Diuretic-induced hypokalaemia: an updated review.

Diuretic-induced hypokalaemia is a common and potentially life-threatening adverse drug reaction in clinical practice. Previous studies revealed a prevalence of 7%-56% of hypokalaemia in patients taking thiazide diuretics. The clinical manifestations of hypokalaemia due to diuretics are non-specific, varying from asymptomatic to fatal arrhythmia. Diagnosis of hypokalaemia is based on the level of serum potassium. ECG is useful in identifying the more severe consequences. A high dosage of diuretics and concomitant use of other drugs that increase the risk of potassium depletion or cardiac arrhythmias can increase the risk of cardiovascular events and mortality. Thiazide-induced potassium depletion may cause dysglycaemia. The risk of thiazide-induced hypokalaemia is higher in women and in black people. Reducing diuretic dose and potassium supplementation are the most direct and effective therapies for hypokalaemia. Combining with a potassium-sparing diuretic or blocker of the renin-angiotensin system also reduces the risk of hypokalaemia. Lowering salt intake and increasing intake of vegetables and fruits help to reduce blood pressure as well as prevent hypokalaemia.

Association between potassium supplementation and the occurrence of acute kidney injury in patients with hypokalemia administered liposomal amphotericin B: a nationwide observational study.

BACKGROUND: Hypokalemia and acute kidney injury (AKI) occur in patients administered liposomal amphotericin B (L-AMB), a wide-spectrum anti-fungicidal drug. However, the association between potassium supplementation and the occurrence of AKI in patients with hypokalemia who were administered L-AMB is not well understood. METHODS: Using nationwide claims data and laboratory data, the occurrence of AKI during L-AMB treatment was retrospectively compared between patients with hypokalemia who were or were not supplemented with potassium and between those adequately or inadequately supplemented with potassium (serum potassium levels corrected to ≥3.5 mEq/L or remained < 3.5 mEq/L, respectively) before or after L-AMB treatment initiation. RESULTS: We identified 118 patients who developed hypokalemia before L-AMB treatment initiation (43 received potassium supplementation [25 adequate and 18 inadequate supplementation] and 75 did not receive potassium supplementation), and 117 patients who developed hypokalemia after L-AMB initiation (79 received potassium supplementation [including 23 adequate and 15 inadequate supplementation] and 38 did not receive potassium supplementation). The occurrence of any stage of AKI was similar between patients with hypokalemia, regardless of potassium supplementation (i.e., before L-AMB treatment initiation [supplementation, 51%; non-supplementation, 45%; P = 0.570] or after L-AMB initiation [supplementation, 28%; non-supplementation, 32%; P = 0.671]). After adjusting for confounding factors, we found that the occurrence of any stage of AKI was not associated with potassium supplementation before L-AMB initiation (odds ratio [OR]: 1.291, 95% confidence interval [CI]: 0.584-2.852, P = 0.528) or after L-AMB initiation (OR: 0.954, 95% CI: 0.400-2.275, P = 0.915). The occurrence of any stage of AKI tended to decline in patients with hypokalemia who were adequately supplemented with potassium (44%) before, but not after, L-AMB initiation relative to that in patients inadequately supplemented with potassium (61%), however this result was not significant (P = 0.358). CONCLUSION: Potassium supplementation was not associated with any stage of AKI in patients with hypokalemia who were administered L-AMB.

Decision support system for NPK fertilization: a solution method for minimizing the impact on human health, climate change, ecosystem quality and resources.

Sugarcane cultivation requires correct fertilizer rates. However, when nutrients are not available, or there is over-fertilization, the yields are significantly reduced and the environmental burden increase. In this study, it is proposed a decision support system (DSS) for the correct NPK (nitrogen, phosphorus and potassium) fertilization. The DSS consists of two fuzzy models; the edaphic condition model (EDC-M) and the NPK fertilization model (NPK-M). The DSS using parameters from soil analysis and is based on the experience of two groups of experts to avoid the bias to the reality of a single group of professionals. The results of the DSS are compared with the results of soil analysis and those of the group of experts. One hundred and sixty tests were developed in the NPK-M. The N rate shows R 2=0.981 for the DSS and R 2=0.963 for soil analyzes. The P rate shows R 2=0.9702 for the DSS and R 2=0.9183 for the soil analyzes. The K rate shows R 2=0.9691 for the DSS and R 2=0.9663 for the soil analyzes. Environmental results indicate that the estimated rates with the DSS do reduce the environmental impact on the tests performed.

