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BACKGROUND: Periostitis, usually seen on X-ray, may be diagnosed on bone scan as non-nodular cortical bone hyperactivity. Both the complete form (including clubbing, arthritis and periostitis) and the incomplete form have been described in association with chronic pulmonary disease, neoplasm, hepatopathy and inflammatory bowel disease. It is not known whether the bone scan pattern of non-nodular cortical bone hyperactivity varies with the etiology. METHODS: We conducted a retrospective study to analyze the etiologies and bone scan patterns of 115 cases of non-nodular cortical bone hyperactivity. RESULTS: Eighty percent of our patients were asymptomatic. Thirty-four percent of all cases of periostitis (all bilateral) were associated with cancer. The rate of cancer in cases of periostitis involving both lower limbs was 28.5%; it was 61.3% when both lower and upper limbs were involved. The duration of the disease was not correlated with either the distribution of periostitis or the intensity of uptake. Moreover, the intensity of uptake was not correlated with the importance of the symptomatology. Bone scan pattern (regular versus heterogenous uptake, localized versus diffuse uptake) was not correlated with the etiology. CONCLUSIONS: Bilateral upper and lower uptake should alert the clinician to the risk of association with neoplasm. Bone scan pattern and intensity of uptake are not necessarily correlated with etiology.

Unlabelled: 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%., (Copyright 2004 S. Karger AG, Basel)

Inadequate treatment of severe hyponatremia (<120 mEq/L) can be associated with severe neurological damage. In acute (<48 hours) hyponatremia, usually observed in the postoperative period, prompt treatment with hypertonic saline (3%) can prevent seizures and respiratory arrest. For patients with chronic (>48-72 hours) symptomatic hyponatremia, correction must be rapid during the first few hours (to decrease brain edema) followed by a slow correction limited to 10 mmol/L over 24 hours to avoid the development of osmotic demyelinating syndrome. In patients with asymptomatic hyponatremia, slow correction is the appropriate approach. When patients are overtreated, neurologic damage can be prevented by relowering the serum sodium (SNa) so that the daily increase in SNa remains below 10 mmol/L/24 hours. Frequent measurements of SNa during the correction phase of SNa are mandatory to avoid overcorrection. The use of urea to treat hyponatremia represents an advantageous alternative to hypertonic saline.

Background: Polydipsia-related hyponatraemia is generally considered an acute dilutional state., Aim: To determine whether solute loss plays a role in the pathogenesis of polydipsia-related hyponatraemia., Design: Prospective uncontrolled study., Methods: We studied routine biochemical volume-related parameters before and after 2 l isotonic saline infusion over 24 h, in 10 consecutive hyponatraemic polydipsia patients (mean age 55 +/- 11 years; 6 beer drinkers and 4 compulsive water drinkers) with initial urinary osmolality <220 mosm/kg H(2)O. In five of these patients, we measured balance data over 24 h., Results: Mean initial plasma protein concentration in the 10 studied polydipsia patients was 7 +/- 0.7 g/dl, unexpectedly high for an acute dilutional state. Mean plasma sodium concentration increased from 126 +/- 5 mmol/l before saline, to 135 +/- 5 mmol/l after infusion of 2 l isotonic saline (p < 0.01). Balance data in five polydipsia patients showed a mean decrease of 1.6 kg of their initial body weight and a mean salt retention of 406 mosm., Discussion: Polydipsia-related hyponatraemia is a mixed disorder, in which about half of sodium decrease is due to solute loss. This explains the apparent paradox of a normal plasma protein concentration, despite the increase in body weight due to water intoxication.

Clubbing was first described by Hippocrates more than 2.500 years ago. It may be seen alone or as part of an entity called hypertrophic osteoarthropathy which include periostitis, arthritis and sometimes thickening and edema of the skin around the affected joints. Pulmonary diseases such as cancer, abscess, empyema, bronchiectasis and cystic fibrosis are the major diseases known to be associate with hypertrophic osteoarthropathy. Digestive tract cancer, cyanogenic congenital heart disease are well known association. Many theories have attempted to explain the appearance of this sign but few have persisted. In this article, we review characteristics, relation with etiology and the basis of the pathophysiology of hypertrophic osteoarthropathy and particularly of clubbing.

Background & Aims: Dilutional hyponatremia is a frequent complication of cirrhosis partly because of nonosmotic vasopressin release. No effective therapy exists for this complication. Therefore, we investigated the effects of VPA-985, an orally active vasopressin V2 receptor antagonist, in patients with cirrhosis and dilutional hyponatremia. Primary endpoint was normalization of serum sodium (serum sodium >or=136 mmol/L)., Methods: Sixty patients with cirrhosis and dilutional hyponatremia were randomly assigned to 100 or 200 mg/day of VPA-985 or placebo in a double-blind study. Treatment was given with fluid restriction (1000 mL/day) until normalization of serum sodium or for 7 days., Results: Normalization of serum sodium concentration was achieved in 27% and 50% of patients in the VPA-985 100 mg/day and 200 mg/day groups, respectively, but in none of the patients in the placebo group (P < 0.05 and P < 0.001, respectively). Treatment with VPA-985 was associated with a significant reduction in urine osmolality and body weight. Thirst sensation increased significantly in the VPA 200 mg group but not in the VPA 100 mg or placebo group. Serious adverse events were similar among the 3 groups., Conclusions: An orally active vasopressin receptor antagonist can correct hyponatremia in patients with cirrhosis and ascites. This represents a novel therapy of water retention in cirrhosis.

It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myo-inositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 micromol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.

The Department of General Internal Medicine is devoted to the evaluation of patients with autoimmune systemic diseases, multiorganic disorders or presenting non specific symptoms such as chronic fatigue, unexplained weight loss or fever of unknown origin. The interest in salt and water metabolisms had led to original contributions in the treatment of hyponatremia in man and to the understanding of the osmotic demyelinating syndrome in a rat model of hyponatremia. The study of ageing in man and rodents had contributed to better understand lymphocyte and thyroid function in the elderly. The care for patients with various autoimmune disorders led to original observations in the pathogenicity of Sjögren's syndrome adult onset Still disease or sarcoidosis as well as the follow up of patients treated with azathioprine. Intensive collaboration with the Department of Immunology led to identify Th2 clonal lymphocytes as the cause of the so-called idiopathic hypereosinophilic syndrome in some patients and to define the clinical and biological features in this subset of patients.

