Loop Diuretic Therapy Research Articles

Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

BackgroundType 2 diabetes and the metabolic syndrome are associated with impaired diastolic function and increased heart failure risk. Animal models and autopsy studies of diabetic patients implicate myocardial fibrosis, cardiomyocyte hypertrophy, altered myocardial microvascular structure and advanced glycation end-products (AGEs) in the pathogenesis of diabetic cardiomyopathy. We investigated whether type 2 diabetes and the metabolic syndrome are associated with altered myocardial structure, microvasculature, and expression of AGEs and receptor for AGEs (RAGE) in men with coronary artery disease.MethodsWe performed histological analysis of left ventricular biopsies from 13 control, 10 diabetic and 23 metabolic syndrome men undergoing coronary artery bypass graft surgery who did not have heart failure or atrial fibrillation, had not received loop diuretic therapy, and did not have evidence of previous myocardial infarction.ResultsAll three patient groups had similar extent of coronary artery disease and clinical characteristics, apart from differences in metabolic parameters. Diabetic and metabolic syndrome patients had higher pulmonary capillary wedge pressure than controls, and diabetic patients had reduced mitral diastolic peak velocity of the septal mitral annulus (E'), consistent with impaired diastolic function. Neither diabetic nor metabolic syndrome patients had increased myocardial interstitial fibrosis (picrosirius red), or increased immunostaining for collagen I and III, the AGE Nε-(carboxymethyl)lysine, or RAGE. Cardiomyocyte width, capillary length density, diffusion radius, and arteriolar dimensions did not differ between the three patient groups, whereas diabetic and metabolic syndrome patients had reduced perivascular fibrosis.ConclusionsImpaired diastolic function of type 2 diabetic and metabolic syndrome patients was not dependent on increased myocardial fibrosis, cardiomyocyte hypertrophy, alteration of the myocardial microvascular structure, or increased myocardial expression of Nε-(carboxymethyl)lysine or RAGE. These findings suggest that the increased myocardial fibrosis and AGE expression, cardiomyocyte hypertrophy, and altered microvasculature structure described in diabetic heart disease were a consequence, rather than an initiating cause, of cardiac dysfunction.

Loop diuretic therapy in left ventricular systolic dysfunction: has familiarity bred contempt for a critical but potentially nephrotoxic cardio renal therapy?

Loop diuretic therapy in left ventricular systolic dysfunction: has familiarity bred contempt for a critical but potentially nephrotoxic cardio renal therapy?

Loop Diuretic Therapy in Heart Failure: The Need for Solid Evidence on a Fluid Issue

Heart failure (HF) is a common condition associated with substantial cost, morbidity, and mortality. Because results of clinical trials in the acute decompensated heart failure (ADHF) setting have been mostly neutral, loop diuretics remain the mainstay of treatment. Loop diuretic use may be associated with unfavorable outcomes. A MEDLINE literature search was performed to identify articles relating to heart failure and loop diuretics. The current evidence on the risks and benefits of loop diuretics for the treatment of ADHF is reviewed. Loop diuretics are associated with symptomatic improvements in congestion, urine output, and body weight, but have shown no long-term mortality benefit. Loop diuretics, especially at high doses, are associated with worsened renal function and other poor outcomes. Loop diuretics still prove useful in HF treatment, but risk-benefit analysis of these agents in the treatment of ADHF requires a well-designed prospective study.

Hyponatremia in Heart Failure: Revisiting Pathophysiology and Therapeutic Strategies

Hyponatremia is frequently encountered in patients with heart failure (HF), and its association with adverse outcomes is well-established in this population. While hyponatremia is an independent marker for severity of HF, it is not certain whether it has a causal impact on the progression of the disease. There are no universally accepted consensus guidelines regarding therapeutic strategies for HF-associated hyponatremia and volume overload; current societal guidelines do not address management of this complication. Whereas thiazide diuretics are known to induce or worsen hyponatremia in this setting through a number of mechanisms, loop diuretics can be considered a readily available first-line pharmacologic therapy. Consistent with pathophysiology of the disease and mechanisms of action of loop diuretics, available clinical evidence supports such an approach provided that patients can be closely monitored. Use of vasopressin receptor antagonists is an emerging therapeutic strategy in this setting, and the efficacy of these agents has so far been shown in a number of clinical studies. These agents can be reserved for patients with HF in whom initial appropriate loop diuretic therapy fails to improve serum sodium levels.

