Treatment of symptomatic hyponatremia with hypertonic saline: a real-life observational study.

OBJECTIVE: Treatment of symptomatic hyponatremia is not well established. The European guidelines recommend bolus-wise administration of 150 mL of 3% hypertonic saline. This recommendation is, however, based on low level of evidence. DESIGN: Observational study. METHODS: Sixty-two consecutive hyponatremic patients admitted to the emergency department or intensive care unit of the University Hospital Wuerzburg were divided in subgroups according to treatment (150 mL bolus of 3% hypertonic saline or conventional treatment) and symptom severity. Treatment target was defined as an increase in serum sodium by 5-10 mEq/L within first 24 h and maximum 8 mEq/L during subsequent 24 h. RESULTS: Thirty-three out of sixty-two patients (53%) were presented with moderate symptoms and 29/62 (47%) with severe symptoms. Thirty-six were treated with hypertonic saline and 26 conventionally. In the hypertonic saline group, serum sodium increased from 116 ± 7 to 123 ± 6 (24 h) and 127 ± 6 mEq/L (48 h) and from 121 ± 6 to 126 ± 5 and 129 ± 4 mEq/L in the conventional group, respectively. Overcorrection at 24 h occurred more frequent in patients with severe symptoms than with moderate symptoms (38% vs 6%, P < 0.05). Diuresis correlated positively with the degree of sodium overcorrection at 24 h (r = 0.6, P < 0.01). Conventional therapies exposed patients to higher degrees of sodium fluctuations and an increased risk for insufficient sodium correction at 24 h compared to hypertonic saline (RR: 2.8, 95% CI: 1.4-5.5). CONCLUSION: Sodium increase was more constant with hypertonic saline, but overcorrection rate was high, especially in severely symptomatic patients. Reducing bolus-volume and reevaluation before repeating bolus infusion might prevent overcorrection. Symptoms caused by hypovolemia can be misinterpreted as severely symptomatic hyponatremia and diuresis should be monitored.

Vasopressin escape and memory impairment in a model of chronic syndrome of inappropriate secretion of antidiuretic hormone in mice.

Recently, chronic hyponatremia, even mild, has shown to be associated with poor quality of life and high mortality. The mechanism by which hyponatremia contributes to those symptoms, however, remains to be elucidated. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a primary cause of hyponatremia. Appropriate animal models are crucial for investigating the pathophysiology of SIADH. A rat model of SIADH has been generally used and mouse models have been rarely used. In this study, we developed a mouse model of chronic SIADH in which stable and sustained hyponatremia occurred after 3-week continuous infusion of the vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) and liquid diet feeding to produce chronic water loading. Weight gain in chronic SIADH mice at week 2 and 3 after starting dDAVP injection was similar to that of control mice, suggesting that the animals adapted to chronic hyponatremia and grew up normally. AQP2 expression in the kidney, which reflects the renal action of vasopressin, was decreased in dDAVP-infused water-loaded mice as compared with control mice that received the same dDAVP infusion but were fed pelleted chow. These results suggest that "vasopressin escape" occurred, which is an important process for limiting potentially fatal severe hyponatremia. Behavioral analyses using the contextual and cued fear conditioning test and T-maze test demonstrated cognitive impairment, especially working memory impairment, in chronic SIADH mice, which was partially restored after correcting hyponatremia. Our results suggest that vasopressin escape occurred in chronic SIADH mice and that chronic hyponatremia contributed to their memory impairment.

Inappropriate antidiuretic hormone secretion in amyotrophic lateral sclerosis.

Only a few cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the setting of amyotrophic lateral sclerosis (ALS) have been described in the literature. We present the case of an 81-year-old male who developed severe hyponatremia following elective total hip replacement. His past medical history included prostate cancer, which was under surveillance, and ischemic heart disease. He reported recent weight loss, worsening shortness of breath, and lethargy. SIADH was diagnosed on the basis of hyponatremia, elevated urinary sodium, and decreased serum osmolality, presumed secondary to surgery. Investigations revealed no occult malignancy and no other cause for hyponatremia. He was discharged when sodium levels had normalized, however, he then had several further admissions for hyponatremia, general fatigue, and breathlessness. His condition continued to decline, and he developed dysphagia, weakness, and tongue fasciculations. Neurological examination showed globally decreased power, increased tone, and fasciculations. MRI of the brain was normal. He did not respond to neostigmine treatment, and a presumed diagnosis of motor neuron disease was made. The patient passed away shortly after this, and a post-mortem confirmed the diagnosis of ALS. Drug, post-operative, and cancer-related causes were precluded by the timing of onset of hyponatremia. We present this case and an analysis of previously published cases alongside a discussion on the potential causative mechanisms.