Inadequate treatment of severe hyponatremia (< 120 mEq/l) can be associated with severe neurological damage. Acute hyponatremia (< 48 h) is usually observed in the postoperative period, these patients need prompt treatment with hypertonic saline (3%) to avoid epilepsia and respiratory arrest. Patients with chronic symptomatic hyponatremia (> 48-72 h) need a rapid correction of SNa the first hours (to decrease brain oedema) followed by a slow correction so that the daily increase in SNa stay under 10 mEq/l/24 h, to avoid the "Osmotic Demyelinating Syndrome" (ODS). Patients with asymptomatic hyponatremia need a slow correction. In patients who are overtreated, decreasing the SNa by giving hypotonic solutions (eventually with DDAVP) so that the daily increase in SNa stays under 10 mEq/l/24 h could protect them again ODS. Frequent measurements of SNa during the correction phase of SNa are mandatory to avoid overcorrection. The use of urea for the management of hyponatremia could represent a good alternative to hypertonic saline. In animals, urea treatment has been clearly shown to protect again ODS, this protective effect could be due to its ability to induce quickly brain "organic osmolytes" reaccumulation.

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 <4 mg/dL, while 27% of SIADH patients showed plasma uric acid >4 mg/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 to 12 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, developing mild pulmonary congestion at the end of the test infusion.

The high fractional excretion (FE) of uric acid observed in hyponatremia associated with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is commonly attributed to the volume-expanded state, although volume expansion in normonatremic volunteers is unable to increase urate clearance to a degree similar to that in SIADH. The goal of the present study is to analyze whether hyponatremia by itself could influence the FE of uric acid, as well as the effects of intravascular volume and glomerular filtration rate on FE of uric acid in SIADH. This study examines the effects of a 2-L infusion of isotonic saline over 24 hours on FE of uric acid in 9 normonatremic volunteers and 17 hyponatremic patients with SIADH. We also studied the FE of uric acid in 6 patients with SIADH with only mild water retention and the urate and creatinine clearances in 18 hyponatremic patients with SIADH before and after normalization of serum sodium levels by water restriction. When infusing 2 L of isotonic saline over 24 hours in healthy subjects, there was a decrease in plasma protein concentration of 8%, suggesting a similar degree of volume expansion than in patients with SIADH. The FE of uric acid did not increase to the same extent (9% +/- 1.5% versus 17% +/- 1.5%; P: < 0.01). Conversely, in 6 hyponatremic patients with mild water retention (1 L), the FE of uric acid was still high despite indirect signs of only a small increase in plasma volume. The mainstay of these observations is that chronicity of hyponatremia by itself could affect urate excretion. We also observed that in the patients with SIADH, high FE of uric acid inversely correlated with glomerular filtration rate (r = -0.66; P: < 0.01) only during the hyponatremic state. These data suggest that hyponatremia by itself, combined with mild volume expansion and glomerular filtration rate, has a role in the high FE of uric acid in the SIADH.

Background: Inappropriate correction of chronic hyponatremia could lead to major neuropathological sequelae. In man, the risk of brain myelinolysis increases strikingly when correction of the serum sodium exceeds 10-15 mEq/l/24 h. No treatment is actually available for this iatrogenic brain injury. However, recent experimental data showed that rapid reinduction of the hyponatremia greatly reduces the incidence of brain damage and death in case of serum sodium overshooting., Subjects and Methods: We tested this rescue manoeuver in a 71-year-old woman with nausea, confusion and severe (SNa 106 mEq/l) chronic hyponatremia related to thiazides. It was associated with hypokalemia (SK: 3.2 mEq/l)., Results: Treatment with isotonic saline produced inappropriately high SNa correction level of +21 mEq/l after the first 24 h. After initial improvement, the neurological status deteriorated after 72 h. Rapid reinduction of the hyponatremia was then ordered. Administration of hypotonic fluids (by oral and i.v. route) combined with dDAVP induced a prompt decline in the SNa (-16 mEq/l/14 h) with a final gradient of correction of deltaSNa +9 mEq/l. This manoeuver was well tolerated without untoward effects. The natremia then progressively normalized and the patient completely recovered without neurological sequelae., Conclusion: Hypotonic fluids may be safely administered to decrease the natremia after excessive correction of hyponatremia for potential prevention of myelinolysis.

A 35-year-old patient with severe gout and mild renal insufficiency presented very low urinary urate excretion. Volume expansion induced by fludrocortisone combined or not with a uricosuric drug (Benzbromarone) was unable to significantly increase his urate excretion. A combined Probenecid (PB) and Pyrazinamide (PZA) test was performed. These drugs being considered to affect renal tubular reabsorption or secretion. No significant modification of uric acid fractional excretion (FE.uric acid) was observed after PB and PZA. When the same test was performed after the administration of Triglycyl-lysine vasopressine (TGLV), a potent V1 receptor stimulator, we observed a three fold increase in FE.uric acid after PB intake (from 6 to 18%) followed by a decrease after PZA (from 18 to 5.6%). When TGLV was administered alone their was no significant modification of uric acid fractional excretion. We propose that TGLV decrease proximal tubular urate reabsorption that could only be detected when postsecretory reabsorption is blocked by an uricosuric drug.