Melatonin receptor activation protects against low potassium-induced ventricular fibrillation by preserving action potentials and connexin-43 topology in isolated rat hearts.

Hypokalemia prolongs the QRS and QT intervals, deteriorates intercellular coupling, and increases the risk for arrhythmia. Melatonin preserves gap junctions and shortens action potential as potential antiarrhythmic mechanisms, but its properties under hypokalemia remain unknown. We hypothesized that melatonin protects against low potassium-induced arrhythmias through the activation of its receptors, resulting in action potential shortening and connexin-43 preservation. After stabilization in Krebs-Henseleit solution (4.5 mEq/L K+ ), isolated hearts from Wistar rats underwent perfusion with low-potassium (1 mEq/L) solution and melatonin (100 µmol/L), a melatonin receptor blocker (luzindole, 5 µmol/L), melatonin + luzindole or vehicle. The primary endpoint of the study was the prevention of ventricular fibrillation. Electrocardiography was used, and epicardial action potentials and heart function were measured and analyzed. The ventricular expression, dephosphorylation, and distribution of connexin-43 were examined. Melatonin reduced the incidence of low potassium-induced ventricular fibrillation from 100% to 59%, delayed the occurrence of ventricular fibrillation and induced a faster recovery of sinus rhythm during potassium restitution. Melatonin prevented QRS widening, action potential activation delay, and the prolongation of action potential duration at 50% of repolarization. Other ECG and action potential parameters, the left ventricular developed pressure, and nonsustained ventricular arrhythmias did not differ among groups. Melatonin prevented connexin-43 dephosphorylation and its abnormal topology (lateralization). Luzindole abrogated the protective effects of melatonin on electrophysiological properties and connexin-43 misdistribution. Our results indicate that melatonin receptor activation protects against low potassium-induced ventricular fibrillation, shortens action potential duration, preserves ventricular electrical activation, and prevents acute changes in connexin-43 distribution. All of these properties make melatonin a remarkable antifibrillatory agent.

Left ventricular dysfunction after two hours of polarizing or depolarizing cardioplegic arrest in a porcine model.

INTRODUCTION: This experimental study compares myocardial function after prolonged arrest by St. Thomas' Hospital polarizing cardioplegic solution (esmolol, adenosine, Mg2+) with depolarizing (hyperkalaemic) St. Thomas' Hospital No 2, both administered as cold oxygenated blood cardioplegia. METHODS: Twenty anaesthetized pigs on tepid (34°C) cardiopulmonary bypass (CPB) were randomised to cardioplegic arrest for 120 min with antegrade, repeated, cold, oxygenated, polarizing (STH-POL) or depolarizing (STH-2) blood cardioplegia every 20 min. Cardiac function was evaluated at Baseline and 60, 150 and 240 min after weaning from CPB, using a pressure-conductance catheter and epicardial echocardiography. Regional tissue blood flow, cleaved caspase-3 activity and levels of malondialdehyde were evaluated in myocardial tissue samples. RESULTS: Preload recruitable stroke work (PRSW) was increased after polarizing compared to depolarizing cardioplegia 150 min after declamping (73.0±3.2 vs. 64.3±2.4 mmHg, p=0.047). Myocardial tissue blood flow rate was high in both groups compared to the Baseline levels and decreased significantly in the STH-POL group only, from 60 min to 150 min after declamping (p<0.005). Blood flow was significantly reduced in the STH-POL compared to the STH-2 group 240 min after declamping (p<0.05). Left ventricular mechanical efficiency, the ratio between total pressure-volume area and blood flow rate, gradually decreased after STH-2 cardioplegia and was significantly reduced compared to STH-POL cardioplegia after 150 and 240 min (p<0.05 for both). CONCLUSION: Myocardial protection for two hours of polarizing cardioplegic arrest with STH-POL in oxygenated blood is non-inferior compared to STH-2 blood cardioplegia. STH-POL cardioplegia alleviates the mismatch between myocardial function and perfusion after weaning from CPB.

