1.
Balanced Crystalloids versus Saline in Critically Ill Adults.
Semler, MW, Self, WH, Wanderer, JP, Ehrenfeld, JM, Wang, L, Byrne, DW, Stollings, JL, Kumar, AB, Hughes, CG, Hernandez, A, et al
The New England journal of medicine. 2018;(9):829-839
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Abstract
BACKGROUND Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes. METHODS In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first. RESULTS Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60). CONCLUSIONS Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .).
2.
Mineralocorticoid receptor-related markers and outcome of major depression: focus on blood pressure and electrolytes.
Murck, H, Ploch, M, Montgomery, S
International clinical psychopharmacology. 2018;(4):224-228
Abstract
A close association between vegetative regulation and affect is common knowledge. Recently, the role of aldosterone and the activity of its receptor [mineralocorticoid receptor (MR)] in the clinical outcome for treatment with standard antidepressants has been shown including low systolic blood pressure and a low concentration of plasma sodium (Na), both of which appear to be related to therapy resistance to standard antidepressants. We carried out a retrospective analysis of a double-blind placebo-controlled trial of St John's wort extract LI160 in 247 outpatients with major depression. The study did not show a difference between the treatment groups; therefore, a pooled dataset of the 6-week completer population of the trial was analyzed. The focus was on the moderating effect of blood pressure and electrolytes on clinical outcome (relative change in Montgomery-Asberg Depression Rating Scale). Low Na/K ratio and high K at screening predicted worse outcome after 6 weeks as measures with the Montgomery-Asberg Depression Rating Scale (P<0.01). Systolic blood pressure at the same time point did not influence the treatment outcome. In conclusion, signs of reduced peripheral MR sensitivity, as reflected by a lower plasma Na/K ratio and/or higher K concentration, predict worse outcome. This is in line with our recent data as well as neuroendocrine findings. The data indicate that widely collected biomarkers, which are related to MR activity, may be useful to identify patients, who are at risk of nonresponse to antidepressant treatment.
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Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes.
Miles, DR, Lacy, SA, Wada, DR, Milwee, S, Yaron, Y, Nguyen, LT
Cancer chemotherapy and pharmacology. 2017;(2):295-306
Abstract
PURPOSE This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC). METHODS Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration. RESULTS Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10-15 ms increase in delta-delta Fridericia corrected QT (∆∆QTcF) and delta-delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study. CONCLUSIONS Cabozantinib treatment prolongs the ∆∆QTcF interval by 10-15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.