Severe hyponatremia may be chronic (days) or acute (hours), symptomatic or asymptomatic. Severe chronic symptomatic hyponatremia (serum sodium concentration < 110 to 115 mM/liter) occurs most commonly in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The treatment of this hyponatremia is a challenge to practicing physicians, in part because an overly rapid correction of hyponatremia may cause brain damage. The latter sometimes takes the form of central pontine myelinolysis (CPM). On the basis of available clinical and experimental literature, the rate of correction of this symptomatic hyponatremia should be no more than 0.5 mM per liter per hour, and the initial treatment should be halted once a mildly hyponatremic range of the serum sodium concentration has been reached (approximately 125 to 130 mM/liter). In contrast, severe chronic asymptomatic hyponatremia may be treated sufficiently by a fluid restriction. On the other hand, severe symptomatic acute hyponatremia should be treated promptly and rapidly, using hypertonic saline, to initially reach a mildly hyponatremic level.

Purpose: In the differential diagnosis of patients with polyuria-polydipsia one must distinguish usually between primary polydipsia (PP) and central diabetes insipidus (CDI). The first situation is a state of volume expansion and the second of volume contraction. We evaluate whether serum uric acid determination could help to differentiate between the two conditions., Patients and Methods: We analyzed the score of 13 consecutive patients with CDI, 7 patients with PP, and 7 patients with nephrogenic diabetes insipidus (NDI). Serum uric acid concentration was available during normonatremia without treatment with 1-desamino-8-D-arginine vasopressin (dDAVP), during mild dehydration and during treatment with dDAVP. In 8 of these patients plasma renin activity (PRA), urate, urea and creatinine clearances were also available. These data were also obtained in the patients with NDI. In 1 patient with CDI, we studied the effect on urate clearance of dDAVP, which stimulates exclusively the V2 receptors, and of triglycyl-lysine-vasopressin (TGLV), a potent V1-receptor agonist., Results: Normonatremic polydypsic patients with CDI presented an increase in uric acid concentration (7.1 +/- 2.2 mg/dL), whereas in the PP group the value was decreased (3 +/- 0.75 mg/dL; P <0.001). All the normonatremic PP presented a serum uric acid concentration lower than 5 mg/dL, whereas all the normonatremic CDI patients, exept 1, presented a value higher than 5 mg/dL. In both groups blood urea concentration was decreased as a consequence of high renal clearances. The hyperuricemia of CDI was related to low uric acid clearances. Patients with hypernatremia and NDI presented a lower increase in serum uric acid concentration than those with similar levels of hypernatremia and CDI (NDI: 5.7 +/- 0.8 mg/dL and CDI: 7.9 +/- 2.3 mg/dL; P <0.05) and the NDI patients presented an urate clearance corrected for creatinine clearance which was significantly higher than in CDI (9% +/- 3% and 4% +/- 1.1%; P <0.01). When the patients with CDI were treated with dDAVP and normalyzed their PRA (0.9 +/- 0.4 ng/mL/h) we observed still mild hyperuricemia compared to controls (5.5 +/- 1.4 mg/dL and 4.3 +/- 0.9 mg/dL; P <0.01) and a low fractional excretion of filtered uric acid (6.5% +/- 1.7% compared to 8.2% +/- 2% in controls; P <0.05). Acute administration of dDAVP, stimulating the V2 receptors, in one patient with CDI, had no effect on urate clerance, while TGLV, which stimulates the V1 receptor, increased urate clearance., Conclusion: The presence of an serum uric acid concentration higher than 5 mg/dL in polyuric polydipsic patients is highly suggestive of CDI. Even when these patients are treated with dDAVP many of them remain hyperuricemic, and this seems to be the consequence of a lack of V1 receptor stimulation.

Brain myelinolysis could complicate the excessive correction of chronic hyponatremia. Recently it was suggested that hypoxia rather than correction of hyponatremia would be responsible for myelinolysis. We analyzed the incidence and the severity of potentially associated hypoxia and its consequences on survival and on the development of brain damage in rats in which major hyponatremic encephalopathy had developed after either pure acute hyponatremia (serum sodium concentration: -40 mEq/L/3 hr, group I, n = 8) or acute hyponatremia (serum sodium concentration: -30 mEq/L/3 hr, group II, n = 12) superimposed on chronic hyponatremia of 3 days' duration (serum sodium concentration: 113 mEq/L). Our study revealed the following: (1) Despite dramatic hyponatremic encephalopathy (convulsions, coma), hypoxia (PO2 < 70 mm Hg) was present, but the PO2 was not decreased below 40 mm Hg. All of these rats died rapidly if they remained hyponatremic. (2) In the animals rescued by NaCl, the incidence of brain myelinolysis was low (10%), whatever the duration (pure acute or chronic plus acute) of the hyponatremia and despite the combination of hypoxia with major hyponatremic encephalopathy. (3) When acute hyponatremia is superimposed on a chronic preexisting hyponatremic state, the acute component of serum sodium concentration decrease could be rapidly corrected (serum sodium concentration: +35 mEq/L/21 hr) without fear of permanent brain damage. Our results suggest that even in the presence of dramatic hyponatremic encephalopathy and associated hypoxia, neuropathologic sequelae are uncommon. Brain lesions related to post-anoxic encephalopathy probably develop only after respiratory arrest occurs.

DDAVP-related hyponatremia induces a blood volume expansion, but the analysis of fluid distribution in the vascular compartment has given controversial results in previous animal and human studies. In 5 healthy males, hyponatremia was induced by DDAVP and a free water intake during 3 days. Serum sodium concentration decreased from 138 +/- 0.8 mEq/L to 123 +/- 2.7 mEq/L on day 3. The plasma volume measured by dilution of marked albumin rose from 3033 +/- 230 ml to 3320 +/- 295 ml (p < 0.01). The mean corpuscular volume measured by microhematocrit increased slightly from 91.5 +/- 3.8 pl to 92.6 +/- 3.7 pl (p < 0.02). The red blood cell volume calculated with hematocrit and plasma volume did not change significantly (2565 ml to 2567 ml; not significant). In the present work, we demonstrated that in males the expansion of the plasma compartment almost completely amounted for the water retention in the intravascular volume. The erythrocyte volume increased only slightly, a finding that is consistent with an almost perfect adaptation of the erythrocyte cells to the hypoosmolality.