Emergency Department Visits for Adverse Events Related to Dietary Supplements.

BACKGROUND: Dietary supplements, such as herbal or complementary nutritional products and micronutrients (vitamins and minerals), are commonly used in the United States, yet national data on adverse effects are limited. METHODS: We used nationally representative surveillance data from 63 emergency departments obtained from 2004 through 2013 to describe visits to U.S. emergency departments because of adverse events related to dietary supplements. RESULTS: On the basis of 3667 cases, we estimated that 23,005 (95% confidence interval [CI], 18,611 to 27,398) emergency department visits per year were attributed to adverse events related to dietary supplements. These visits resulted in an estimated 2154 hospitalizations (95% CI, 1342 to 2967) annually. Such visits frequently involved young adults between the ages of 20 and 34 years (28.0% of visits; 95% CI, 25.1 to 30.8) and unsupervised children (21.2% of visits; 95% CI, 18.4 to 24.0). After the exclusion of unsupervised ingestion of dietary supplements by children, 65.9% (95% CI, 63.2 to 68.5) of emergency department visits for single-supplement-related adverse events involved herbal or complementary nutritional products; 31.8% (95% CI, 29.2 to 34.3) involved micronutrients. Herbal or complementary nutritional products for weight loss (25.5%; 95% CI, 23.1 to 27.9) and increased energy (10.0%; 95% CI, 8.0 to 11.9) were commonly implicated. Weight-loss or energy products caused 71.8% (95% CI, 67.6 to 76.1) of supplement-related adverse events involving palpitations, chest pain, or tachycardia, and 58.0% (95% CI, 52.2 to 63.7) involved persons 20 to 34 years of age. Among adults 65 years of age or older, choking or pill-induced dysphagia or globus caused 37.6% (95% CI, 29.1 to 46.2) of all emergency department visits for supplement-related adverse events; micronutrients were implicated in 83.1% (95% CI, 73.3 to 92.9) of these visits. CONCLUSIONS: An estimated 23,000 emergency department visits in the United States every year are attributed to adverse events related to dietary supplements. Such visits commonly involve cardiovascular manifestations from weight-loss or energy products among young adults and swallowing problems, often associated with micronutrients, among older adults. (Funded by the Department of Health and Human Services.).

Myocardial Protection by Glucose-Insulin-Potassium in Moderate- to High-Risk Patients Undergoing Elective On-Pump Cardiac Surgery: A Randomized Controlled Trial.

