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.

Candesartan Cilexetil Attenuates Arrhythmogenicity Following Pressure Overload in Rats via the Modulation of Cardiac Electrical and Structural Remodeling and Calcium Handling Dysfunction.

Background Cardiac hypertrophy is associated with abnormal electrophysiology and increased arrhythmia risk. This study assessed whether candesartan cilexetil, an angiotensin II type 1 receptor blocker, could suppress arrhythmogenecity by attenuating cardiac electrical remodeling and calcium mishandling in rats with pressure-overload hypertrophy. Methods and Results Male Sprague-Dawley rats were randomly subjected to abdominal aorta banding or sham procedure and received either candesartan cilexetil (3.0 mg/kg per day) or vehicle by gavage for 5 weeks. Pressure overload was characterized by compensated left ventricular (LV) hypertrophy and fibrosis, increased LV pressure and its decay time, and prolonged corrected QT interval, all of which were attenuated by candesartan cilexetil treatment. Candesartan cilexetil-treated banded rat hearts displayed shorter QT intervals and lower vulnerability to atrial and ventricular tachyarrhythmias than vehicle-treated banded hearts. Candesartan cilexetil prevented banding-induced prolonged action potential duration and reduced the occurrence of triggered activity in LV papillary muscles. In addition, the prolonged time to 50% cell relengthening and calcium transient decay time were normalized in LV myocytes from candesartan cilexetil-treated banded rats, along with a normalization of decreased SERCA2a (sarco[endo]plasmic reticulum calcium-ATPase) expression in LV tissues. Furthermore, candesartan cilexetil normalized depressed transient outward potassium current densities and protein and mRNA levels of both voltage-gated potassium 4.2 and 4.3 channel subunits (Kv4.2 and Kv4.3) in banded rats. Conclusions Candesartan cilexetil protects the heart from pressure overload-induced adverse electrical remodeling by preserving potassium channel densities. In addition, calcium handling and its molecular regulation also improved after treatment. These beneficial effects may contribute to a lower susceptibility to arrhythmias in hearts from candesartan cilexetil-treated pressure-overloaded rats.

Fludrocortisone Among Adult Renal Transplant Recipients With Persistent Hyperkalemia: Single-Center Experience.

OBJECTIVES: Calcineurin inhibitors are the cornerstone of immunosuppression following solid-organ transplant. However, hyperkalemia may occur by multiple mechanisms affecting potassium in the distal tubule. Hyperkalemia is commonly observed in renal transplant recipients, and it is dose-dependent. Here, we evaluated the impact of fludrocortisone in the management of calcineurin inhibitor-induced hyperkalemia after renal transplant. MATERIALS AND METHODS: We evaluated newly transplanted patients who developed hyperkalemia or those with hyperkalemia who attended our outpatient renal transplant clinic (Hamed Al-Essa Organ Transplant Center, Kuwait). Clinical and laboratory parameters were collected before starting fludrocortisone (baseline values) and then at 1, 2, 4, and 8 weeks. Drug history was assessed, with any drugs that could induce hyperkalemia being discontinued (such as spironolactone); otherwise, essential drugs like prophylactic agents (sulfamethoxazole-trimethoprim) were maintained. Oral anti-hyperkalemic doses (bicarbonate, resonium calcium, fludrocortisone) were noted. RESULTS: Our study included 29 patients; most were men (aged 45.8 ± 15 years). Body weight did not significantly change after introduction of fludrocortisone (79.53 ± 24.31, 79.82 ± 23.85, 80.62 ± 24.24, 77.03 ± 20.7, and 79.21 ± 27.93 kg at baseline and at postdose week 1, 2, 4, and 8, respectively). Systolic and diastolic blood pressure levels were also similar at baseline versus postdose. Steroid doses (prednisolone) were significantly reduced over 1 month (15.7 ± 12.4, 14.1 ± 10.19, 12.6 ± 8.7, 9.5 ± 5.2, and 9.5 ± 5.2 mg/ day). Serum potassium levels significantly improved (5.18 ± 0.58, 4.9 ± 0.49, 4.8 ± 0.54, 4.8 ± 0.65, and 4.4 ± 0.72 mmol/L). Serum creatinine levels significantly improved by postdose week 8 (129.28 ± 48.9, 130.92 ± 52.2, 127.66 ± 50.9, 121.42 ± 41.7, and 124.1 ± 51.27 µmol/L). Serum bicarbonate levels remained similar. CONCLUSIONS: Fludrocortisone was a safe and effective option in management of calcineurin inhibitor-induced hyperkalemia among renal transplant recipients.