[Clinical characteristics of 128 hospitalized patients with syndrome of inappropriate antidiuretics of different etiologies].

Objective: To summarize and analyze the clinical features and etiologies in hospitalized patients with syndrome of inappropriate antidiuretics (SIAD) during the past 25 years. Methods: All data of 128 patients with SIAD admitted to Chinese PLA General Hospital since January 1991 to January 2016 were collected. SIAD was diagnosed based on the 1957 criterion. Results: (1) The most frequent causes of increased inappropriate secretion of vasopressin were malignant tumors, lung diseases (e. g. pneumonia), and central nervous system diseases, in which malignant tumors accounted for 38.28% of the SIAD. (2) During the past 25 years, the proportion of malignant diseases declined from 4/7 to 35.29%, while, the proportion of pulmonary infection increased from 1/7 to 35.29% (P<0.05). (3) The patients with malignant tumors had the lowest serum sodium and serum osmolality among all SIAD patients. (4) CT scan had a high diagnostic value for chest and brain detection. (5) Among three SIAD subjects with unknown reasons at onset, two were diagnosed with small cell lung cancer and one with gastric cancer during follow-up. Conclusion: The etiology of SIAD is complex and it could be attributed to multifarious etiological factors. Malignant tumors account for the largest proportion of all patients, and pulmonary infection was ranked in second place. Cautions on tumors have to be taken when serum sodium of a SIAD patient is below 118.1 mmol/L.

Pure small cell recurrent prostate cancer developing syndrome of inappropriate antidiuretic hormone secretion.

PURPOSE: Pure small cell neuroendocrine carcinoma of the prostate is a rare entity characterized by a poor prognosis due to early metastatic spread as well as resistance to treatment. Considering its increasing occurrence, clinicians should be aware of its aggressive behavior, the relevance of an early diagnosis, and proper management. METHODS: A 71-year-old man treated with brachytherapy for localized low-risk prostate cancer developed widespread disease 7 years later with a prostate-specific antigen-negative neuroendocrine small cell phenotype. He was also diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH) soon after starting chemotherapy. RESULTS: A substantial radiologic and clinical response to chemotherapy was observed and the paraneoplastic SIADH was successfully treated with oral vaptan therapy. CONCLUSIONS: Secondary small cell prostate carcinoma is an underestimated entity with high sensitivity to chemotherapy, although a standard treatment has not yet been defined. Moreover, oral vaptans demonstrated prompt efficacy and simple management in correcting SIADH-related hyponatremia.

Severe hyponatraemia with absence of hyperkalaemia in rapidly progressive Addison's disease.

We present a case of rapidly progressing Addison's disease in adrenal crisis with severe hyponatraemia and absence of hyperkalaemia in a 10-year-old girl. She presented with 2 weeks of vomiting, fatigue and weight loss. Her serum electrolytes obtained 1 week prior to presentation were normal, except for mild hyponatraemia at 131 mmol/L, which dropped to 112 mmol/L on admission. She had normal serum potassium, low-serum osmolality, with elevated urine sodium and osmolality, indistinguishable from syndrome of inappropriate antidiuretic hormone (SIADH). Subsequently, Addison's disease was diagnosed on the basis of gingival hyperpigmentation and undetectable cortisol on adrenocorticotropic hormone stimulation test. She rapidly responded to stress dose hydrocortisone, followed by hydrocortisone and fludrocortisone replacement therapy. The absence of hyperkalaemia in the presence of severe hyponatraemia cannot rule out Addison's disease in children. The mechanism of hypo-osmolar hyponatraemia in primary adrenal insufficiency and clinical clues to differentiate it from SIADH are discussed.