BACKGROUND: Low cardiac output syndrome is a main cause of death after cardiac surgery. We sought to assess the impact of glucose-insulin-potassium (GIK) to enhance myocardial protection in moderate- to high-risk patients undergoing on-pump heart surgery. METHODS: A randomized controlled trial was performed in adult patients (Bernstein-Parsonnet score >7) scheduled for elective aortic valve replacement and/or coronary artery bypass surgery. Patients were randomized to GIK (20 IU of insulin, 10 mEq of potassium chloride in 50 mL of glucose 40%) or saline infusion given over 60 minutes on anesthetic induction. The primary end point was postcardiotomy ventricular dysfunction (PCVD), defined as new/worsening left ventricular dysfunction requiring inotropic support (≥120 minutes). Secondary end points were the intraoperative changes in left ventricular function as assessed by transoesophageal echocardiography, postoperative troponin levels, cardiovascular and respiratory complications, and intensive care unit and hospital length of stay. RESULTS: From 224 randomized patients, 222 were analyzed (112 and 110 in the placebo and GIK groups, respectively). GIK pretreatment was associated with a reduced occurrence of PCVD (risk ratio [RR], 0.41; 95% confidence interval [CI], 0.25-0.66). In GIK-treated patients, the left systolic ventricular function was better preserved after weaning from bypass, plasma troponin levels were lower on the first postoperative day (2.9 ng·mL(-) [interquartile range {IQR}, 1.5-6.6] vs 4.3 ng·mL(-) [IQR, 2.4-8.2]), and cardiovascular (RR, 0.69; 95% CI, 0.50-0.89) and respiratory complications (RR, 0.5; 95% CI, 0.38-0.74) were reduced, along with a shorter length of stay in intensive care unit (3 days [IQR, 2-4] vs 3.5 days [IQR, 2-7]) and in hospital (14 days [IQR, 11-18.5] vs 16 days [IQR, 12.5-23.5]), compared with placebo-treated patients. CONCLUSIONS: GIK pretreatment was shown to attenuate PCVD and to improve clinical outcome in moderate- to high-risk patients undergoing on-pump cardiac surgery.

Mutation profile and treatment of Gitelman syndrome in Chinese patients.

BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive disease caused by loss-of-function mutations in the SLC12A3 gene, and is characterized by hypokalemia and metabolic alkalosis. In this study, we aimed to study the genotype, phenotype, and treatment in 42 GS patients, the largest sample size so far in mainland China. METHOD: We retrospectively studied the clinical data and genetic characteristics of 42 patients diagnosed with GS in Peking Union Medical College Hospital from 2012 to 2015. Therapeutic efficacy of spironolactone and potassium supplements was also studied retrospectively. RESULTS: Eighty-one mutation alleles were found in 42 patients, and total of 52 distinctly different mutation alleles were identified, of which 15 were new mutation alleles. p.Asp486Asn was a hotspot in our series, with the allele frequency being 19.7 % (16/81), and was found in 13 patients (31.0 %). Treatment with spironolactone or potassium supplements alone significantly increased serum potassium concentration by 0.36 ± 0.37 and 0.45 ± 0.35 mmol/l, respectively (both P < 0.05), and combined therapy with spironolactone and potassium increased serum potassium concentration by 0.69 ± 0.64 mmol/l (P < 0.05). CONCLUSIONS: 18.5 % (15/81) mutation sites identified in 42 Chinese GS patients are novel. p.Asp486Asn mutation is a hotspot, which is different from the reports from other countries. Spironolactone could moderately elevate serum potassium level, and spironolactone in combination with potassium supplements tended to be more effective.

Potassium supplementation and heart rate: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Increasing the intake of potassium has been shown to lower blood pressure, but whether it also affects heart rate (HR) is largely unknown. We therefore assessed the effect of potassium supplementation on HR in a meta-analysis of randomized controlled trials. METHODS AND RESULTS: We searched PubMed (1966-October 2014) for randomized, placebo-controlled trials in healthy adults with a minimum duration of two weeks in which the effect of increased potassium intake on HR was assessed. In addition, reference lists from meta-analysis papers on potassium and blood pressure were hand-searched for publications. Two investigators independently extracted the data. We performed random effects meta-analyses, subgroup and meta-regression analyses for characteristics of the study (e.g. design, intervention duration, potassium dose and salt type, change in potassium excretion, sodium excretion during intervention) and study population (e.g. gender, age, hypertensive status, pre-study HR, pre-study potassium excretion). A total of 22 trials (1086 subjects), with a median potassium dose of 2.5 g/day (range: 0.9-4.7 g/day), and median intervention duration of 4 weeks (range: 2-24 weeks) were included. The meta-analysis showed no overall effect of increased potassium intake on HR (0.19 bpm, 95% CI: -0.44, 0.82). Stratified analyses yielded no significant effects of potassium intake on HR in subgroups, and there was no evidence for a dose-response relationship in meta-regression analyses. CONCLUSION: A chronic increase in potassium intake with supplemental doses of 2-3 g/day is unlikely to affect HR in apparently healthy adults.