Patients with hyponatremia are exposed to major neurological complications. On the one hand hyponatremia itself produces brain edema, increased intracranial pressure which potentially leads to subsequent neuropathological sequelae or death. On the other hand excessive correction could be followed by development of brain demyelinating lesions (central pontine or extrapontine myelinolysis) with major disability or fatal outcome. Understanding of brain adaptative mechanisms to changes in osmolality largely contributes to explain these neurological events. When serum sodium decreases, the brain prevents swelling by extruding electrolytes and organic osmolytes, a process almost fully achieved after 48 h. Conversely, during subsequent increase in serum sodium, reestablishment of intracerebral osmolytes occurs but their reuptake is more delayed (+/- 5 days). In both circumstances, these mechanisms can be overwhelmed, leading to brain damage. Acute hyponatremia (< 48 h) is generally hospital-acquired, mainly in the postoperative state and/or after excessive fluid administration. After abrupt fall in serum sodium, seizure, respiratory arrest and coma may develop and these manifestations are sometimes explosive in nature. Recognition of even minor symptoms is crucial and implies prompt correction. There is generally no risk of brain myelinolysis in acute hyponatremia. Some factors are suspected to aggravate the prognosis of hyponatremic encephalopathy, including female gender (menstruant women), hypoxia and young age. Chronic hyponatremia (> 48 h) usually develops outside the hospital and is generally better tolerated. The risks of brain myelinolysis can be largely reduced by limiting the correction level to < or = 15 mEq/1/24 h. However, if necessary, the initial rate of correction can be rapid provided that the final correction remains < 15 mEq/1/24 h. However, when other recognized risk factors for myelinolysis (hypokalemia, liver disease, poor nutritional state, burns) are present, correction should not exceed 10 mEq/1/24 h. Demyelinization is also observed in hypernatremia but it follows greater (50%) increase in serum sodium than from hyponatremic baseline. For symptomatic hyponatremia, rapid correction is usually obtained by hypertonic saline (3%) infusion. Another option consists in administration of intravenous or oral urea. Urea allows a rapid reduction of brain edema and intracranial pressure which is followed by subsequent correction of hyponatremia. Experimental data also suggest that treatment of hyponatremia with urea is associated with a lower incidence of myelinolysis. In hyponatremic patients without symptoms, there is no need for rapid correction and the treatment should be more conservative. Close monitoring of the serum sodium is indicated initially and if necessary, correction must be stopped and diuresis interrupted with dDAVP. Given recent experimental data, in patients overly corrected (delta SNa > 15 mEq/1/24 h), the risk of myelinolysis could be greatly reduced by rapidly decreasing the serum sodium through hypotonic fluids administration and dDAVP.

Brain myelinolysis occurs after excessive correction (delta SNa > 20 mEq/1/24 hours) of chronic hyponatremia. However, we showed recently that the mechanisms leading to brain myelinolysis remain reversible. Indeed, reinduction of the hyponatremia by water administration despite 12 hours of sustained excessive correction could prevent the development of demyelination in rats still asymptomatic at that time. Whether this therapeutic maneuver could be also beneficial to rats with preexisting myelinolysis-related neurologic symptoms is unknown. Therefore we evaluated here the effect of reinduction of the hyponatremia on the survival and on brain damage in rats presenting obvious neurologic symptoms after excessive correction of hyponatremia. After 3 days of severe hyponatremia induced by 2.5 D-glucose in water and continuous infusion of AVP, rats were submitted to a large correction (delta SNa approximately 30 mEq/l) by 2 i.p. injections of hypertonic saline given over 24 hours. In group I (n = 15) the rats developing neurologic symptoms during the first 24 hours of correction received one i.p. injection of distilled water which rapidly decreased the natremia to a final correction gradient <20 mEq/l/24 hour. In group II (n = 13, controls) the symptomatic rats were left permanently overcorrected. In group I, after water administration, the neurological manifestations were generally attenuated or disappeared. Seven of the 15 rats (47%) in this group survived up to day 10 with a mean survival time of 7.5 +/- 2 days, an outcome clearly improved as compared to group II (controls): only 1 of the 13 rats (7%, p < 0.03) was still alive on day 10 and the mean survival time was 3.3 +/- 2 days (p < 0.001) in this group II. The duration of the symptoms also influences the prognosis. In group I, in 9 rats the water administration was performed 4 hours after symptoms onset. These rats had a better outcome than the 6 rats with more sustained (8-10 hours) neurologic symptoms before water loading. Brain analysis in the 7 surviving rats of group I demonstrated demyelinating lesions in only 2 of them, suggesting the reversibility of the process even when neurologic manifestation developed. In conclusion, after exposure to an excessive correction of chronic hyponatremia, even when rats have developed myelinolysis-related neurologic symptoms, hypotonic fluids administration could improve survival and could prevent the subsequent development of brain myelinolysis.

In hyponatremia related to syndrome of inappropriate antidiuretic hormone (SIADH), hypouricemia is explained primarily by the high uric acid clearance rate that results from the decrease in tubular uric acid reabsorption. This modification of tubular handling of uric acid is considered to be induced by the increase in the "effective vascular volume". This study was designed to determine if V1-receptor stimulation participates in the development of a high uric acid clearance rate as in SIADH, in which the antidiuretic hormone acts on V1 and V2 receptors. Therefore, the urate clearance rate was measured in seven volunteers with 1-desamino-8-D-arginine vasopressin (dDAVP)-induced hyponatremia, with dDVAP stimulating exclusively the V2 receptors (Group I), and in six patients with SIADH (Group II) during both normo- and hyponatremia. As expected, in both groups, the serum uric acid concentration decreased during hyponatremia, but did so to a larger extent in the patients with SIADH (-53% versus -29%, P < 0.02). Despite similar levels of hyponatremia (126 +/- 5 mmol/L and 125 +/- 5.5 mmol/L), of hypoproteinemia (64 +/- 5 g/L and 63 +/- 5 g/L) and of salt excretion (FENa, 0.66 +/- 0.28% and 0.73 +/- 0.25%), the urate clearance (8.3 +/- 3.3 mL/min) and the fractional excretion of filtered uric acid (5.7 +/- 2%) in Group I were not significantly different during hyponatremia than during normonatremia (6.4 +/- 1.5 mL/min and 5.4 +/- 0.9%). On the other hand, in Group II, both parameters were increased (17.8 +/- 2.9 mL/min and 19.6 +/- 5.3%; P < 0.001) and both values were higher than in the dDAVP-induced hyponatremia (P < 0.01). Additionally, the administration of a potent V1-receptor agonist (triglycyl-lysine-vasopressin) in a patient with central diabetes insipidus with preexisting dDAVP-induced hyponatremia produced a rapid increase of urate clearance. Because dDAVP acts only on the V2 receptors, these data suggest that the higher urate clearance observed during hyponatremia related to SIADH is not only the consequence of an increased "effective vascular volume," but that V1-receptor stimulation also contributes to it, by a mechanism that remains to be determined.

