Management of the syndrome of inappropriate secretion of antidiuretic hormone

The etiology, pathophysiology, clinical features, diagnosis, and medical treatment of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are reviewed. SIADH is a common cause of hyponatremia in hospitalized patients. Increased concentrations of antidiuretic hormone (ADH) result in retention of free water, increased excretion of sodium, and hyponatremia. Symptoms generally occur only when hyponatremia is severe (less than or equal to 125 meq/L) and may include anorexia, vomiting, and confusion, followed by seizures, coma, and death. SIADH may result from a variety of diseases, as well as from the use of drugs such as chlorpropamide, carbamazepine, diuretics, and some antineoplastic agents. Diagnosis of SIADH is confirmed by demonstration of a high urine osmolality with a low plasma osmolality, in the absence of diuretic use. Immediate treatment of the symptomatic patient with SIADH includes intravenous furosemide and 3% sodium chloride injection to produce a negative free-water balance. If the underlying cause of SIADH cannot be corrected, the treatment of choice for chronic SIADH is fluid restriction. If this is not tolerated by the patient, demeclocycline can be used to induce a negative free-water balance. Urea, lithium, phenytoin, and loop diuretics have been reported to be effective, but there are few data to support their use. Future research into the treatment of SIADH must be directed at developing effective antagonists of ADH. Treatment of SIADH consists of elimination of underlying causes and restriction of fluid intake; if these measures are unsuccessful or poorly tolerated, long-term drug therapy may be indicated.     

Effects of acute metabolic stress on the peripheral vasopressinergic system in schizophrenia

Although both vasopressin and stress have been implicated in the course of schizophrenia, it is unknown whether schizophrenic patients have altered stress-induced function of the vasopressinergic system. We examined the effects of acute metabolic stress induced by pharmacological doses (40 mg/kg) of 2-deoxyglucose (2DG) on plasma concentrations of vasopressin in 13 patients with schizophrenia (with no history of polydipsia and hyponatremia) and 12 healthy control subjects. Baseline vasopressin levels were lower in the schizophrenic patients and progressively increased in both groups throughout the 60 min following 2DG administration to a similar absolute amount, thus remaining lower in the schizophrenic group. Concomitantly, patients with schizophrenia had significantly higher 2DG-induced plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid levels. Vasopressin responses correlated positively and significantly with the HVA responses in schizophrenics and with the pituitary-adrenal axis responses in controls. These results suggest two different patterns of neuroendocrine alterations in schizophrenia, namely a relatively normal vasopressin response to 2DG despite significantly decreased baseline levels and exaggerated responses of the peripheral dopaminegic and serotonergic systems in the face of normal baseline concentrations.     

Efficacy of clozapine in a non-schizophrenic patient with psychogenic polydipsia and central pontine myelinolysis

Clozapine is an atypical antipsychotic drug that has been demonstrated to be a highly effective treatment for polydipsia in schizophrenic patients. The authors report the first case of a non-schizophrenic patient affected by polydipsia and central pontine myelinolysis who was successfully treated with clozapine.     

Syndrome of inappropriate antidiuretic hormone-induced hyponatremia associated with amiodarone

The syndrome of inappropriate antidiuretic hormone (SIADH), the most common cause of euvolemic hyponatremia, is due to nonphysiologic release of arginine vasopressin from the posterior pituitary. Hyponatremia induced by SIADH can be caused by several conditions, such as central nervous system disorders, malignancies, various nonmalignant lung diseases, hypoadrenalism, and hypothyroidism. A 67-year-old man developed hyponatremia consistent with SIADH. Although common comorbid conditions associated with SIADH were excluded as possible causes, his medical history and drug regimen were extensive. However, he had been taking spironolactone, amiodarone, and simvastatin for less than 3 months. Amiodarone was discontinued based on a case report suggesting that this drug can cause SIADH-induced hyponatremia. The patient's serum sodium level began to rise within 3 days of discontinuation and returned to normal within 1 month. Although SIADH-induced hyponatremia occurs only rarely, it should be recognized as a possible adverse effect of amiodarone.     

