Chloride and Potassium Assessment Is a Helpful Tool for Differential Diagnosis of Thiazide-Associated Hyponatremia.

CONTEXT: Differential diagnosis of thiazide-associated hyponatremia (TAH) is challenging. Patients can either have volume depletion or a syndrome of inappropriate antidiuresis (SIAD)-like presentation. OBJECTIVE: To evaluate the impact of the simplified apparent strong ion difference in serum (aSID; sodium + potassium - chloride) as well as the urine chloride and potassium score (ChU; chloride - potassium in urine) in the differential diagnosis of TAH, in addition to assessment of fractional uric acid excretion (FUA). METHODS: Post hoc analysis of prospectively collected data from June 2011 to August 2013 from 98 hospitalized patients with TAH < 125 mmol/L enrolled at University Hospital Basel and University Medical Clinic Aarau, Switzerland. Patients were categorized according to treatment response in volume-depleted TAH requiring volume substitution or SIAD-like TAH requiring fluid restriction. We computed sensitivity analyses with ROC curves for positive predictive value (PPV) and negative predictive value (NPV) of aSID, ChU, and FUA in differential diagnosis of TAH. RESULTS: An aSID > 42 mmol/L had a PPV of 79.1% in identifying patients with volume-depleted TAH, whereas a value < 39 mmol/L excluded it with a NPV of 76.5%. In patients for whom aSID was inconclusive, a ChU < 15 mmol/L had a PPV of 100% and a NPV of 83.3%, whereas FUA < 12% had a PPV of 85.7% and a NPV of 64.3% in identifying patients with volume-depleted TAH. CONCLUSION: In patients with TAH, assessment of aSID, potassium, and chloride in urine can help identifying patients with volume-depleted TAH requiring fluid substitution vs patients with SIAD-like TAH requiring fluid restriction.

Association of Hyponatraemia and Antidepressant Drugs: A Pharmacovigilance-Pharmacodynamic Assessment Through an Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

BACKGROUND: Hyponatraemia induced by antidepressant drugs is a rare but potentially life-threatening adverse reaction. Whether it is associated with all or only some antidepressant drugs is still unclear. This needs to be clarified to guide antidepressant therapies, especially in patients with electrolytic imbalances. OBJECTIVES: The primary objective of this study was to quantify the strength of association between the use of different antidepressant drugs and hyponatraemia by using information reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The secondary objective was to investigate the putative relationship between different antidepressant pharmacological targets and the risks of hyponatraemia induced by antidepressant drugs using the 'pharmacovigilance-pharmacodynamic' method. METHODS: We used the FAERS database to conduct a case/non-case analysis on spontaneous reports, focusing on events of hyponatraemia/syndrome of inappropriate antidiuretic hormone secretion (SIADH) reported in connection with the use of antidepressant drugs. Risk was expressed as a measure of disproportionality using the reporting odds ratio while adjusting for sex, age and concomitant medications associated with hyponatraemia/SIADH. We assessed to what extent the receptor-binding properties of antidepressant drugs could associate with the reporting odds ratios of hyponatraemia/SIADH of antidepressant drugs, building a linear regression model that included as independent variables the binding affinities (pKi) to the serotonin transporter, dopamine transporter, norepinephrine transporter, and serotonin 5-HT2C, 5-HT2A and 5-HT1A, and α1- and α2-adrenergic receptors. RESULTS: There were 2233 reports identified. The adjusted reporting odds ratio for the association between antidepressant drug use and hyponatraemia was 1.91 (95% confidence interval 1.83-2.00). The association was strongest for mirtazapine, followed by selective serotonin reuptake inhibitors, and lowest with serotonin-modulating antidepressant drugs. A significant linear correlation was found between the adjusted reporting odds ratios for hyponatraemia and pKi for the adrenergic receptors α1 and α2. CONCLUSIONS: Hyponatraemia is reported at a disproportionately higher level with classes of antidepressant drugs (noradrenergic and specific serotonergic antidepressant [mirtazapine] and serotonin modulators [vortioxetine]) that are in general considered to have a better profile of tolerability in terms of hyponatraemia. With regard to the presented results, the risk of hyponatraemia with mirtazapine appears to be greater than what was reported in the literature; however, confounding by indication cannot be ruled out. Our pharmacovigilance-pharmacodynamic analysis also indicates that inhibition of the serotonin transporter may not be involved in the hyponatraemia linked to the use of antidepressant drugs.

["Serious" adverse drug reactions with tramadol: a 2010-2011 pharmacovigilance survey in France]. / Effets indésirables « graves ¼ du tramadol : bilan 2010-2011 de pharmacovigilance en France.

OBJECTIVE: Tramadol is a weak opioid used as a step 2 analgesic, approved in France for moderate to severe pain. After dextropropoxyphene withdrawal, a national pharmacovigilance follow-up of tramadol was decided by the French Drug Agency. METHODS: All Serious Adverse Drug Reactions (SADR) notified with tramadol to the French PharmacoVigilance Centres (CRPV) and pharmaceutical companies between August 1(st), 2010 and July 31(th), 2011 were analyzed. RESULTS: During the study period, 296 cases of SADR were notified to CRPV and 59 to pharmaceutical companies. Apart from opiate-related SADR, tramadol induced serotoninergic SADR, including seizures or serotoninergic syndromes. Several « unlabelled ¼ SADR were also identified: some of them, like hyponatremia or hypoglycemia, are poorly known by health professionals. Other were never published: peripheral edema or pancreatitis. CONCLUSION: This study shows that besides well-known opioid or serotoninergic ADR, tramadol can also induce 2 other relatively unknown ADR: hypoglycemia and hyponatremia.