Brain myelinolysis could develop after excessive correction (delta SNa > 20-25 mEq/1/24 hour [h]) of chronic hyponatremia; however, this neurological event is not recognized as a complication of hypernatremia when arising from a normonatremic baseline. Previous animal studies were unable to reproduce these brain lesions in hypernatremia after acute increase of serum sodium to moderately hypernatremic levels. We hypothesize that to produce brain dehydration and myelinolysis from normonatremic baseline requires a more important osmotic gradient than when starting from hyponatremic state. Rapid and sustained hypernatremia (at least > 6 to 12 h) was induced in male rats by i.p. administration of NaCl 2 M (3 injections at 6 h intervals). The NaCl doses were determined to define two groups of hypernatremic rats (moderate and severe hypernatremia) for further analysis of the neurological outcome. In group 1 (moderate hypernatremia, n = 26) 8 rats died early (< 12 h) after the beginning of the NaCl administration without specific neurologic manifestations. All the surviving rats fared well and were asymptomatic at time of death (day 8). They were submitted for at least 6 to 12 h to a serum sodium gradient of 28 +/- 6 mEq/l. Brain analysis was normal in all of them without brain demyelinating lesions. In group 2 (n = 51), 24 rats also died rapidly (< 12 h). The surviving rats developed severe neurologic symptoms as typically encountered in hyponatremic rats with myelinolysis. The majority of them died before day 8. The hypernatremic gradient in this group was significantly higher than rats in group 1 that completely recovered (mean delta SNa: 39 +/- 8 mEq/l, p < 0.001). In the 7 surviving rats (mean delta SNa: 33 +/- 3 mEq/l) brain analysis demonstrated severe demyelinating lesions similar to the histologic changes observed in hyponatremia-related myelinolysis. We demonstrated for the first time that high and sustained levels of hypernatremia could induce brain myelinolysis and that the osmotic gradient necessary to produce brain lesions is higher for normonatremic than for hyponatremic rats.

A man aged 68 years presents superior limbal infiltrates at his left eye two weeks before a marginal ulcer which quickly perforates. He has no systemic complaint. Clinical, biological, radiologic and histological evaluations disclose superior airways and lungs implications, an inflammatory syndrome, high ANCA (antineutrophiles cytoplamic antibodies) titer and vasculitis. There is no sign of renal involvement. A limited form of Wegener's granulomatosis is diagnosed. The outcome is favorable with a partial penetrating keratoplasty and systemic corticosteroid therapy in association with immunosuppressive drugs. This so called limited form of Wegener's granulomatosis is sight threatening when eye is the initial presentation. The early diagnostic and treatment will be performed by the help of ANCA in cases with subclinical systemic manifestations.

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.

1. In the syndrome of inappropriate secretion of antidiuretic hormone, hyponatraemia is associated with a normal bicarbonate concentration despite dilution. This normal bicarbonate concentration is related to the development of a hyperaldosteronism, which is attributed to a direct stimulation of the zona glomerulosa by the hyponatraemic state. Some workers have suggested that, to develop this hyperaldosteronism requires the presence of a pituitary factor. To determine whether the pituitary gland plays a role in this hyponatraemia-induced hyperaldosteronism, water intoxication was performed for 24 h in normal and in panhypopituitaric rats. 2. In normal rats, hyponatraemia (108 mmol/l), induced by the administration of 1-desamino-8-D-arginine vasopressin and 2.5% D-glucose-0.45% NaCl by gavage (15% body weight) was associated with a mild increase in bicarbonate concentration, and blood acid-base equilibrium showed a mixed metabolic and respiratory alkalosis (pH 7.57, partial pressure of CO2 29 mmHg, base excess +5.5 mmol/l), and aldosterone concentration was increased 3-fold as compared with the control value. When hyponatraemia (110 mmol/l) was induced in a similar manner in panhypopituitaric rats, we observed a very low aldosterone concentration (< 50 pg/ml) and a compensated respiratory alkalosis (pH 7.45, partial pressure of CO2 30 mmHg, base excess -2.6 mmol/l). The restoration of a hyperaldosteronaemic state in this group of rats was related essentially to corticosteroid intake. 3. These data suggest that corticosteroids play a critical role in the development of hyponatraemia-related hyperaldosteronism, a phenomenon not necessarily dependent on a pituitary factor.

The major and minor diagnostic criteria of the chronic fatigue syndrome are described. The stages of the differential diagnosis, the diagnostic strategies and the controversies, while insisting on certain sleeping disorders are discussed. The cause of the syndrome may be a viral infection, and an anxious-depressive state may increase somatic complaints. Patients with chronic fatigue syndrome did not demonstrate a specific response to therapy. Spontaneous remission after a few years is a typical feature of this syndrome.