Lixivaptan: a novel vasopressin receptor antagonist

Arginine vasopressin, also known as antidiuretic hormone, is a neuropeptide that functions in the maintenance of body water homeostasis. Inappropriate secretion of vasopressin has been implicated in the pathophysiology of multiple diseases, including polycystic kidney disease, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and the hyponatremia commonly associated with cirrhosis and congestive heart failure. Vasopressin receptor antagonists are novel agents that block the physiologic actions of vasopressin. Lixivaptan is a vasopressin receptor antagonist with high V2 receptor affinity and is now undergoing Phase III clinical trials. Studies so far have demonstrated that lixivaptan is efficacious in the correction of hyponatremia in SIADH, heart failure and liver cirrhosis with ascites, and few adverse effects have been noted. Thus, lixivaptan remains a promising therapeutic modality for the treatment of multiple diseases and prevention of the associated morbidity and mortality associated with hyponatremia.     

A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

We investigated the effects of intravenous administration of conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on blood electrolytes and plasma osmolality in rats with an experimental syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The experimental SIADH rat model was developed by means of continuous administration of arginine vasopressin (AVP) via a subcutaneously implanted osmotic mini pump, and hyponatremia was induced by additional water loading. This model possesses similar characteristics to those observed in patients with SIADH, specifically decreases in blood sodium concentration and plasma osmolality. In this experimental model, intravenous administration of conivaptan (0.1, 1 mg/kg) significantly increased blood sodium concentration and plasma osmolality. On the other hand, intravenous administration of furosemide (10 mg/kg) did not increase either blood sodium concentration or plasma osmolality in the SIADH rats. Moreover, furosemide significantly lowered blood potassium concentration. These results show that conivaptan improves hyponatremia in rats with SIADH, supporting the therapeutic potential of conivaptan in treatment of patients with hyponatremia associated with SIADH.     

Treatment of hyponatremia: the role of lixivaptan

Hyponatremia is the most common electrolyte disorder and is associated with serious neurologic sequelae and increased mortality. Conventional treatment options for hyponatremia, such as fluid restriction, hypertonic saline, loop diuretics, demeclocycline or urea, are ineffective in the long-term. The present review considers the role of vasopressin receptor inhibitors (vaptans), focusing on lixivaptan, in the treatment of patients with euvolemic or hypervolemic hyponatremia. Lixivaptan is an oral selective V2 receptor inhibitor, which produces a significantly greater increase of serum sodium levels compared with placebo. These effects seem promising, but more trials are needed to examine whether the beneficial effect of lixivaptan on serum sodium concentration translates into clinical benefit in these patient populations.     

Tolvaptan: a vasopressin antagonist for the management of euvolemic and hypervolemic hyponatremia

Tolvaptan is a new vasopressin antagonist developed for the treatment of hypervolemic or euvolemic hyponatremia. It has greater affinity for the V(2) receptor than native vasopressin or any other vasopressin antagonist. Blockade of the V(2) receptor induces solute-free water excretion without affecting normal electrolyte excretion. The pharmacokinetics and pharmacodynamics of tolvaptan are suitable for once-daily dosing. Throughout all phases of clinical studies, it was shown to be safe for short- and long-term use. Tolvaptan effectively increases serum sodium levels in patients with heart failure, cirrhosis and syndrome of inappropriate secretion of antidiuretic hormone. In patients hospitalized owing to heart failure, tolvaptan decreased bodyweight, increased urine output and improved dyspnea compared with placebo. However, tolvaptan has not proven to be beneficial for the long-term management of heart failure. Currently, tolvaptan is the only oral agent in its class available in the USA and Europe.     

Tolvaptan: a vasopressin antagonist for the management of euvolemic and hypervolemic hyponatremia

Tolvaptan is a new vasopressin antagonist developed for the treatment of hypervolemic or euvolemic hyponatremia. It has greater affinity for the V₂ receptor than native vasopressin or any other vasopressin antagonist. Blockade of the V₂ receptor induces solute-free water excretion without affecting normal electrolyte excretion. The pharmacokinetics and pharmacodynamics of tolvaptan are suitable for once-daily dosing. Throughout all phases of clinical studies, it was shown to be safe for short- and long-term use. Tolvaptan effectively increases serum sodium levels in patients with heart failure, cirrhosis and syndrome of inappropriate secretion of antidiuretic hormone. In patients hospitalized owing to heart failure, tolvaptan decreased bodyweight, increased urine output and improved dyspnea compared with placebo. However, tolvaptan has not proven to be beneficial for the long-term management of heart failure. Currently, tolvaptan is the only oral agent in its class available in the USA and Europe.     