Syndrome of inappropriate antidiuretic hormone secretion in patients with aquaporin-4 antibody.

The objective of this study was to analyze the frequency of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with positive aquaporin-4 (AQP4) antibodies and evaluate the relationship between SIADH and hypothalamic lesions in patients with NMO and NMO spectrum disorder (NMOSD). AQP4 antibodies were tested by an indirect immunofluorescence assay employing HEK-293 cells transfected with recombinant human AQP4. Clinical data of patients were analyzed retrospectively. In total, 192 patients with AQP4 antibodies were certified, of which 41 patients (21.4 %) were included in the present study. Six patients (14.6 %, 6/41) met the criteria of SIADH, of which hyponatremia was mild in one patient, and severe in five. Five patients experienced confusion or decreased consciousness. Four patients were diagnosed with NMO and two were diagnosed with recurrent optic neuritis. Magnetic resonance imaging showed 11 of 41 patients (26.8 %) had hypothalamic lesions. All patients with SIADH had hypothalamic abnormalities. Hyponatremia resolved in all patients after intravenous methylprednisolone and intravenous immunoglobulin therapy. SIADH is not rare in patients with NMO/NMOSD, especially in patients with lesions close to the hypothalamus.

Inappropriate antidiuretic syndrome hypersecretion after a single dose of cisplatin.

Severe hyponatremia with seizure owing to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral/renal salt wasting syndrome related with high mortality. The correct diagnosis of the hyponatremia for each case is important because of the alteration of the treatment approach. SIADH is an important clinical manifestation that does not occur after all chemotherapy courses. We cannot estimate whether the disease will occur on, which course of the chemotherapy in this case.

An autopsy case of macroglobulinemia complicated with syndrome of inappropriate secretion of ADH (SIADH) like hyponatremia, hypopituitarism and AL amyloidosis.

An 88-year-old male patient with macroglobulinemia was admitted to our hospital because of severe hyponatremia and unconsciousness. Laboratory findings showed decreased inhibition of antidiuretic hormone (ADH) and he was diagnosed with syndrome of inappropriate secretion of ADH (SIADH). Hyponatremia improved with only limitation of water intake and the patient was followed up on a continuing outpatient basis. However, soon after discharge from hospital, his legs started swelling with edema and hyponatremia worsened. He was re-admitted due to a fall at home. Hyponatremia was observed at re-admission. A CRH challenge test showed partial dysfunction of ACTH secretion. Corticosteroid therapy was performed, but the patient subsequently died from pneumonia. Pathological findings at autopsy revealed invasion of plasma cells and amyloid depositions in multiple organs, including the pituitary, adrenal cortex, heart, liver, kidney, lymph nodes and bone marrow. Consistent with these results, fibrosis was observed in the anterior lobe of the pituitary, suggesting that the autopsy findings were related to the clinical observations and diagnosis. This is the first reported case of macroglobulinemia complicated with multiple hormone dysfunction.

Retrospective evaluation of standard diagnostic procedures in identification of the causes of new-onset syndrome of inappropriate antidiuresis.

BACKGROUND: Many diagnostic procedures are conducted in patients with syndrome of inappropriate antidiuresis (SIAD). However, the contribution in identification of the cause of SIAD remains unknown. METHODS: The study was conducted at Kaohsiung Veterans General Hospital in southern Taiwan. From January 2000 to December 2009, medical records of 439 adult patients hospitalized for new-onset SIAD at a single center were retrospectively collected. All diagnostic procedures during hospitalization were divided into four groups: chest/lung, central nervous system, abdomen, and bone marrow to evaluate their positive rate leading to the cause of SIAD. Factors associated with "procedures leading to the cause" were also analyzed to improve efficacy of survey. RESULTS: Cause of SIAD was identified in 267 (60.8%). Of them, 150 were pulmonary disorders, 44 were drugs, 37 were central nervous system disorders, 32 were malignancy and 4 were post-surgery. Survey for chest/lung, central nervous system, abdomen, and bone marrow were performed in 96.6%, 29.2%, 38.0% and 3.6% of patients, respectively; positive findings leading to the cause of SIAD were 39.6%, 12.5%, 5.3% and 6.3%, respectively. Among the diagnostic procedures, chest x-ray (424/439, 96.6%) was most frequently performed with the highest identification rate of 34.7% (147 cases). Major significant independent factors that associated with "procedure leading to a cause" were: absence of SIAD-associated drug history, presence of fever/chills, and presence of respiratory symptoms. Cause of SIAD became evident later during the follow-up period in 10 of 172 (5.8%) patients who were initially thought to be cause-unknown. Malignancy was the cause for 5 cases and pulmonary tuberculosis was for the other five. Eight of these causes became evident within one year after the diagnosis of SIAD. CONCLUSIONS: SIAD with unidentified causes were prevalent. Current diagnostic procedures remain not satisfying in determining the cause of SIAD, but chest radiograph did demonstrate higher diagnostic rate, especially in patients presented with fever, chills, respiratory symptoms, and without SIAD-associated drug history. Patients with unidentified cause should be followed for at least one year when most hidden causes (e.g. malignancy and tuberculosis) become obvious.