We analyzed the serum anion gap (AG = sodium plus potassium minus chloride plus bicarbonate, N = 11-21 mEq/l), serum uric acid and urea concentrations in hyponatremia of various origins. We found that characteristic chemical patterns emerged in association with different hypotonic states: Low uric acid concentration was typically observed in the SIADH and in hyponatremia related to hypopituitarism. The same observation was also frequently noted in hyponatremia secondary to diuretics or to polydypsia. In the SIADH, we observed a decrease in the AG but to a greater extent (-26%) than one would expect from the simple dilutional effect (-16%). Fifty percent of the patients presented an AG lower than 11 mEq/l. In patients with diuretic-related hyponatremia, one group presented an hypouricemia and a low AG as in SIADH (reflecting volume expansion), in the other group the AG was normal or increased as was uric acid concentration (reflecting volume depletion). In adrenocorticotropin deficiency, hyponatremia was typically associated with a low bicarbonate concentration, a normal AG and hypouricemia. In polydypsic patients with hyponatremia, the AG was usually normal or increased despite sometimes very low sodium levels. Uric acid levels were highly variable, most often decreased. We also noted in these patients that the serum urea levels were correlated with urine osmolality (R = +0.8; p < 0.001), and in 40% of them we observed very low blood urea concentration (0.5-2 mmol/l) at the admission time. In hyponatremia related to cardiac failure or cirrhosis, the AG was usually normal despite mild hypoproteinemia.

The effects of acute and chronic water intoxication induced by the administration of oral water and arginine vasopressin (AVP) or 1-deamino-8-D-arginine-vasopressin (DDAVP) on blood acid-base equilibrium and aldosterone, corticosterone, and thyroxine secretion were studied in rats. Acute hyponatremia (3 hours) was associated with normal bicarbonate and blood acid-base equilibrium and a decrease in aldosterone and thyroxine concentrations, while corticosterone was increased. When similar levels of hyponatremia (serum sodium 110 mEq/L) were maintained for 24 or 72 hours, a normal serum bicarbonate concentration was observed, but blood acid-base equilibrium showed a mixed respiratory and metabolic alkalosis. Blood pH was negatively correlated with serum sodium concentration (R = -0.65; p < 0.001), as was the metabolic alkalosis (base excess; R = -0.64; p < 0.001) and the aldosterone concentration (R = -0.52; p < 0.01), while the PCO2 was positively correlated (R = +0.49; p < 0.01). Hyperaldosteronism was similar whether hyponatremia was induced with AVP or DDAVP and was observed even for mild hyponatremia. When hyponatremia was induced by a high water and salt intake (2.5% D-glucose, 0.45% NaCl; 15% body weight), aldosterone concentration was as high (about three times control values) as in rats with similar levels of hyponatremia but with a salt-free diet. The high salt intake was associated with a more severe metabolic alkalosis (base excess +5,5 mEq/L). In chronic hyponatremia, corticosterone and thyroxine values were normal. In hyponatremia related to syndrome of inappropriate secretion of antidiuretic hormone, the normal serum bicarbonate level is an expected observation; as in acute water intoxication, it stays normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyponatraemia secondary to inappropriate secretion of antidiuretic hormone (SIADH) induces some biological modifications which are relatively characteristic of this condition. The disturbed acid-base equilibrium and the mechanism involved in the high urea and uric acid clearances observed in SIADH are discussed.

Inappropriately slow or excessive correction of severe (< 115 mEq/l) hyponatremia could induce a high morbidity and mortality rate. In acute (< 48 hr) hyponatremia, there is an increased risk for death and permanent brain damage due to grand mal seizure and respiratory arrest. Indeed, if correction is delayed, the ability of brain to adapt to hyponatremia by limiting the amount of brain swelling is not sufficient and brain stem herniation occurs. Menstruant women are particularly likely to experience these complications. In chronic (> 48 hr) hyponatremia, the extrusion of intracerebral osmolytes decreases the brain size which returns to an almost normal volume. In this situation, an excessive correction (> 15-20 mEq/l/24 h) will lead to brain dehydration and brain demyelination also called "central pontine myelinolysis" or "osmotic demyelination syndrome" (ODS) could develop. Asymptomatic patients with chronic hyponatremia are particularly at risk to develop brain demyelination, therefore, they must be corrected cautiously with frequent monitoring of the natremia and with a magnitude of correction not exceeding 15 mEq/l/24 h. The different therapeutic approach regarding to the origin of the hyponatremia are considered.

Brain myelinolysis occurs after correction of chronic hyponatremia in rats when the magnitude of increase in serum sodium (delta SNa) exceeds 20 to 25 mEq/liter/24 hr (the critical threshold for brain). We tested the hypothesis that after a sustained excessive correction, brain lesions (BL) could be prevented by subsequently decreasing the serum sodium below the critical threshold for brain through the administration of hypotonic fluids. After three days of severe (< 115 mEq/liter) chronic (3 days) hyponatremia, 55 rats were submitted to an excessive correction (delta SNa > 25 mEq/liter) by a single i.p. infusion of hypertonic saline (NaCl). This osmotic stress was maintained during 12 hours before the serum sodium decrease was initiated. Thirty-two rats reached the twelfth post-correction hour without symptoms. In group 1 after a large (delta SNa 32 mEq/liter) and sustained (12 hr) osmotic stress, the natremia was rapidly (2 hr) decreased by the administration of oral tap water and, at the end of the first 24 hours, the magnitude of correction was maintained below 20 mEq/liter/24 hr. All the rats fared well in this group and were free of neurologic symptoms. Mild BL were noticed in only 20% of them. On the contrary, in controls (no hypotonic fluids administration at the twelfth hour) whose serum sodium was left overcorrected, all the rats became symptomatic and 57% of them died rapidly. Brain damage developed in 100% of the surviving rats. In group 2, despite hypotonic fluids administration, the serum sodium decreased insufficiently and the correction was > 20 mEq/liter at the end of the first 24 hours (delta SNa 25 mEq/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanisms responsible for the increased renal clearance of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are not fully clarified. Studies using either pyrazinamide or probenecid, or both drugs but at an interval of several days, could not undoubtedly distinguish the 'hypersecretory theory' from the one favoring a defect in either post- or presecretory reabsorption. We decided to do a combined pyrazinamide and probenecid test in 5 patients with hyponatremia due to SIADH in order to evaluate more clearly the respective importance of these different pathways. Our results allow the conclusion of a diminished presecretory and mainly postsecretory reabsorption (80 +/- 4.6 and 14 +/- 3% of filtered load, respectively). As far as the secretion of uric acid is concerned (17 +/- 10% of filtered load), we may say that this pathway is adapted to the amount of hypouricemia.

