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.     

重型颅脑损伤合并低钠血症115例临床分析

目的探讨重型颅脑损伤合并低钠血症的诊治方法。方法对115例重型颅脑损伤合并低钠血症患者的临床诊治情况进行总结分析。结果营养性低钠血症70例,抗利尿激素异常分泌综合征14例,脑性耗盐综合征31例。营养性低钠血症和脑性耗盐综合征均给予补盐、补水治疗,抗利尿激素异常分泌综合征行限水治疗或限水补盐治疗。42例1周内纠正,29例2周内纠正,11例3周内纠正,5例4周内纠正,28例因病情较重死亡。结论临床上营养性低钠血症最常见,也最易纠正;抗利尿激素异常分泌综合征较少见,易误诊误治;营养性低钠血症和脑性耗盐综合征需要补液补盐治疗,而抗利尿激素异常分泌综合征则应该以限水治疗为原则。故要重视三者间的鉴别诊断,正确的诊断是治愈的关键。     

托伐普坦治疗小细胞肺癌伴抗利尿激素异常分泌综合征所致的低钠血症

目的：观察托伐普坦治疗小细胞肺癌伴低钠血症的效果。方法：确诊小细胞肺癌伴抗利尿激素异常分泌综合征患者7例,均予以托伐普坦,每日口服1次：7.5 mg,前3天;15 mg,后4天,于第4天、第8天晨查血钠和体质量,并进行ECOG评分。结果：与治疗前比较,所有患者血钠均恢复正常,ECOG评分亦有显著改善,且体质量呈下降趋势。结论：托伐普坦应成为小细胞肺癌伴抗利尿激素异常分泌综合征所致的低钠血症患者的推荐用药。     

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.     

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。     

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...     

Syndrome of inappropriate antidiuretic hormone with imipramine

Among the various medications that have been associated with the development of syndrome of inappropriate antidiuretic hormone secretion (SIADH) are the tricyclic antidepressants. A 69-year-old man admitted for treatment of a depressive disorder that had not responded to trazodone was prescribed imipramine. Twenty-two days after initiation of therapy, the patient developed hyponatremia. The patient also had depressed serum osmolality and elevated urine sodium concentrations consistent with SIADH. With the discontinuation of imipramine, fluid restriction, and several doses of furosemide, normal serum sodium concentrations were attained. As antidepressant therapy was indicated, doxepin was selected. The patient maintained normal electrolyte values and water balance over the next two months of follow-up. No reports of doxepin-related SIADH were found in the literature; therefore, this agent may be considered as an alternative therapy in patients developing SIADH during antidepressant drug therapy.     

Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine

Objective To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with desvenlafaxine. Case summary A 57-year-old female with hyponatraemia. Her medications included desvenlafaxine, and symptoms included nausea, anxiety and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. Desvenlafaxine was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. Discussion SIADH has been widely reported with a range of antidepressants. This case report suggests that desvenlafaxine might cause clinically significant hyponatremia. Conclusions Clinicians should be aware of the potential for antidepressants to cause hyponatremia, and take appropriate corrective action where necessary.     

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.     

脑性盐耗综合征27例临床分析

目的：探讨神经外科患者并发脑性盐耗综合征（CSWS）病因、发病机制、诊断及治疗方法。方法：回顾性分析27例低钠血症患者的临床表现和实验室检查指标,明确诊断,确定有效的治疗方法。结果：22例患者低钠血症恢复,5例死于其他并发症。结论：虽然CSWS发生机制尚不太明确,可能与神经对肾脏的传出障碍亦或利尿钠因子分泌紊乱有关。不同的是,SIADH需限制补液,而CSWS需补液、补钠。因此,两者的鉴别诊断至关重要。CVP测定和血浆ADH水平对鉴别诊断有重要意义。     

脑性盐耗综合征27例临床分析

目的探讨神经外科患者并发脑性盐耗综合征(CSW S)病因、发病机制、诊断及治疗方法。方法回顾性分析27例低钠血症患者的临床表现和实验室检查指标,明确诊断,确定有效的治疗方法。结果22例患者低钠血症恢复,5例死于其他并发症。结论虽然CSW S发生机制尚不太明确,可能与神经对肾脏的传出障碍或利尿钠因子分泌紊乱有关。不同的是,S IADH需限制补液,而CSW S需补液、补钠。因此,两者的鉴别诊断至关重要。CVP测定和血浆ADH水平对鉴别诊断有重要意义。     

Basic and clinical pharmacology of amiodarone: relationship of antiarrhythmic effects, dose and drug concentrations to intracellular inclusion bodies