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.

Impact of Plasma Potassium Normalization on Short-Term Mortality in Patients With Hypertension and Hyperkalemia.

Background Hyperkalemia can be harmful, but the effect of correcting hyperkalemia is sparsely studied. We used nationwide data to examine hyperkalemia follow-up in patients with hypertension. Methods and Results We identified 7620 patients with hypertension, who had the first plasma potassium measurement ≥4.7 mmol/L (hyperkalemia) within 100 days of combination antihypertensive therapy initiation. A second potassium was measured 6 to 100 days after the episode of hyperkalemia. All-cause mortality within 90 days of the second potassium measurement was assessed using Cox regression. Mortality was examined for 8 predefined potassium intervals derived from the second measurement: 2.2 to 2.9 mmol/L (n=37), 3.0 to 3.4 mmol/L (n=184), 3.5 to 3.7 mmol/L (n=325), 3.8 to 4.0 mmol/L (n=791), 4.1 to 4.6 mmol/L (n=3533, reference), 4.7 to 5.0 mmol/L (n=1786), 5.1 to 5.5 mmol/L (n=720), and 5.6 to 7.8 mmol/L (n=244). Ninety-day mortality in the 8 strata was 37.8%, 21.2%, 14.5%, 9.6%, 6.3%, 6.2%, 10.0%, and 16.4%, respectively. The multivariable analysis showed that patients with concentrations >5.5 mmol/L after an episode of hyperkalemia had increased mortality risk compared with the reference (hazard ratio [HR], 2.27; 95% CI, 1.60-3.20; P<0.001). Potassium intervals 3.5 to 3.7 mmol/L and 3.8 to 4.0 mmol/L were also associated with increased risk of death (HR, 1.71; 95% CI, 1.23-2.37; P<0.001; HR, 1.36; 95% CI, 1.04-1.76; P<0.001, respectively) compared with the reference group. We observed a trend toward increased risk of death within the interval 5.1 to 5.5 mmol/L (HR, 1.29; 95% CI, 0.98-1.69). Potassium concentrations <4.1 mmol/L and >5.0 mmol/L were associated with increased risk of cardiovascular death. Conclusions Overcorrection of hyperkalemia to levels <4.1 mmol/L was frequent and associated with increased all-cause and cardiovascular mortality. Potassium concentrations >5.5 mmol/L were also associated with an increased all-cause and cardiovascular mortality.

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.

Modified Glucose-Insulin-Potassium Regimen Provides Cardioprotection With Improved Tissue Perfusion in Patients Undergoing Cardiopulmonary Bypass Surgery.

Background Laboratory studies demonstrate glucose-insulin-potassium (GIK) as a potent cardioprotective intervention, but clinical trials have yielded mixed results, likely because of varying formulas and timing of GIK treatment and different clinical settings. This study sought to evaluate the effects of modified GIK regimen given perioperatively with an insulin-glucose ratio of 1:3 in patients undergoing cardiopulmonary bypass surgery. Methods and Results In this prospective, randomized, double-blinded trial with 930 patients referred for cardiac surgery with cardiopulmonary bypass, GIK (200 g/L glucose, 66.7 U/L insulin, and 80 mmol/L KCl) or placebo treatment was administered intravenously at 1 mL/kg per hour 10 minutes before anesthesia and continuously for 12.5 hours. The primary outcome was the incidence of in-hospital major adverse cardiac events including all-cause death, low cardiac output syndrome, acute myocardial infarction, cardiac arrest with successful resuscitation, congestive heart failure, and arrhythmia. GIK therapy reduced the incidence of major adverse cardiac events and enhanced cardiac function recovery without increasing perioperative blood glucose compared with the control group. Mechanistically, this treatment resulted in increased glucose uptake and less lactate excretion calculated by the differences between arterial and coronary sinus, and increased phosphorylation of insulin receptor substrate-1 and protein kinase B in the hearts of GIK-treated patients. Systemic blood lactate was also reduced in GIK-treated patients during cardiopulmonary bypass surgery. Conclusions A modified GIK regimen administered perioperatively reduces the incidence of in-hospital major adverse cardiac events in patients undergoing cardiopulmonary bypass surgery. These benefits are likely a result of enhanced systemic tissue perfusion and improved myocardial metabolism via activation of insulin signaling by GIK. Clinical Trial Registration URL: clinicaltrials.gov. Identifier: NCT01516138.