Exploratory study of acid-forming potential of commercial cheeses: impact of cheese type.

Due to their composition, cheeses are suspected to induce an acid load to the body. To better understand this nutritional feature, the acid-forming potential of five cheeses from different cheese-making technologies and two milk was evaluated on the basis of their potential renal acid load (PRAL) index (considering protein, P, Cl, Na, K, Mg and Ca contents) and organic anions contents. PRAL index ranged from -0.8 mEq/100 g edible portion for fresh cheese to 25.3 mEq/100 g for hard cheese Cantal and 28 mEq/100 g for blue-veined cheese Fourme d'Ambert. PRAL values were greatly subjected to interbatch fluctuations. This work emphasized a great imbalance between acidifying elements of PRAL calculation (Cl, P and proteins elements) and alkalinizing ones (Na and Ca). Particularly, Cl followed by P elements had a strong impact on the PRAL value. Hard cheeses were rich in lactate, thus, might be less acidifying than suspected by their PRAL values only.

Particulate matter composition and respiratory health: the PIAMA Birth Cohort study.

BACKGROUND: Ambient particulate matter (PM) exposure is associated with children's respiratory health. Little is known about the importance of different PM constituents. We investigated the effects of PM constituents on asthma, allergy, and lung function until the age of 11-12 years. METHODS: For 3,702 participants of a prospective birth cohort study, questionnaire-reported asthma and hay fever and measurements of allergic sensitization and lung function were linked with annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc in particles with diameters of less than 2.5 and 10 µm (PM2.5 and PM10) at birth addresses and current addresses from land-use regression models. Exposure-health relations were analyzed by multiple (repeated measures) logistic and linear regressions. RESULTS: Asthma incidence and prevalence of asthma symptoms and rhinitis were positively associated with zinc in PM10 at the birth address (odds ratio [95% confidence interval] per interquartile range increase in exposure 1.13 [1.02, 1.25], 1.08 [1.00, 1.17], and 1.16 [1.04, 1.30], respectively). Moreover, asthma symptoms were positively associated with copper in PM10 at the current address (1.06 [1.00, 1.12]). Allergic sensitization was positively associated with copper and iron in PM10 at the birth address (relative risk [95% confidence interval] 1.07 [1.01, 1.14] and 1.10 [1.03, 1.18]) and current address. Forced expiratory volume in 1 second was negatively associated with copper and iron in PM2.5 (change [95% confidence interval] -2.1% [-1.1, -0.1%] and -1.0% [-2.0, -0.0%]) and FEF75-50 with copper in PM10 at the current address (-2.3% [-4.3, -0.3%]). CONCLUSION: PM constituents, in particular iron, copper, and zinc, reflecting poorly regulated non-tailpipe road traffic emissions, may increase the risk of asthma and allergy in schoolchildren.

Does Hemodialysis Dialysate Potassium Composition Matter?.

Dyskalemia is known to cause cardiac arrhythmias and cardiac arrest. In persons undergoing hemodialysis, potassium dialysate composition has been identified as a contributingfactor in addition to co-morbidities, medications, dietary potassium intake, and stage of kidney disease. Current evidence recommends a thorough evaluation of all factors affecting potassium balance, and lower potassium concentration should be used cautiously in patients who are likely to develop cardiac arrhythmias. Nephrology nurses play a key role inpatient assessment and edu- cation related to potassium balance.

Glucose-insulin-potassium therapy in patients with acute coronary syndrome: a meta-analysis of randomized controlled trials.