Characterization of three vasopressin receptor 2 variants: an apparent polymorphism (V266A) and two loss-of-function mutations (R181C and M311V).

Arginine vasopressin (AVP) is released from the posterior pituitary and controls water homeostasis. AVP binding to vasopressin V2 receptors (V2Rs) located on kidney collecting duct epithelial cells triggers activation of Gs proteins, leading to increased cAMP levels, trafficking of aquaporin-2 water channels, and consequent increased water permeability and antidiuresis. Typically, loss-of-function V2R mutations cause nephrogenic diabetes insipidus (NDI), whereas gain-of-function mutations cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Here we provide further characterization of two mutant V2Rs, R181C and M311V, reported to cause complete and partial NDI respectively, together with a V266A variant, in a patient diagnosed with NSIAD. Our data in HEK293FT cells revealed that for cAMP accumulation, AVP was about 500- or 30-fold less potent at the R181C and M311V mutants than at the wild-type receptor respectively (and about 4000- and 60-fold in COS7 cells respectively). However, in contrast to wild type V2R, the R181C mutant failed to increase inositol phosphate production, while with the M311V mutant, AVP exhibited only partial agonism in addition to a 37-fold potency decrease. Similar responses were detected in a BRET assay for ß-arrestin recruitment, with the R181C receptor unresponsive to AVP, and partial agonism with a 23-fold decrease in potency observed with M311V in both HEK293FT and COS7 cells. Notably, the V266A V2R appeared functionally identical to the wild-type receptor in all assays tested, including cAMP and inositol phosphate accumulation, ß-arrestin interaction, and in a BRET assay of receptor ubiquitination. Each receptor was expressed at comparable levels. Hence, the M311V V2R retains greater activity than the R181C mutant, consistent with the milder phenotype of NDI associated with this mutant. Notably, the R181C mutant appears to be a Gs protein-biased receptor incapable of signaling to inositol phosphate or recruiting ß-arrestin. The etiology of NSIAD in the patient with V266A V2R remains unknown.

Heterogeneous data fusion for brain tumor classification.

Current research in biomedical informatics involves analysis of multiple heterogeneous data sets. This includes patient demographics, clinical and pathology data, treatment history, patient outcomes as well as gene expression, DNA sequences and other information sources such as gene ontology. Analysis of these data sets could lead to better disease diagnosis, prognosis, treatment and drug discovery. In this report, we present a novel machine learning framework for brain tumor classification based on heterogeneous data fusion of metabolic and molecular datasets, including state-of-the-art high-resolution magic angle spinning (HRMAS) proton (1H) magnetic resonance spectroscopy and gene transcriptome profiling, obtained from intact brain tumor biopsies. Our experimental results show that our novel framework outperforms any analysis using individual dataset.

Syndrome of inappropriate antidiuretic hormone secretion in a patient with large cell neuroendocrine carcinoma.

The syndrome of inappropriate antidiuretic hormone secretion has only been reported in a few patients with large cell neuroendocrine carcinoma (LCNEC); however, it has never been reported in a patient with LCNEC of the lung, whose serum sodium levels were normalized after surgical resection of the mass. A 63-year-old male presented with a two-day history of dizziness and recent memory loss. On admission, his serum sodium level was 113 mEq/L with a serum osmolality of 236 mosm/kg, a urine osmolality of 441 mosm/kg, and a urine sodium level of 65 mEq/L. His chest computed tomography revealed a 2.7×2.3 cm-sized mass in the left lower lobe. After surgical removal of the mass, his serum sodium concentrations were normalized, and histopathology of the mass revealed LCNEC.

