urea excretion was 27% and the daily creatinine excretion was 42% lower than in young women. An age-related decrease of same magnitude in both creatinine production and creatinine clearance explains why plasma creatinine remains stable with increasing age. The observation of a more important decrease in urea clearance (56%) than in urea production (27%) in older women led to an expected increase in plasma urea of 29%. These observations incited a comparison of biochemical profiles from younger and older patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Young patients with SIADH present lower mean plasma urea (18 +/- 8 mg/dl) and higher mean FE urea (58 +/- 14%), compared with both young control subjects (mean plasma urea 27 +/- 7 mg/dl; mean FE urea 46 +/- 10%) and old patients with SIADH (mean plasma urea 29 +/- 8 mg/dl; mean FE urea 44 +/- 15%). Physicians must realize that frankly low plasma urea values and high FE urea values can be expected only in young patients with SIADH, whereas old patients with SIADH will present values of plasma urea and FE urea in the same range than young control subjects. However, old patients with SIADH show still lower mean plasma urea values and higher mean FE urea values, compared with old control subjects (mean plasma urea 39 +/- 8 mg/dl; mean FE urea 36 +/- 9%), in whom plasma urea values between 40 and 50 mg/dl must be considered as usual.

Utility and limitations of biochemical parameters in the evaluation of hyponatremia in the elderly

We evaluated in 110 consecutive elderly hyponatremic patients the value of traditional clinical and biochemical data and the place of a test infusion of 2 liters isotonic saline over 24 hours, in establishing the etiology of the hyponatremia. The causes of hyponatremia were as follows: 31% SIADH patients, 23% patients with hyponatremia due to diuretics, 18% potomania patients, 15%salt depleted patients, 5% salt depleted SIADH patients, 5%patients with a salt loosing syndrome and 3% patients with hyponatremia of unknown origin. Several salt depleted (SD) and SIADH patients could be confounded. Usually, adults with SIADH show plasma uric acid values <4 mg/dL. In our elderly population, 41% of SD patients presented plasma uric acid <4mg/dL, while 27% of SIADH patients showed plasma uric acid >4mg/dL. Eighty-two percent of SD patients appeared to have plasma urea levels >30 mg/dL, but this was also the case in 21% of SIADH patients. Twenty-nine of the SD patients presented a urinary sodium >30 mEq/L, but all had fractional sodium excretion (FENa) lower than 0.5%. However, in SIADH, 42% of the patients presented also FENa <0.5%. Fractional excretion of urea (FE urea) below 50%was encountered in 82% of SD patients and FE urea above 50% in only 52% of the SIADH patients. Plasma renin and aldosterone values were poorly discriminative. A test infusion with 2 liters isotonic saline over 24 hours allowed a correct classification of all the patients. In about 2/3 of the population, administration of isotonic saline could be considered as useful (SD, most diuretic patients, potomania patients, salt loosing syndrome patients and some SD SIADH patients). A plasma sodium (Pna) increase of at least 5 mEq/L 24 hours after saline infusion has been suggested as highly suggestive of SD. Nevertheless, 29% of our SD patients did not increase their PNa level by 5 mEq/L or more,while 30% of our SIADH patients did. PNa improved after 2 liters isotonic saline over 24 hours in 90 patients (85%) as opposed to12 others (9 SIADH and 3 diuretic patients), decreasing their plasma sodium. The isotonic saline infusion test, only allows a reliable classification of hyponatremia, as far as both PNa and sodium excretion were taken into account. In the SIADH group, 6 patients (5%) presented initially manifest solute depletion and retained the 2 liters isotonic saline before developping inappropriate natriuresis. Six patients showed a transient salt loosing syndrome with high fractional potassium excretion (FEK) and high calciuria, which differentiates them from thiazide patients presenting also high FEK, but low calciuria. These patients were also polyuric at admission. The saline infusion was well tolerated in all but 2 patients, developping mild pulmonary congestion at the end of the test infusion.

Hyponatremia in the intensive care: from diagnosis to treatment.

Hyponatremia is the most common fluid and electrolyte abnormality particularly in the intensive care unit. It is associated with much higher mortality rates than found in non hyponatremic patients (1). When the physician is faced to an hyponatremic patient he first has to confirm that hyponatremia is associated with hypoosmolality. Then he must answer to a series of questions: what is its origin? Is it acute or chronic? Is it symptomatic? Which treatment is the most appropriate? We will briefly develop some of these points. When the measured osmolality is normal, or exceeds the calculated one (2 x Na mmoVl + glucose mmoVl (or mg/dl/l8) + urea mmolll (or mgldll6) by more than 10 mOsm1kg H,O, it implies the presence of an osmolal gap. This occurs either when there is a decrease in the water content of the serum, or when there is addition of a solute other than urea or glucose in the serum. About 93% of the normal serum is represented by water. Sodium is diluted only in the aqueous phase where its mean concentration is 154 mEq/l (154 x 0.93 = 142 mEq/l). Thus a major increase in triglyceride or protein will artefactually decrease the serum sodium concentration. However, these macromolecules do not influence the serum osmolality. It has been estimated that for each mgldl of lipid the serum sodium concentration will artefactually decrease by 0.002 mEq/l and that a decrease of 0.25 mEq/l will be observed for each gram of proteins above 8 g/dl (2). With the use of direct Na ionspecific electrode instead of flame photometry, lipids or proteins have lower influence on serum sodium measurement; but unfortunaly many instruments dilute the