BACKGROUND: Glucose-insulin-potassium (GIK) has been advocated in the setting of acute coronary syndrome (ACS) to reduce ischemia-related arrhythmias and myocardial injury. We conducted a meta-analysis of randomized controlled trials (RCTs) to assess whether the use of GIK infusions >3 or <3 hours after the onset of symptoms reduce mortality or cardiac arrest. METHODS: Electronic databases (Medline, EMBASE, and Cochrane Central Register of Controlled Trials) and references of retrieved articles were searched for RCTs evaluating the effect of GIK infusions, <3 hours or >3 hours after the onset of symptoms, on mortality and/or cardiac arrest. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each outcome. RESULTS: Nine trials were identified and eligible for review. The summary OR for in-hospital mortality was 1.01 (95% CI 0.94 to 1.09), based on 2,542 deaths among 27,294 patients. The subgroup analysis according to the study enrollment time (within 3 hours [OR, 0.77, 95% CI 0.50-1.16], vs. >3 hours [OR, 0.90; 95% CI, 0.67-1.21]) did not reveal any difference in mortality. CONCLUSIONS: Administration of GIK in ACS patients does not significantly reduce mortality whether or not GIK administration >3 or <3 hours after the onset of symptoms.

Safety and efficacy of intensive intraoperative glycaemic control in cardiopulmonary bypass surgery: a randomised trial.

BACKGROUND: This study aimed to determine the safety and efficacy of intraoperative intensive glycaemic treatment with modified glucose-insulin-potassium solution by hyperinsulinemic normoglycaemic clamp in cardiopulmonary bypass surgery patients. We hypothesised that the treatment would reduce infection rates in this group of patients. METHODS: A prospective, randomised, double-blind trial was conducted in cardiopulmonary bypass surgery patients. A total of 199 adult patients (out of a planned 400) were randomly allocated to intensive or conventional treatment with target glucose levels of 4.4-8.3 mmol/l and < 13.8 mmol/l, respectively. The primary outcomes were clinical infection and cytokine levels, including interleukin (IL)-6 and IL-10. The secondary outcomes were morbidity and mortality. RESULTS: The study was terminated early because of safety concerns (hypoglycaemia). The clinical post-operative infection rate was 17% in the intensive group and 13% in the conventional group (P = 0.53). The proportion of patients with hypoglycaemia was significantly higher in the intensive group (23%) compared with the conventional group (3%) (P < 0.001). Morbidity and mortality rates were similar for both groups. Anaesthetic duration > 2 h (vs. ≤ 2 h), pre-operative IL-6 level > 15 pg/ml (vs. ≤ 15 pg/ml) and post-operative IL-6 level 56-110 pg/ml (vs. ≤ 55 pg/ml) were independent predictors for post-operative infection. CONCLUSIONS: Intraoperative intensive glycaemic treatment significantly increased the risk of hypoglycaemia, but its effect on post-operative infection by clinical assessment could not be determined. Anaesthetic duration, pre-operative and post-operative IL-6 levels can independently predict post-operative infection.

Glucosa-Insulin-Potassium (GIK) solution used with diabetic patients provides better recovery after coronary bypass operations.

INTRODUCTION: Tight blood glucose control has become a therapeutical goal for anesthetic management for patients scheduled for cardiac surgery, especially if they are diabetic patients. AIM: This study was created to confirm the benefits of intraoperative GIK solution usage during coronary bypass operation of diabetic patients. METHODS: Patients with type 1 and 2 diabetes mellitus (DM) referred for coronary artery bypass grafting (CABG) were randomized to receive GIK solution (GIK--study group) in the first 24 hours intraoperatively or to receive official Clinical protocol without GIK solution (non GIK - control group). The primary clinical outcome was the cardiac index (CI) since it represents the most sensitive measure of cardiac work in the immediate postoperative period, and the secondary clinical outcomes were the glycemic control, insulin consumption, duration of mechanical ventilation (MV), potassium level and atrial fibrillation (AF) appearance. RESULTS: One hundred diabetic patients, divided into two groups, were included in the study. The cardiac index did not show a significant difference, although the study group had CI with only minor variations than those of the controlled group, hence the reason we considered the study group as the more stable. The atrial fibrillation showed a difference between two groups, with 14 (28%) patients with postoperative AF in the control group compared with 3 (6%) patients with postoperative AF in the study group. As potassium values were stable in study group, we concluded that it can be one of the reasons for less postoperative AF in this group. The duration of MV showed a significant difference (0,003) between the two groups as well. In the study group the average MV time was 534,38 minutes, compared with the control group with 749,20 minutes. The average value of glucose was 11.1 mmol/l in the control group vs. 9.8 mmol/l in the study group. The study group had less insulin consumption in order to maintain target glycemia (p = 0.001). In the non GIK group average insulin consumption was 44 IJ per patient vs. 28.5 IJ in the GIK group. CONCLUSION: Intraoperative GIK solution given to diabetic patients with CABG operation provides more stable CI, shorter time of MV, more stable values of potassium which provides normal rhythm and less AF onset, less insulin to maintain target glycemia. All the above mentioned provides more stable intraoperative hemodynamic and better recovery of diabetic

Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity.

BACKGROUND AND OBJECTIVE: In silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods. METHODS: Pharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels. RESULTS: Fifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p<0.05). Our simulations indicated that women with impaired renal function were particularly susceptible to drug-induced arrhythmias, whereas healthy men were less prone to TdP. Differences between patient groups were more pronounced for high TdP-risk drugs. The proposed in silico tool also revealed that individuals with impaired renal function, electrophysiologically simulated with hyperkalemia (extracellular potassium concentration [K+]o = 7 mM) exhibited less pronounced APD prolongation than individuals with normal potassium levels. The pharmacokinetic/electrophysiological framework was used to determine the maximum safe dose of dofetilide in different patient groups. As a proof of concept, 3D simulations were also run for dofetilide obtaining QT prolongation in accordance with previously reported clinical values. CONCLUSIONS: This study presents a novel methodology that combines pharmacokinetic and electrophysiological models to incorporate the effects of sex and renal function into in silico drug simulations and highlights their impact on TdP-risk assessment. Furthermore, it may also help inform maximum dose regimens that ensure TdP-related safety in a specific sub-population of patients.

Impact of Sodium Zirconium Cyclosilicate Plus Renin-Angiotensin-Aldosterone System Inhibitor Therapy on Short-Term Medical Costs in Hyperkalemia: OPTIMIZE II Real-World Study.

INTRODUCTION: Patients receiving cardiorenal-protective renin-angiotensin-aldosterone system inhibitors (RAASis) are at increased risk of developing hyperkalemia, which is associated with increased medical costs. The aim of this study was to evaluate the impact of adding sodium zirconium cyclosilicate (SZC) therapy on 3-month medical costs in patients who experienced hyperkalemia while receiving RAASi therapy. METHODS: The retrospective OPTIMIZE II study used medical and pharmacy claims data from IQVIA PharMetrics® Plus. Patients aged ≥ 18 years who received SZC (≥ 60 day supply over 3 months' follow-up) and continued RAASi between July 2019 and December 2021 (Continue RAASi + SZC cohort) were 1:1 exact and propensity score matched with patients who discontinued RAASi after hyperkalemia diagnosis and did not receive SZC (Discontinue RAASi + no SZC cohort). The primary outcome was hyperkalemia-related medical costs to payers over 3 months; all-cause medical and pharmacy costs were also analyzed. RESULTS: In the Continue RAASi + SZC (n = 467) versus Discontinue RAASi + no SZC (n = 467) cohort, there were significant reductions in mean per-patient hyperkalemia-related medical costs (reduction of $2216.07; p = 0.01) and all-cause medical costs (reduction of $6102.43; p < 0.001); mean hyperkalemia-related inpatient medical costs and all-cause inpatient and emergency department medical costs were significantly reduced. The reduction in all-cause medical cost in the Continue RAASi + SZC cohort offset an increase in the mean per-patient all-cause pharmacy cost (increase of $3117.71; p < 0.001). CONCLUSION: RAASi therapy has well-established cardiorenal benefits. In OPTIMIZE II, management of RAASi-induced hyperkalemia with SZC was associated with lower hyperkalemia-related and all-cause medical costs than RAASi discontinuation without SZC, demonstrating medical cost savings with maintaining RAASi therapy with SZC.