Loop Diuretics in Acute Decompensated Heart Failure

Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Most hospitalizations for ADHF are related to symptoms of congestion, and the vast majority of ADHF patients are treated with intravenous loop diuretics. Despite this nearly ubiquitous use, data supporting the safety and efficacy of loop diuretics in ADHF are limited, and controversy exists about the best way to use loop diuretics with regard to both dosing and means of administration (continuous infusion vs. intermittent boluses). We reviewed the data supporting the safety and efficacy of loop diuretics in patients with ADHF. A large body of observational literature suggests that loop diuretics, especially at higher doses, may be associated with increased mortality in patients with heart failure even after detailed adjustment for other measures of disease severity. Additionally, multiple small underpowered trials suggest that continuous infusion may be equivalent or superior to intermittent bolus dosing. In summary, there is a critical need to develop more robust data on the use of loop diuretics in ADHF. In that context, the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF. The DOSE study will randomize patients using a 2 × 2 factorial design to low dose vs. high dose furosemide, and intermittent bolus vs. continuous infusion. Successful completion of the DOSE study will provide important data on the optimal clinical use of loop diuretics in ADHF.

Habitual Dietary Intake among Stable Heart Failure Patients: Identification of Widespread Nutritional Inadequacies

Objective: Dietary counseling for HF patients primarily focuses on sodium restriction. HF patients may also have altered nutrient requirements occuring with chronic loop diuretic (LD) therapy, which increases renal losses potassium, thiamin, calcium, and magnesium. No studies have comprehensively evaluated dietary intake in a large group of stable HF patients with a relevant control group. We hypothesized that intake would differ between HF patients and controls, and between HF patients based on LD usage.

Management of constrictive pericarditic in the 21st century

Definitive treatment for constrictive pericarditis is surgical pericardiectomy. Because constriction may be transient in a small proportion of patients, particularly those with exudative effusions, the initial treatment for constrictive pericarditis should be conservative, with loop diuretic therapy to manage volume expansion and edema and the use of colchicine, nonsteroidal anti-inflammatory agents, or, if necessary, glucocorticoid therapy for active inflammation. For subjects with persisting evidence of constriction, symptomatic management is advised for those with only minimal symptoms. Surgical pericardiectomy is advised for subjects with New York Heart Association class II or III symptoms and persisting evidence of constriction at echocardiography and cardiac catheterization and with associated pericardial abnormality on CT or MRI. Complete resection of the pericardium and, where possible, the diseased epicardium via a midline sternotomy is the favored approach, although a video-assisted thoracoscopic approach may be suitable in some subjects. Lateral thoracotomy should be used for suppurative pericarditis to avoid sternal infection. Because of higher mortality, increased complication rates, and suboptimal clinical outcomes, pericardiectomy should be avoided in older patients or those with radiation-induced disease, very advanced symptoms, or evidence of myocardial fibrosis.

Potassium and magnesium depletions in congestive heart failure--pathophysiology, consequences and replenishment.

Congestive heart failure (CHF) is becoming more frequent worldwide. Both potassium (K) and magnesium (Mg) deficiencies are common and can be associated with risk factors and complications of heart failure (HF). The major causes of K and Mg depletions are the effects of compensatory neuroendocrine mechanisms (activation of the renin-angiotensin-aldosterone and sympathoadrenergic systems), digoxin therapy, and administration of thiazide or loop diuretic therapy in CHF. Particular attention should be paid to K and Mg restoration in CHF, because of the consequences of both deficiencies (increased arrhythmic risk, vasoconstriction), and the co-supplementation of both ions is necessary in order to achieve K repletion. Mg and K should be employed as first-line therapy in digitalis intoxication and drug-related arrhythmias, and should be considered an important adjuvant therapy in diuretic treated patients with CHF. Another possibility to restore normal K and Mg status is usage of a K, Mg sparing diuretics.

Serum uric acid levels as a predictor of in-hospital death in patients hospitalized for decompensated heart failure

Objectives — The aim of this study was to determine the value of serum uric acid levels in predicting in-hospital mortality of chronic heart failure patients hospitalized for decompensation in spite of appropriate medical therapy.Methods and results — This study was conducted in patients who were admitted to our clinic between January 2003 and April 2004 due to decompensated heart failure. Only patients who had a functional capacity of class IV and who already received loop diuretic and ACE inhibitor therapy before their admission were included. Patients with recurrent admissions during this period were excluded. Eighty-five patients fulfilled these criteria: group I consisted of 25 patients who died during hospitalization whereas group II consisted of 60 patients who were discharged alive after treatment. Age, sex, left ventricular ejection fraction derived from 2-D echocardiography, serum sodium (Na), gamma-glutamyl transpeptidase (GGT), creatinine, uric acid levels, white blood cell counts and drugs used on admission were the selected parameters as predictors of in-hospital mortality in these patients.When stepwise logistic regression analysis was used, female sex and serum uric acid levels at admission appear to be the only predictors of death during that hospitalization independent of other variables.Conclusions — Serum uric acid levels may be used as a predictor of death in hospitalized heart failure patients with class IV symptoms.