Glucose-insulin-potassium infusion for the treatment of acute aluminum phosphide poisoning: an open-label pilot study.

Introduction: Acute aluminum phosphide poisoning is common in low- and middle-income countries, and is associated with very high case fatality. The addition of glucose-insulin-potassium (GIK) infusion to the standard supportive care has been proposed to improve outcomes. We aimed to assess the effectiveness of GIK infusion in acute aluminum phosphide toxicity.Methods: We performed a prospective open-label pilot study in a tertiary care hospital in north India in patients over 13 years of age with acute aluminum phosphide poisoning, to determine whether the treatment with GIK infusion improved outcomes. The primary outcome was in-hospital case fatality, and the secondary outcomes were the duration of hospital stay, the requirement of mechanical ventilation, and the change in hemodynamic and metabolic parameters.Results: A total of 60 patients were randomly assigned to groups that received either GIK infusion with supportive care or supportive care alone. Baseline parameters in both groups were comparable. Treatment with GIK infusion was associated with significantly lower in-hospital case fatality compared with supportive care alone (46.7% versus 73.3%; p-value 0.03). It was associated with a longer duration of hospital stay (p-value < 0.01) and reduced requirement of mechanical ventilation (p-value < 0.01). The treatment improved blood pressure (systolic, diastolic, and mean arterial pressure) and Glasgow coma scale score at various time intervals; however, pulse rate and metabolic acidosis (blood pH and bicarbonate levels) remained comparable in both the groups. Hyperglycemia was significantly higher in the GIK group but was easily managed.Conclusion: Treatment with GIK infusion may improve survival and hemodynamics in patients with acute aluminum phosphide poisoning.

Hyperkalemia in chronic kidney disease.

Hyperkalemia is a frequent finding in patients with chronic kidney disease (CKD). This increase in serum potassium levels is associated with decreased renal ion excretion, as well as the use of medications to reduce the progression of CKD or to control associated diseases such as diabetes mellitus and heart failure. Hyperkalemia increases the risk of cardiac arrhythmia episodes and sudden death. Thus, the control of potassium elevation is essential for reducing the mortality rate in this population. Initially, the management of hyperkalemia includes orientation of low potassium diets and monitoring of patients' adherence to this procedure. It is also important to know the medications in use and the presence of comorbidities to guide dose reduction or even temporary withdrawal of any of the potassium retention-related drugs. And finally, the use of potassium binders is indicated in both acute episodes and chronic hyperkalemia.

Hyperkalemia in chronic kidney disease

SUMMARY Hyperkalemia is a frequent finding in patients with chronic kidney disease (CKD). This increase in serum potassium levels is associated with decreased renal ion excretion, as well as the use of medications to reduce the progression of CKD or to control associated diseases such as diabetes mellitus and heart failure. Hyperkalemia increases the risk of cardiac arrhythmia episodes and sudden death. Thus, the control of potassium elevation is essential for reducing the mortality rate in this population. Initially, the management of hyperkalemia includes orientation of low potassium diets and monitoring of patients' adherence to this procedure. It is also important to know the medications in use and the presence of comorbidities to guide dose reduction or even temporary withdrawal of any of the potassium retention-related drugs. And finally, the use of potassium binders is indicated in both acute episodes and chronic hyperkalemia.