Sertraline-Associated Syndrome of Inappropriate Antidiuretic Hormone: Case Report and Review of the Literature

Selective serotonin reuptake inhibitors have gained widespread use in the treatment of depression. A 78-year-old woman became hyponatremic 3 days after being treated with sertraline and was subsequently diagnosed with the syndrome of inappropriate antidiuretic hormone (SIADH). She became symptomatic, but experienced rapid resolution of the laboratory and clinical abnormalities associated with SIADH on discontinuing sertraline and receiving fluid restriction, hypertonic saline, and demeclocycline. Several mechanisms may relate SIADH and vasopressin release to serotonin.     

Duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics

Hyponatremia is a known adverse effect of duloxetine, and it can lead to potentially life-threatening complications. Administration of thiazide diuretics also has been the cause of hyponatremia. We report a case of duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics. An 86-year-old woman treated with the trichlormethiazide was admitted for vertebral compression fracture with disorientation and nausea on the 6^th day of treatment with duloxetine. Laboratory findings revealed hyponatremia, hypo-osmolality, concentrated urine, and increased urine sodium. Syndrome of inappropriate antidiuretic hormone was considered, therefore, duloxetine, and trichlormethiazide was discontinued and treated with fluid restriction, furosemide and sodium chloride administered orally. Disorientation and nausea were improved after correction of hyponatremia. Health care practitioners should be aware of the possibility of duloxetine-induced hyponatremia, particularly in patients treated with thiazide diuretics.KEY WORDS: Drug interaction, duloxetine, syndrome of inappropriate secretion of antidiuretic hormone syndrome, trichlormethiazide     

The pharmacologic management of the syndrome of inappropriate secretion of antidiuretic hormone

There have been numerous treatment modalities reported in the literature concerning the acute and chronic treatment of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Water restriction remains the mainstay of therapy. However, patient noncompliance for this regimen often makes additional treatment modalities necessary. In the long-term treatment of chronic SIADH, lithium, demeclocycline, loop diuretics, and urea are helpful, regardless of the origin of the SIADH. The use of lithium is not recommended due to the incidence of digestive, cardiac, thyroid, and central nervous system side effects, as well as the demonstrated superiority of demeclocycline. Urea and loop diuretics, although shown to be effective, have not been used clinically to the extent as demeclocyline, and are not free of adverse effects. Phenytoin is limited in its use to the treatment of SIADH secondary to abnormalities of the hypothalamic-pituitary axis, and plays no role in the treatment of tumor-induced SIADH. Demeclocyline has been shown to be effective in all types of SIADH. The lack of comparative studies of long-term treatment regimens makes the selection of a regimen of choice difficult. At this point loop diuretics or demeclocycline appear to be the regimens of choice based primarily upon case reports and relatively small comparative study patient populations. Further comparative studies are needed in an attempt to identify the most efficacious regimen with the minimal incidence of adverse effects.     

重型颅脑损伤后中枢性低钠血症临床观察及治疗

目的探讨重型颅脑损伤后中枢性低钠血症的治疗方法及临床疗效。方法选取本院26例重型颅脑损伤后中枢性低钠血症的患者为研究对象,根据其临床特点及检查结果分为抗利尿激素分泌不当综合征（SIADH）5例和脑性盐耗综合征（CSWS）21例,给予相应的治疗,总结两组的治疗效果。结果 CSWS组的中心静脉压（CVP）、抗利尿激素（ADH）显著低于SIADH组,CSWS组血浆心钠素（ANP）值显著高于SIADH组,P〈0.05。26例患者中,有2例患者死亡,24例患者低钠血症得到纠正。结论 SIADH和CSWS是引起重型颅脑损伤后中枢性低钠血症的主要原因,应针对不同的病因采取有针对性的治疗,降低病死率。     

Partial reversal of carbamazepine-induced water intolerance by demeclocycline.

The anti-diuretic action of carbamazepine, before and after concurrent treatment with demeclocycline, has been studied in a single epileptic subject, in whom two episodes of status epilepticus had been associated with excessive fluid intake and hyponatraemia. After addition of demeclocyline, free water clearance, plasma arginine vasopressin concentration and serum osmolality (all appreciably reduced after carbamazepine alone) increased but did not revert to normal. The findings are consistent with direct antagonism by demeclocycline of the enhancing effect of carbamazepine on endogenous ADH activity.     

Atypical antipsychotics and polydipsia: a cause or a treatment?