We report the case of a patient with an idiopathic syndrome of inappropriate secretion of ADH for more than 6 years. Water restriction was effective only during hospital care but was socially difficult to maintain at home, so that the patient presented frequent symptoms of water intoxication. Normal natremia was also obtained with a high salt intake (9 g/day) but this induced leg edema mild dyspnea and gastric intolerance. The patient was however successfully treated for more than 5 years without any side effects with oral urea (30 g/day) allowing her a normal fluid intake (1-1.5 liters/day). Oral urea, even during long periods, is a safe and effective therapeutic approach for patients with chronic SIADH which is not controlled by water restriction alone.

Our purpose was to compare the effect of urea and indomethacin on solute excretion in hyponatremic patients with inappropriate secretion of antidiuretic hormone (SIADH). In 6 patients (serum Na: 126 +/- 3 mmol/l), the intake of urea (0.1 g/kg) induced a decrease in sodium excretion while urine osmolality, urine flow and osmotic clearance (Cosm) did not change. In the control group, the urinary flow and Cosm were increased as expected, while sodium excretion tended to increase. In the SIADH group, the decrease in the fractional excretion (FE) of Na+ (FE.Na+) (or FE.Cl-) after urea intake was negatively correlated with urinary urea concentration while the FE.K+ was positively correlated with FE.Na+ (or FE.Cl-), which suggests that the effect of urea on sodium excretion takes place proximally to the distal tubule, probably at the thin ascending limb. After indomethacin intake, FE.Na+ (or FE.Cl-), FE.K+, Fe.osm and Fe.urea decreased in the normal and hyponatremic groups. The mean free water reabsorption relatively to osmolar delivery was lower in SIADH (p < 0.05), and did not change significantly after indomethacin intake. The fact that the decrease of FE.Na+ (or FE.Cl-) after indomethacin was associated with a decrease in FE.K+ suggests that the increase in sodium (or chloride) reabsorption occurred more proximally to the distal tubule (probably a the medullary segment of the thick ascending limb of the loop of Henle).

Increments in serum ferritin levels in adult onset Still's disease (AOSD) were reported to be higher than one could expect for a simple inflammatory state. When we analyzed the scores of 40 patients with various severe inflammatory diseases aside from AOSD, we recorded no serum ferritin values higher than 3,300 ng/ml (N less than 200 ng/ml). In 3 of 10 consecutive patients with AOSD, the ferritin levels were higher than 3,500. Among these 3 patients, one case had a ferritin value of 3,600 ng/ml and bone marrow aspirate showed a marked hyperplasia of mature appearing histiocytes, and the 2 other patients (serum ferritin levels of 65,000 ng/ml and 250,000 ng/ml) displayed the features of a hemophagocytic syndrome. In 2 patients with normal or mildly increased levels of ferritin, the bone marrow examination was normal. We suggest that very high serum ferritin levels encountered in AOSD reflect the presence of histiocytic hyperactivity that sometimes leads to a hemophagocytic syndrome.

In cirrhotic patients without renal failure, salt retention could result from a decreased effective intravascular volume or could be a primary event leading to increased intravascular volume. Clearance of urea and uric acid depend on an effective intravascular volume. In the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)--a state of increased intravascular volume--uric acid clearance is increased and that of urea is increased only when salt excretion is low. The intravascular volume of 60 consecutive cirrhotic patients without renal failure was estimated indirectly by studying the relationship between fractional excretion of filtered (FE) sodium, urea, and uric acid. Forty five per cent had a high FE uric acid (> 12%), which could mean a high intravascular volume, and presented with an FE urea that was inversely correlated with FE sodium (r = 0, 62; p < 0.001) as in SIADH, while in the controls the FE urea was positively correlated with FE sodium (r = +0, 46; p < 0.01). In patients who had a normal FE uric acid and low FE sodium (< 0.2%), the FE urea was significantly lower (40 (13)%, n = 20) than in subjects with high FE uric acid and a low FE sodium (61 (9)%, n = 16, p < 0.001); this last group also presented with lower mean blood urea concentrations (3.1 (1.2) mmol/l and 4.0 (1.8) mmol/l; p < 0.05) and a lower supine renin activity (p < 0.01). As observed in the SIADH, cirrhotic patient with high FE uric acid have raised FE urea only when salt excretion is low. It is believed that the low salt excretion is not caused by a decrease in effective intravascular volume and that this is increased in cirrhotic patients with raised FE uric acid.

The role of the rate of correction in the development of demyelinating brain lesions after correction of chronic severe hyponatremia is controversial. It has been recently suggested in rats treated by intravenous (i.v.) hypertonic saline (NaCl) that both the rate and the absolute change in serum sodium represent critical risk factors. However, we previously demonstrated in rats treated by intraperitoneal (i.p.) injections of NaCl that below a threshold of serum sodium rise of 20 mEq/liter/24 hr, only 5% of the brain lesions were recorded, even in rats submitted to a rapid (1 hr) serum sodium increment following the i.p. injection. Working below this threshold (serum sodium rise less than 20 mEq/liter/24 hr) in the present work, allowed us to independently determine the role of the rate in the outcome of the correction. This was done by submitting the rats to a rapid (1 hr) intravenous infusion of NaCl. As a difference between the i.p. and i.v. route in the degree of volume expansion produced by the NaCl administration could also play a role in the pathogenesis of the brain lesions, rats treated with rapid i.v. infusion of NaCl (associated with volume expansion) were compared to a group of rats treated with water restriction (associated to volume contraction) to evaluate the role of volemia on the incidence of neurological damage. Hyponatremia was induced over three days with d-glucose in water and vasopressin. The group 1 was corrected by intravenous (i.v.) infusion of hypertonic saline over one hour.(ABSTRACT TRUNCATED AT 250 WORDS)

The different clinical aspects of Behçet disease are reviewed. This systemic disease is related to vasculitis involving small vessels. New diagnostic criteria have been established and new therapeutic approaches can be applied.