Role of vasopressin antagonists in the management of acute decompensated heart failure

Vasopressin antagonists are a class of neurohormonal antagonists with applications in both the short-term and long-term management of patients with acute decompensated heart failure (ADHF). The pharmacologic effects of vasopressin antagonists include changes in fluid balance and hemodynamics that may improve symptoms and outcomes in patients hospitalized with ADHF. With chronic therapy, vasopressin antagonists offer the potential to improve outcomes through a variety of mechanisms, including more effective treatment of congestion, preservation or improvement of renal function, or a reduction in the use of concomitant loop diuretic therapy. Several vasopressin antagonists are currently in advanced clinical trials for the treatment of ADHF, chronic stable heart failure, and hyponatremia.

Pharmacology Review

After completing this article, readers should be able to: 1. Review the actions of the diuretic agents commonly used in neonates. 2. Delineate the adverse effects of diuretic therapy. 3. Determine the roles of diuretics in therapy. Diuretics represent one of the most common classes of drugs administered to sick neonates and infants. Unwanted fluid retention arising from myriad neonatal disorders can and does complicate the optimal care of sick infants. To appreciate the many factors that influence a patient’s response to diuretic therapy and clinical and laboratory monitoring, we direct readers to the article “The Ontogeny of Human Kidney Development: Influence on Neonatal Diuretic Therapy” in this issue. All the clinically relevant diuretics, with the exception of aldosterone receptor antagonists (eg, spironolactone), must achieve sufficient free drug concentrations within the renal tubular lumen to reach their sites of action. Thus, diuretic effectiveness ultimately is guided by the functional capacity of the kidney, which clearly is influenced by infants’ gestational and postnatal ages. This article addresses the most common diuretics used in the neonate and young infant, focusing on the pharmacokinetic and pharmacodynamic characteristics of each drug relative to the infant’s postconceptional age and other factors that influence the infant’s overall response to therapy. ### “Loop” or “High Ceiling” Diuretics All diuretics, with the exception of spironolactone, must reach the renal tubular lumen to exert their pharmacologic effect. A lower renal blood flow (RBF) in preterm infants reduces the amount of drug delivered to the kidney, potentially limiting diuretic effectiveness. Highly protein-bound, loop diuretics (Table 1) are filtered minimally at the glomerulus. Instead, these agents are carried to the proximal tubule where they are actively secreted into the lumen via the organic acid transport pump. Luminal flow then carries the loop diuretics to their sites of action. | Loop Diuretics | || | •Bumetanide | | •Furosemide | | •Torsemide | | Thiazide Diuretics | | •Chlorothiazide | | •Chlorthalidone | | •Hydrochlorothiazide | | •Indapamide | | •Metolazone | | Aldosterone Antagonists | | •Eplerenone | | •Spironolactone | Table 1. Commonly Used Diuretic Drugs in Preterm and Newborn Infants Loop diuretics bind …

Diuretic withdrawal in CHF patients on optimal medical therapy

Effective management of congestive heart failure (CHF) requires modulation and control of the neurohormonal systems of the body. The cornerstone of CHF therapy includes angiotensin converting enzyme inhibition (ACE-I), beta blockade (BB) of sympathetic nervous system and blockade of renin-aldosterone system. It has been shown that patients treated with these therapies are much less prone to exacerbation of CHF. Another aspect in CHF management is that of fluid/volume control, which is achieved by sodium and fluid restriction and administration of diuretic therapy. Although diuretic therapy is effective in controlling volume overload, it can lead to volume depletion, activation of the renin-angiotensin system and contribute to the polypharmacy of CHF therapy. It was our hypothesis that it is clinically feasible to gradually withdraw loop diuretics from CHF patients who do not demonstrate volume overload and are treated with optimal medical therapy. Fifteen consecutive patients with left ventricular systolic dysfunction (mean age 71years, mean ejection fraction 27%, males 47%, ischemic cardiomyopathy 47%) who did not demonstrate volume overload and who were on therapeutic doses of ACE-I and BB had their loop diuretics (mean furosemide 42.7 mg QD with range of 20–80 mg QD) gradually withdrawn. The study cohort received comprehensive education related to recommendations for daily weight monitoring, dietary sodium and fluid restrictions, and sliding scale guidelines for diuretic adjustments. They were followed for evidence of fluid retention requiring re-initiation of diuretic therapy or hospitalization. At the conclusion of the six month study period, six patients (40%) had discontinued their furosemide, three patients (20%) required PRN diuretic admininistration (less than one dose per week) and five patients (33%) had the daily furosemide requirement reduced by one-half. One patient required hospitalization for exacerbation of CHF and re-initiation of daily loop diuretic therapy. Conclusion: Loop diuretics can be safely withdrawn from euvolemic CHF patients who are treated on optimal medical therapy.