Amiodarone is a unique class III antiarrhythmic drug with several unusual pharmacokinetic, pharmacodynamic, and toxicological actions which are quite distinct from those of the standard antiarrhythmic drugs. Extensive animal and clinical studies have demonstrated that amiodarone and its major metabolite, desethylamiodarone, both produce a marked increase in the duration of transmembrane action potential, which may be related to their antiarrhythmic as well as clinical electrophysiological activity. Unlike most other cardiovascular drugs, it has been recognized for more than 20 years that optimal antiarrhythmic effects may take several days to weeks after onset of oral therapy. Amiodarone is highly lipid soluble and exhibits at least three separate compartments of drug distribution, with a long elimination half-life of 14-120 days after chronic therapy. The pharmacokinetic profile of desethylamiodarone is qualitatively similar to that of amiodarone, but its elimination half-life is even longer and its tissue distribution may be slightly different. Although there may not be any correlation between serum drug levels and clinical toxicity of amiodarone during long-term therapy, recent animal as well as clinical data suggest that multilamellar intracellular inclusions can be dissociated from cell death or clinical toxicity. Thus, it is possible that amiodarone toxicity can be minimized with low doses or low serum drug concentrations. The metabolite(s) of amiodarone may play a major role in its pharmacological and toxicological actions.     

Allosteric modulation of [3H]nitrendipine binding to cardiac and cerebral cortex membranes by amiodarone

The possible interaction between the antianginal and antiarrhythmic drug amiodarone and the slow calcium channel was investigated by competition binding experiments in guinea-pig cerebral cortex and rat heart membranes using [3H]nitrendipine as radioligand. Amiodarone displaced specifically bound [3H]nitrendipine from cerebral cortex and cardiac membranes in an apparently competitive manner. In saturation binding experiments, apparent affinity for [3H]nitrendipine progressively decreased with increasing concentrations of amiodarone, whereas maximal binding capacity (Bmax remained unchanged. Both diltiazem and verapamil reversed the inhibitory effect of amiodarone on [3H]nitrendipine binding to cerebral cortex membranes. Together these results suggest that amiodarone exerts a pseudocompetitive inhibition on [3H]nitrendipine binding by acting at a site in allosteric interaction with the 1,4 dihydropyridine binding site associated with the calcium channel. The data are compatible with the existence of a common binding site for diltiazem, verapamil, and amiodarone. These observations are discussed in connection with the pharmacological properties of the drug.     

Methyldopa-induced syndrome of inappropriate antidiuretic hormone secretion and bone marrow granulomatosis

A case of an elderly man who developed severe hyponatremia and bone marrow granulomatosis while taking methyldopa is described. The hyponatremia was found to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Bone marrow biopsy revealed granulomas. A MEDLINE search of the English literature was done, yielding only one previous report of methyldopa-induced bone marrow granulomatosis and no previous reports of methyldopa-induced SIADH.     

Syndrome of inappropriate secretion of antidiuretic hormone caused by pituitary macroadenoma with hemangiomatous stroma

A 55-year-old Japanese man was referred to our hospital because of disturbance of consciousness and hyponatremia. He had been aware of general fatigue, nausea, and headache for two weeks. Tests revealed hyponatremia, plasma hypoosmolarity with urine hyperosmolarity, an elevated level of urine sodium excretion, and normal functions of the kidney, adrenal gland, and thyroid. These findings were compatible with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Head magnetic resonance imaging (MRI) demonstrated a pituitary tumor measuring 20 x 22 x 21 mm that pushed the pituitary stalk upward. Endocrinological evaluations suggested that the pituitary adenoma was non-functional. The pituitary adenoma was surgically removed, and histological examination revealed a biphasic appearance characterized by endocrine cells and a hemangiomatous stroma. After surgery, the patient developed pituitary hypothyroidism, pituitary adrenal insufficiency, and pituitary gonadal failure. Therefore, levothyroxine sodium, 50 μg per day, and hydrocortisone, 10 mg per day, were administered orally. Androgen depot, 250 mg every two months, was also injected intramuscularly. The hyponatremia did not recur, and the patient has done well for the last five years. The pituitary adenoma in this case showed two features: one was the cause of SIADH, and the other was a biphasic histological picture of endocrine cells with a hemangiomatous stroma.     