RESUMO A hiperpotassemia é um achado frequente em pacientes com doença renal crônica (DRC). Esta elevação do nível sérico de potássio está associada à diminuição da excreção renal do íon, assim como ao uso de medicações para retardar a progressão da DRC ou para controlar doenças associadas, como diabetes mellitus e insuficiência cardíaca. A hiperpotassemia aumenta o risco de episódios de arritmia cardíaca e morte súbita. Assim, o controle da elevação de potássio é essencial para a diminuição da taxa de mortalidade nessa população. O manejo da hiperpotassemia inclui, inicialmente, orientação de dietas com baixo teor de potássio e acompanhamento da aderência dos pacientes a esse procedimento. Também é importante conhecer as medicações em uso e a presença de comorbidades, a fim de orientar a redução de doses ou até mesmo a suspensão temporária de alguma das drogas relacionadas à retenção de potássio. E, finalmente, o uso de quelantes de potássio é indicado tanto em episódios agudos como nos casos de hiperpotassemia crônica.

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.

Extracorporeal Filtration of Potassium in a Swine Model of Bilateral Hindlimb Ischemia-Reperfusion Injury With Severe Acute Hyperkalemia.

Introduction: Options for the treatment of hyperkalemia in the pre-hospital setting are limited, particularly in the context of natural disaster or during combat operations. Contemporary interventions require extensive resources and technical expertise. Here we examined the potential for a simple, field deployable bridge-dialysis as a countermeasure for acute hyperkalemia induced by prolonged ischemia-reperfusion. Methods: Twenty female swine were randomized into two experimental groups undergoing a 2-hour bilateral hindlimb ischemia-reperfusion injury. Subsequent to injury, hemoperfusion was performed in the presence (Column) and absence (Sham Control) of a high-affinity potassium-binding column (CytoSorbents, Monmouth Junction, NJ, USA). Serial blood gas and chemistries were sampled. Primary endpoint was changed in serum potassium concentrations post-injury and filtration. Results: Serum potassium was significantly elevated following ischemia-reperfusion injury in both groups (149% (12) and 150% (22), p < 0.05 vs respective baseline values). There were no differences observed between groups in respect to physiologic parameters; mean arterial pressure, heart rate, systemic vascular resistance, cardiac output, or central venous oxygenation. Filtration resulted in a significant relative decrease in potassium compared with controls after the first hour as determined by repeated measures two-way ANOVA (p < 0.0001) which continued through end of the study. Significant thrombocytopenia was observed in animals undergoing filtration with a mean reduction in platelets measured at T = 480 minutes (168 × 103µL, p < 0.0001 vs baseline). Conclusions: We demonstrate that serum potassium can be filtered via hemoperfusion utilizing a simple extracorporeal potassium-binding platform, though evolution of this technology will be required to achieve meaningful reduction of potassium in clinically significant hyperkalemia after trauma.

Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease.

BACKGROUND/AIMS: Dietary potassium (K+) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K+ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the "K+ in CKD" study. METHODS: The K+ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15-44 mL/min/1.73 m2), and an average eGFR decline > 2 mL/min/1.73 m2/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K+ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K+ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K+ concentrations. CONCLUSION: The K+ in CKD study will demonstrate if K+ sup-plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects.

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.

Higher Fertilizer Inputs Increase Fitness Traits of Brown Planthopper in Rice.

Rice (Oryza sativa L.) is the primary staple food source for more than half of the world's population. In many developing countries, increased use of fertilizers is a response to increase demand for rice. In this study, we investigated the effects of three principal fertilizer components (nitrogen, phosphorus and potassium) on the development of potted rice plants and their effects on fitness traits of the brown planthopper (BPH) [Nilaparvata lugens (Stål) (Homoptera: Delphacidae)], which is a major pest of rice in Bangladesh and elsewhere. Compared to low fertilizer inputs, high fertilizer treatments induced plant growth but also favored BPH development. The BPH had higher survival, developed faster, and the intrinsic rate of natural increase (r m ) was higher on well-fertilized than under-fertilized plants. Among the fertilizer inputs, nitrogen had the strongest effect on the fitness traits of BPH. Furthermore, both the "Plant vigor hypothesis" and the "Plant stress hypothesis" were supported by the results, the former hypothesis more so than the latter. These hypotheses suggest that the most suitable/attractive hosts for insect herbivores are the most vigorous plants. Our findings emphasized that an exclusive focus on yield increases through only enhanced crop fertilization may have unforeseen, indirect, effects on crop susceptibility to pests, such as BPH.