Evaluations of hospitalizations associated with thiazide-associated hyponatremia.

The prevalence of hypertension in the United States has grown dramatically in recent years. Thiazide diuretics have played a major role in the rising rate of blood pressure (BP) control. Accompanying this has been the appearance of adverse drug events, including hospitalizations associated with thiazide-associated hyponatremia (HTAH). Hyponatremia is a common yet often overlooked side effect of this drug class. Identification of HTAH risk factors may aid in creating strategies to prevent hospitalizations. This is a retrospective, case-controlled study of 10,805 patients (1802 cases, 9003 controls) examining HTAH risk factors within a group-model integrated-care organization. Multivariate analysis revealed that age (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.58-1.93), angiotensin-converting enzyme (ACE) inhibitor use (OR, 1.53; 95% CI, 1.16-2.00), and hypokalemia (OR, 40.94; 95% CI, 26.46-66.33) were most associated with HTAH. Urinary tract infection (UTI), type 2 diabetes, hyperlipidemia, and gastroesophageal reflux disease (GERD) were also found to be HTAH risk factors. Potassium supplements (OR, 0.60; 95% CI, 0.44-0.83) and weight (OR, 0.91; 95% CI, 0.88-0.93) had protective effects. A predictive model was developed to determine overall HTAH risk given the presence of individual risk factors. Age, weight, hypokalemia, GERD, type 2 diabetes, UTI, and ACE inhibitor use independently correlated with an increased risk of HTAH. This model may be applied in clinical practice to guide thiazide prescribing.

Venlafaxine hyponatraemia: incidence, mechanism and management.

OBJECTIVE: This prospective study was performed on patients aged >65 years commencing therapy with venlafaxine, in order to determine the incidence of hyponatraemia induced by the drug, to investigate the underlying pathophysiological mechanisms, and to evaluate a simple approach to management of this condition. METHOD: All patients aged >65 years seen by one author (MR) from all referral sources were entered into the study. Baseline biochemical tests were ordered, and if hyponatraemia developed (plasma Na <130 mmol L(-1)) additional tests were performed to ascertain the mechanism, while the patient continued on venlafaxine and fluid restriction was instituted. RESULTS: A total of 58 patients were seen, of whom 10 developed hyponatraemia, giving an incidence of 17.2%. Of these 10 patients, five were excluded from prolonged observation because of either severe medical illness, side-effects from the antidepressant or being lost to follow up. When hyponatraemia developed, it invariably did so within a few days of starting venlafaxine, and was associated with non-suppression of antidiuretic hormone in the face of a low serum osmolality. Fluid restriction (800 mL day(-1)) was effective in raising the plasma sodium to the normal range within 2 weeks, after which the fluid restriction could be relaxed without relapse occurring. These patients remained well for the follow-up period of up to 6 months. CONCLUSIONS: Patients >65 years of age should have their electrolytes measured 3-5 days after starting venlafaxine therapy. If hyponatraemia develops, it can be managed with modest fluid restriction without discontinuing drug treatment, subject to close continued clinical observation and biochemical monitoring.

Carbamazepine-induced hyponatremia: assessment of risk factors.

OBJECTIVE: To report a case of carbamazepine-induced acute hyponatremia resulting in seizures. CASE SUMMARY: A 44-year-old white woman developed acute hyponatremia and 2 subsequent tonic-clonic seizures after ingesting twice her evening dose of carbamazepine (usual evening dose 600 mg). On admission, her serum sodium level was 122 mEq/L. An infusion of NaCl 0.9% was begun and, within 24 hours, the serum sodium level had returned to her previous level of 136 mEq/L. The woman's preadmission carbamazepine concentration was 8.6 microg/mL, and it was 11.3 micorg/mL on admission. Carbamazepine was withheld and, the following day, the concentration was 5.6 microg/mL. The woman had experienced a similar event 6 months earlier when she also took a large dose of carbamazepine. DISCUSSION: We attributed the acute hyponatremia and seizures to the large increase in dose of carbamazepine in the presence of other risk factors for hyponatremia. Hyponatremia associated with carbamazepine has been well described. The incidence ranges from 1.8% to 40% depending on the patient population studied. Severe hyponatremia in patients treated with monotherapy is uncommon. Several risk factors have been reported to increase the risk of hyponatremia including age >40 years, concomitant use of medications associated with hyponatremia, menstruation, psychiatric condition, surgery, psychogenic polydipsia, and female gender. Treatment is focused on removal of the precipitating factors or discontinuation of carbamazepine therapy. Use of the Naranjo probability scale indicated a highly probable relationship between acute hyponatremia and carbamazepine in our patient. CONCLUSIONS: Hyponatremia with carbamazepine is well known. The factors associated with increased risk are less understood. An increased awareness of these risks, careful monitoring, and patient education are important in the prevention of neurologic complications.