Retrospective case series for the last five years have focussed the attention of the authors on some clinical and biological patterns of adult onset Still's disease. Its diagnosis is made difficult because of the great diversity of clinical and biological signs. Organ failures complicate sometimes the disease, and may be fatal. Major high levels of plasma ferritin associated with an haemophagocytic syndrome occur in 20 percent of the acute cases: this association could eventually respond well to an immunodepressive therapy.

The authors evoke how the corticosteroids work (as antiinflammatory and immunosuppressive agents) and how to prescribe them, orally, intravenously, in association with an antimitotic drug. They insist on the suspended and non curative effects of corticotherapy, its side effects and the additive effect of the antimitotic drugs. They suggest different therapeutic programs against rheumatoid arthritis, Still's disease, lupus, dermatomyositis, Behçet's disease, Horton's disease and polymyalgia rheumatica.

1. At present there is no consensus about the optimal management of hyponatraemia to prevent demyelinating brain lesions. We have evaluated in a large series of rats (n = 136) the protective role of urea for the brain in the treatment of severe chronic hyponatraemia. Urea (group I, n = 51) was compared with hypertonic saline in boluses (group II, n = 46) and with hypertonic saline in divided doses (group III, n = 39). Treatment was administered intraperitoneally over 48 h. The severity of brain lesions was assessed by histological scoring. 2. For 95% of the injured animals treated with hypertonic saline, brain lesions appeared for an absolute increment in serum Na+ concentration (delta SNa+) of 20 mmol day-1 l-1. Above this limit neurological injuries gradually worsened, and beyond a transition zone (delta SNa+ greater than or equal to 20 less than or equal to 23 mmol day-1 l-1) 89% (group III) to 100% (group II) of the animals were injured. This limit can be reached rapidly, as attested by the comparable severity of brain lesions observed in group II (mean delta SNa+ 1 h after a bolus injection, 19 mmol/l) and in group III (mean delta SNa+ 1 h after an injection, 2 mmol/l), both groups achieving similar daily delta SNa+. 3. A correction above the threshold of 20 mmol day-1 l-1 is as toxic during the first 24 h as during the second day of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Our purpose was to determine why hypouricaemia is more frequently observed than hypouraemia in the syndrome of inappropriate secretion of antidiuretic hormone. We have retrospectively analysed the scores of 35 patients with a chronic form of hyponatraemia related to the syndrome of inappropriate secretion of antidiuretic hormone and studied prospectively six patients. 2. The patients with high fractional excretion of filtered urea (greater than 55%) presented lower blood urea and lower salt excretion than the patients with normal fractional excretion of filtered urea, despite similar levels of hyponatraemia and of osmotic and uric acid clearances. In six hyponatraemic patients, an increase in salt intake was accompanied by a decrease in fractional excretion of filtered urea. In the syndrome of inappropriate secretion of antidiuretic hormone, the fractional excretion of filtered urea was inversely correlated to the fractional excretion of filtered sodium (r = -0.66; P less than 0.001), whereas the fractional excretion of filtered uric acid was not dependent on sodium excretion. 3. Hypouraemia with high fractional excretion of filtered urea in patients with the syndrome of inappropriate secretion of antidiuretic hormone is related to low urinary sodium excretion and thus reflects low sodium intake.

We have suggested that cirrhotic patients with high uric acid clearances had an increased effective vascular volume. This hypothesis was tested by studying the relationship between the excretion of uric acid, sodium, potassium, and aldosterone in cirrhosis. In 29 consecutive cirrhotic patients, of whom 17 had ascites, and in a control group, the logarithm of urinary sodium and aldosterone excretion highly correlated in control (r = -0.79, p less than 0.001) and cirrhotic patients without (r = -0.72, p less than 0.01) and with (r = -0.80, p less than 0.001) ascites. The regression line significantly shifted to the left in the cirrhotic patients (p less than 0.001). The urinary ratio K/K + Na also correlated with urinary aldosterone in controls (r = +0.66, p less than 0.001) and in cirrhotic patients (r = +0.77, p less than 0.001); this regression line shifted to the right in cirrhosis patients (p less than 0.02). The fractional uric acid excretion significantly correlated with urinary aldosterone only in cirrhotic patients (r = -0.76, p less than 0.001). These data confirmed the existence of hypoaldosteronism in many cirrhotic patients and are consistent with tubular hypersensitivity to aldosterone and emphasize the major role of the effective vascular volume in the control of urid acid clearance in cirrhosis.

The hyponatraemia common in decompensated cirrhosis arises in part from secretion of antidiuretic hormone attributed to a decrease in effective blood volume. Baroreceptors send inhibitory impulses to the midbrain and hypothalamus through the vagus and glossopharyngeal nerves. Since vagal neuropathy often occurs in chronic alcoholism, this might theoretically contribute to the inappropriate secretion of antidiuretic hormone, which might in turn induce hyponatraemia. In a prospective study including 34 patients with cirrhosis a high incidence of vagal neuropathy was found in the alcoholics (64%) and a clear cut increase in the incidence of hyponatraemia in patients with evidence of vagal damage and ascites (seven of eight patients (88%); p = 0.02). Results of a retrospective study of 64 patients with cirrhosis and ascitic decompensation showed hyponatraemia in 17 (50%) of 34 alcoholics but in only four (13%) of 30 patients with non-alcoholic disease (p = 0.006). Vagal neuropathy in alcoholic cirrhosis may contribute to the low serum sodium concentrations commonly found in these patients.