Primary polydipsia (PP) is a frequent complication that affects many chronic schizophrenic inpatients. Due to possible lethal consequences, for example, hyponatremia, coma and death, it's fundamental for the physician achieving early diagnosis and treating this condition. The first step is identifying polydipsia by clinical, biochemical and pharmacological means. Nowadays, the pathophysiology of PP remains unclear, and this limits the possibility of detecting an appropriate drug treatment. Typical antipsychotics have been associated to a worsening of polydipsic behavior, while more recently atypical antipsychotics have been reported as being useful. However results are still mixed and controversial. It appears that risperidone and olanzapine are not clearly effective; clozapine may improve symptoms, although it is difficult to manage from a therapeutic point of view; quetiapine has been poorly studied so far, nonetheless it has given interesting results. Through a case study analysis, this report presents a brief, yet selective, overview of the current state of psychopharmacology in the treatment of PP with atypical antipsychotics in schizophrenia.     

Syndrome of inappropriate antidiuretic hormone secretion in patients with adult Still's disease

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a rare complication of adult Still's disease (ASD). We experienced a male ASD patient who complained of arthralgia and intermittent fever. Chest radiograph and pleural fluid analysis revealed pleurisy with effusion. We diagnosed this patient with SIADH and confirmed the disappearance of hyponatremia and pleurisy after starting treatment with nonsteroidal anti-inflammatory drugs. In this study, we reviewed previous literature and the case of our ASD patient with hyponatremia. This reported case is the fourth case of SIADH in an ASD patient. Further, we found that hyponatremia is a relatively common complication of ASD, and pleurisy has a possibility to develop SIADH in patients with ASD.     

Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia

Lixivaptan (VPA-985), being developed by Biogen Idec and Cardiokine, under license from Wyeth (now part of Pfizer), is a non-peptide, selective vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia associated with heart failure. Arginine vasopressin, the native V2 receptor ligand, stimulates water reabsorption via activation of V2 receptors that are expressed in the collecting ducts of the kidney. In preclinical studies, lixivaptan displayed competitive antagonist activity at V2 receptors in vitro, and increased urine volume and decreased urine osmolality in rats and dogs. The therapeutic benefits of lixivaptan are being evaluated in patients with conditions that are associated with water excess and hyponatremia. Phase II clinical trials in patients with congestive heart failure, liver cirrhosis with ascites or syndrome of inappropriate antidiuretic hormone have demonstrated that, unlike traditional diuretics, lixivaptan increases water clearance without affecting renal sodium excretion or activating the neurohormonal system. Administration of lixivaptan in combination with the diuretic furosemide has been tested in rats as well as in trials in healthy volunteers, in which the two agents were well tolerated. Ongoing phase III trials will determine the role of lixivaptan in the management of hyponatremia, especially when associated with heart failure.     

重型颅脑损伤后低钠血症的临床分析

目的:分析重型颅脑损伤后低钠血症的临床特点。方法:回顾性分析47例重型颅脑损伤后低钠血症患者临床表现及实验室检查结果。结果:20例符合抗利尿激素分泌异常综合征,其中治愈18例,死亡2例;27例符合脑性盐耗综合征,治愈20例,死亡7例。结论:抗利尿激素分泌异常综合征与脑性盐耗综合征的发病机制与治疗措施不同,对其进行正确诊治能降低颅脑损伤病人的致残率和死亡率。     

鞍区肿瘤术后低钠血症的临床处理

目的 探讨鞍区肿瘤术后抗利尿激素分泌异常综合征(SIADH)及脑性盐耗综合征(CSWS)的鉴别诊断及治疗方法.方法回顾性分析86例首次接受鞍区肿瘤术后低钠血症患者的临床表现和实验室检查,总结有效的诊断及治疗方法.将48例垂体腺瘤患者分为A组,28例颅咽管瘤和10例脑膜瘤患者分为B组;CSWS低钠者补钠、迅速扩容、补充高...     

鞍区病变手术后低钠血症的诊断和治疗

目的 探讨鞍区病变手术后并发低钠血症的诊断和治疗方法。方法 回顾性分析我科2001年1月-2005年12月诊治的18例鞍区病变手术后并发低钠血症的临床资料。结果16例患者诊断为脑性盐耗综合症，2例诊断为抗利尿激素不适当分泌综合症。经相应治疗后，全部患者低钠血症纠正，恢复良好17例．自动出院1例。结论 鞍区病变手术后易发生低钠血症，中心静脉压监测对其诊治有指导意义。