Regional increase in extracellular potassium can be arrhythmogenic due to nonuniform muscle contraction in rat ventricular muscle.

In the ischemic myocardium, extracellular potassium ([K(+)](o)) increases to ≥20 mmol/l. To determine how lethal arrhythmias occur during ischemia, we investigated whether the increased spatial pattern of [K(+)](o), i.e., a regional or a global increase, affects the incidence of arrhythmias. Force, sarcomere length, membrane potential, and nonuniform intracellular Ca(2+) ([Ca(2+)](i)) were measured in rat ventricular trabeculae. A "regional" or "global" increase in [K(+)](o) was produced by exposing a restricted region of muscle to a jet of 30 mmol/l KCl or by superfusing trabeculae with a solution containing 30 mmol/l KCl, respectively. The increase in [Ca(2+)](i) (Ca(CW)) during Ca(2+) waves was measured (24°C, 3.0 mmol/l [Ca(2+)](o)). A regional increase in [K(+)](o) caused nonuniform [Ca(2+)](i) and contraction. In the presence of isoproterenol, the regional increase in [K(+)](o) induced sustained arrhythmias in 10 of 14 trabeculae, whereas the global increase did not induce such arrhythmias. During sustained arrhythmias, Ca(2+) surged within the jet-exposed region. In the absence of isoproterenol, the regional increase in [K(+)](o) increased Ca(CW), whereas the global increase decreased it. This increase in Ca(CW) with the regional increase in [K(+)](o) was not suppressed by 100 µmol/l streptomycin, whereas it was suppressed by 1) a combination of 10 µmol/l cilnidipine and 3 µmol/l SEA0400; 2) 20 mmol/l 2,3-butanedione monoxime; and 3) 10 µmol/l blebbistatin. A regional but not a global increase in [K(+)](o) induces sustained arrhythmias, probably due to nonuniform excitation-contraction coupling. The same mechanism may underlie arrhythmias during ischemia.

Intravenous administration of magnesium and potassium solution lowers energy levels and increases success rates electrically cardioverting atrial fibrillation.

BACKGROUND: External biphasic electrical cardioversion (CV) is a standard treatment option for patients suffering from acute symptoms of atrial fibrillation (AF). Nevertheless, CV is not always successful, and thus strategies to increase the success rate are desirable. OBJECTIVE: The purpose of this study was to evaluate the effect of intravenously administered K/Mg solution on the biphasic CV energy threshold and success rate to restore sinus rhythm (SR) in patients with AF. METHODS: The study consisted of 170 patients with persistent AF. The patients were randomly assigned to undergo biphasic CV either with (n = 84) or without (n = 86) pretreatment with K/Mg solution. An energy step-up protocol of 75, 100, and 150 W (J) was used. RESULTS: Biphasic CV of AF was effective in 81 (96.4%) patients in the pretreatment and 74 (86.0%) patients in the control group (P = 0.005). The effective energy level required to achieve SR was significantly lower in the pretreated group (140.8 ± 26.9 J vs 182.5 ± 52.2 J, P = 0.02). No K/Mg-solution-associated side effects such as hypotension or bradycardia were observed. CONCLUSION: Administration of K/Mg solution positively influences the success rate of CV in patients with persistent AF. Furthermore, significantly less energy is required to successfully restore SR and therefore K/Mg pretreatment may facilitate SR restoration in patients undergoing CV for AF.

Management of blood glucose in patients with acute coronary syndromes.

Hyperglycemia during admission for acute myocardial infarction (MI) is common and associated with poor outcomes. Prior studies employed two distinct approaches to improve outcomes in patients with acute MI--one focused on glucose control, and the other on provision of glucose, insulin, and potassium. However, despite multiple largescale studies, the benefits of glucose lowering in the setting of acute MI remain unclear. This article reviews data from observational studies and clinical trials and synthesizes this information into practical recommendations based on available evidence.