Histopathological study of kidney abnormalities in an experimental SIADH rat model and its application to the evaluation of the pharmacologic profile of VP-343, a selective vasopressin V2 receptor antagonist

The aim of this work was to investigate histopathologically the relationship between the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and kidney abnormalities and the therapeutic efficacy of VP-343 ((N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-alqunoxalin-5(1H)-yl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide], a selective vasopressin V2 receptor antagonist, in an experimental SIADH rat model. In the model, which was prepared by continuously administering 1-desamino-8-D-arginine vasopressin (DDAVP), histopathologic abnormalities, such as dilatation of tubules, basophilic changes in tubules, inflammatory cell infiltration, and mineralization were found in the kidney, accompanied by significant increases in the relative weight of the kidney, lung, liver, adrenal gland, and heart. VP-343 was shown to be effective in protecting the kidney from the histopathologic abnormalities and to normalize the relative weight of the kidney and several common pathophysiologic features, such as hyponatremia, hyposmolarity of plasma, hyperosmolarity of urea, and oligurea, as described previously. These results demonstrate the occurrence of histopathologic abnormalities in the kidney and the efficacy of VP-343 in improving abnormalities in the DDAVP-induced SIADH rat model.     

Q-switched laser treatment of amiodarone pigmentation

A number of drugs can cause cutaneous hyperpigmentation through a variety of mechanisms. The pigment is comprised of dermal deposits of the drug and its metabolites, often combined with melanin and hemosiderin. Minocycline and amiodarone are among the most common medications to cause skin-induced pigmentation. Affected individuals generally develop slate-gray pigmentation in affected sites. Treatment with various Q-switched lasers has been shown to be effective at removing drug-induced pigmentation. The author presents a man with amiodarone pigmentation of the face who responded to treatment with the Q-switched neodymium:yttrium-aluminum-garnet (Nd:YAG) laser.     

托伐普坦片治疗低钠血症的效果及安全性观察

目的观察托伐普坦片对抗利尿激素分泌不高(SIADH)及其它原因引起的非低容量性、非急性低钠血症患者的疗效及安全性。方法 38例因充血性心力衰竭、肝功能衰竭伴腹水形成、慢性肾功能不全或抗利尿激素分泌不当等疾病引起体液潴留和低钠血症的患者,予口服托伐普坦片治疗。结果口服托伐普坦片者都有血钠浓度和血渗透压的显著升高。结论托伐普坦片能够显示良好的提高血清钠浓度作用,对低钠血症患者有明显疗效。没有严重并发症和不良反应,临床应用中简便且安全。     

Severe life-threatening hyponatremia during paroxetine therapy

Hyponatremia secondary to the syndrome of inappropriate secretion of antiduretic hormone (SIADH) is an uncommon complication of treatment with the antidepressants the selective serotonin reuptake inhibitors (SSRIs). These effective anti-depressant agents are becoming widely used because of their favorable side effect profile and their safety in overdose. Although most reports have implicated fluoxetine in causing hyponatremia, there have also been a few reports of hyponatremia associated with paroxetine. We describe an elderly patient with severe life-threatening hyponatremia in association with paroxetine therapy. The present case and the others previously reported emphasize the need for greater awareness of the development of this serious and potentially fatal complication, and suggest that serum sodium concentration should be measured periodically in elderly patients soon after they start taking any agent of the SSRIs, especially during the first 2 to 4 weeks of treatment.     

Induction of Apoptosis by Cationic Amphiphilic Drugs Amiodarone and Imipramine

Phospholipidosis is the excessive accumulation of intracellular phospholipids in cell lysosomes. Drugs that induce this disease often share common physiochemical properties and are collectively classified as cationic amphiphilic drugs (CADs). Although the cause of phospholipidosis and morphologic appearance of affected lysosomes have been studied extensively, less is known about the physiologic effects of the condition. In the current study, U-937 cells were incubated with the CADs amiodarone (2.5–10 µg/mL) and imipramine (2.5–20 µg/mL). Treatment of U-937 cells with these compounds for 96 h resulted in concentration-related increases in phospholipids, as assessed by flow cytometry using the fluorophore nile red. These results were verified by measuring the concentrations of choline-derived phospholipids, which were significantly increased in drug-treated cells. Cell number in amiodarone (10 µg/mL) and imipramine (20 µg/mL) cultures following the 96-h incubation period were markedly reduced compared to control cultures. These observations suggested that accumulation of cellular phospholipids could inhibit cell proliferation. Flow cytometric analysis revealed a decrease in the percentage of cells in the S-phase of the cell cycle following drug treatment, yet DNA replication still occurred in a significant portion of cells. Interestingly, amiodarone and imipramine induced apoptosis in U-937 cells as shown by annexin V-FITC staining and DNA fragmentation. Enzymatic assays demonstrated that amiodarone and imipramine induced the activity of caspases 2 and 3. These results suggest that disruption of cell lysosomes in U-937 cells followingaccumulation of phospholipids does not cause a cell cycle arrest but instead induces apoptosis by activation of caspase pathways.