Low Sodium Excretion in SIADH Patients with Low Diuresis

It is well known that during low diuresis or low effective circulating volume, salt excretion is low. The aim of this study was to find out whether salt excretion, expressed as either urinary sodium concentration (UNa) or fractional sodium excretion (FENa), and the combined use of FENa and fractional urea excretion (FEurea) still differentiate between hyponatremic SIADH and hyponatremic salt depletion (SD) patients when diuresis is low. The relationships between UNa, FENa and diuresis, indirectly estimated by the urinary to plasma creatinine ratio (U/P creat), were studied in 42 hyponatremic SIADH patients, 21 hyponatremic SD patients and 66 normonatremic controls (CO) of similar age and sex ratio. There was no significant relationship between UNa and U/P creat either in SIADH or in SD or CO patients. FENa and U/P creat were inversely correlated, both in CO (r = –0.72; p < 0.001) and in SIADH (r = –0.68; p < 0.001). SIADH and SD patients can be fairly well differentiated from one another using FENa and U/P creat. Even with high U/P creat values, SIADH patients, despite a sharp decrease in their FENa values, presented still higher FENa values than SD patients did (mean FENa = 0.3 ± 0.2% in SIADH and 0.1 ± 0.04% in SD; p < 0.05). However, FENa values of SIADH patients with low diuresis (mean FENa = 0.3 ± 0.2% for a mean U/P creat = 191 ± 40) are indistinguishable from those of SD patients with normal urine volumes (mean FENa = 0.2 ± 0.2% for a mean U/P creat = 92 ± 30). The combined use of FENa and FEurea remains a reliable way to discriminate SD patients and SIADH patients, as far as the differential limit value for FENa is narrowed to a value of 0.15%, for hyponatremic patients with U/P creat >140. Conclusion: In SIADH, FENa values are lower than 0.5%, as soon as U/P creat exceeds a value of 180. In SD patients with U/P creat values exceeding 140, FENa is lower than 0.15% and FEurea lower than 45%.

MANAGEMENT OF HYPOTONIC HYPONATREMIA

The management of hypotonic hyponatremia depends on its cause and its severity. The cases of hyponatremia with decreased, increased and normal extracellular fluid (ECF) volumes will be examined, followed by a brief mention concerning severe hyponatremia.

Actual Therapeutic Indication of an Old Drug: Urea for Treatment of Severely Symptomatic and Mild Chronic Hyponatremia Related to SIADH.

Oral urea has been used in the past to treat various diseases like gastric ulcers, liver metastases, sickle cell disease, heart failure, brain oedema, glaucoma, Meniere disease, etc. We have demonstrated for years, the efficacy of urea to treat euvolemic (SIADH) or hypervolemic hyponatremia. We briefly describe the indications of urea use in symptomatic and paucisymptomatic hyponatremic patients. Urea is a non-toxic, cheap product, and protects against osmotic demyelinating syndrome (ODS) in experimental studies. Prospective studies showing the benefit to treat mild chronic hyponatremia due to SIADH and comparing water restriction, urea, high ceiling diuretics, and antivasopressin antagonist antagonist should be done.

Severe Solute Depletion in Patients with Hyponatremia Due to Diuretics Despite Biochemical Pictures Similar Than Those Observed in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Background/AIMS: Hyponatremia secondary to distal diuretics intake could have a biochemical picture similar to the one observed in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In these patients, water retention is considered to be the main causal factor and solute depletion a secondary one. Methods. We compared the level of cation (Na + K) depletion and water balance in patients with high or low uric acid levels (< 4 mg/dL or 238 µmol/L) or with high or low (< 30 mg/dL or 5 mmol/L) urea levels. Data were collected from 15 consecutive patients treated in a similar way by a daily infusion of 2 L isotonic saline with potassium chloride until SNa reached at least 132 mmol/L. The same procedure was performed in 6 patients with hyponatremia due to salt depletion not related to diuretic intake. Results: Hyponatremia, associated with low or high uric acid level is mainly due to severe cation depletion (around 600 mmol) and not due to water retention, since body weight did not change significantly (SNa 122 ± 2.0 mEq/L). If patients were classified according to serum urea levels those with higher urea levels (≥30 mg/dL) presented with a mild increase in BW (0.84 ± 0.37 kg). In patients with salt depletion and hyponatremia not related to diuretic intake, we observe as expected an increase in BW (1.5 ± 0.3 kg) and similar cation retention with the treatment. Conclusion: We therefore suggest that diuretic induced hyponatremia with an SIADH-like biochemical profile, should be treated mainly by solute repletion.

Hyponatremia: terminology and more

As discussed by Karen Yeates and associates[1][1] in their review of hyponatremia, evaluation of extracellular volume is sometimes difficult. In a patient with hyponatremia, a trial of saline infusion may be useful in clarifying the diagnosis; however, contrary to information in the review, most