Syndrome of inappropriate secretion of antidiuretic hormone induced by tacrolimus in a patient with systemic lupus erythematosus.

We describe the first reported case of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) induced by low-dose tacrolimus in a patient with autoimmune disease. A 41-year-old man with systemic lupus erythematosus (SLE) developed hyponatremia induced by SIADH after administration of tacrolimus (0.06 mg/kg per day). In this case, the hyponatremia promptly resolved upon withdrawal of tacrolimus. This case strongly suggests that SIADH is a potentially important complication of tacrolimus administration, irrespective of dosage, and should be borne in mind whenever the drug is used.

Fístula carotidea cavernosa asociada a síndrome de secreción inadecuada de hormona antidiurética / Carotid cavernous fistula associated with syndrome of inappropriate secretion of antidiuretic hormone

La fístula carótido-cavernosa (FCC) es una comunicación anómala que se establece entre la arteria carótida y el seno cavernoso y se produce un shunt arteriovenoso patológico. Actualmente la mayoría de estas lesiones son tratadas por técnicas endovasculares(1,2). La hiponatremia es el trastorno hidroelectrolítico más frecuente y aproximadamente un tercio de las mismas se deben al síndrome de secreción inadecuada de hormona antidiuretica (SIADH). El SIADH se ha relacionado con alteraciones del SNC, entre los que destacan los traumatismos craneoencefálicos(3). Presentamos el caso de una paciente de 43 años que consulta por presentar cuadro de agitación psicomotriz e insomnio asociado a cuadro de síncope y en los días posteriores presenta cefalea y disminución progresiva de la agudeza visual. Como antecedente de importancia tuvo traumatismo craneoencefálico un mes antes de su consulta. Al examen físico se observa edema periorbitario de ojo derecho condilatación de los vasos de la conjuntiva, proptosis; a la auscultación del globo ocular se apreciaba un soplo y en el fondo del ojo se observa la presencia de edema de papila. En los exámenes de laboratorio Sodio: 118 meq/L; Osmolaridad Plasmática: 267 m0sm; Osmolaridad Urinaria: 1100 mosm; Sodio Urinario: 35 meq/L...

The carotid cavernous fistula is an abnormal connectivity between the carotid artery and the cavernous sinus and produces a pathologic shunt between an artery and a vein. These lesions are usually treated with endovascular techniques. Hyponatremia is the most frequent electrolitic disorder found, and approximately one third is due to a syndrome of inappropriate secretion of antidiuretic hormone (ISADH). It has been related to SNC alterations; one of the causes can be craneoencephalic trauma. We present a 43 year old patient who consulted with agitation and insomnia, later on she had an episode of syncope and in the following days headache and impaired vision. This patient had suffered a cranial trauma a month before consultation. At the physical examination a right periorbitary edema, proptosis and vessels dilatation were seen; a murmur could be heard on that eye and the fundus exploration showed papilledema. Laboratory showed: sodium: 118 meq/L; plasmatic osmolarity: 267 mOsm; urinary Osmolarity: 1100 mOms; urinary sodium: 35 meq/L...

Severe hyponatremia due to ACTH insufficiency in a 14 year-old girl with growth hormone deficiency.

SIADH-like hyponatremia as the presenting manifestation of ACTH deficiency is rare in childhood. Here we report a 14 year-old girl who, after 8 years of GH replacement and subsequent treatment for subclinical secondary hypothyroidism, presented with confusion and disorientation due to severe hyponatremia. When her pituitary axis was re-assessed, she was diagnosed as having ACTH deficiency associated with multiple pituitary hormone deficiencies (MPHD) (including GH, FSH, LH, and subclinical TSH deficiencies). She responded poorly to treatment with only hypertonic fluid, but improved after addition of hydrocortisone replacement. The purpose of this paper is to emphasize the importance of suspecting ACTH insufficiency in children with GH deficiency if hyponatremia develops.