Furosemide responsiveness, non-adherence and resistance during the chronic treatment of heart failure: a longitudinal study.

Loop diuretic therapy is an essential part of chronic systolic heart failure (CH)F management, yet response to treatment can be variable. We analysed diuretic responsiveness in 39 stable patients with CHF in the community over 2 years. We measured serum ACE as a marker of adherence to ACE inhibitor therapy and urinary furosemide as a marker of diuretic adherence and action. Patients' clinical outcome was stable and not hospitalized (Group 0); alive but hospitalized (Group 1); or dead during follow up (Group 2). Prescribed furosemide dose was variable (range 20-370 mg generally once daily) and progressive dose increments were common. Failed furosemide adherence (defined as < 10% of a dose excreted in 24 h urine where normal average excretion = 50% of an oral dose) during static prescribed dosing was infrequent relative to all days of therapy; yet was equally common across all outcome groups. Furosemide non-adherence appeared to be independent of non-adherence with ACE inhibitor (as marked by serum ACE activity > 20 U l(-1)) treatment. Furosemide responsiveness (mm of sodium excreted per mg furosemide in urine) showed no relationship to prescribed dose and paradoxically tended to rise in patients with higher basal aldosterone concentrations. Furosemide responsiveness fell by outcome class despite increased dose. Within-patient responsiveness remained relatively constant although highly variable between individuals. Furosemide responsiveness varied greatly between individuals but was constant within an individual. Non-adherence with furosemide was less common among those who died and appeared to occur at different time points from non-adherence with ACE inhibitor treatment, which was slightly more common in all outcome groups. Patients who died were prescribed higher furosemide doses and had greater furosemide excretion yet had similar sodium excretion. The main factor in response to chronic furosemide therapy was intrarenal diuretic resistance. Gross non-adherence was less important.

Tolvaptan (OPC-41061), a V 2 vasopressin receptor antagonist, protects against the decline in renal function observed with loop diuretic therapy

Tolvaptan (OPC-41061), a V 2 vasopressin receptor antagonist, protects against the decline in renal function observed with loop diuretic therapy

Metolazone and Its Role in Edema Management

Metolazone is commonly administered in conjunction with a loop diuretic to manage volume overload in patients otherwise resistant to loop diuretic therapy alone. Metolazone is a thiazide-type diuretic that is characterized by slow and sometimes erratic absorption when administered as the Zaroxylyn product. This absorptive profile together with the large volume of distribution and high degree of renal clearance for metolazone provide the pharmacologic basis for a favorable diuretic combination effect. Zaroxylyn should always be administered cautiously and only with a means of surveillance allowing the patient's weight to be carefully monitored so as to avoid excessive diuresis. If an excessive diuresis occurs with a metolazone and loop diuretic combination both drugs should be stopped temporarily. The temptation should be avoided to simply reduce the doses of either metolazone or the loop diuretic as a means to controlling an active diuresis.

Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload.

BackgroundIcodextrin is a high molecular weight, starch-derived glucose polymer, which is capable of inducing sustained ultrafiltration over prolonged (12–16 hour) peritoneal dialysis (PD) dwells. The aim of this study was to evaluate the ability of icodextrin to alleviate refractory, symptomatic fluid overload and prolong technique survival in PD patients.MethodsA prospective, open-label, pre-test/post-test study was conducted in 17 PD patients (8 females/9 males, mean age 56.8 ± 2.9 years) who were on the verge of being transferred to haemodialysis because of symptomatic fluid retention that was refractory to fluid restriction, loop diuretic therapy, hypertonic glucose exchanges and dwell time optimisation. One icodextrin exchange (2.5 L 7.5%, 12-hour dwell) was substituted for a long-dwell glucose exchange each day.ResultsIcodextrin significantly increased peritoneal ultrafiltration (885 ± 210 ml to 1454 ± 215 ml, p < 0.05) and reduced mean arterial pressure (106 ± 4 to 96 ± 4 mmHg, p < 0.05), but did not affect weight, plasma albumin concentration, haemoglobin levels or dialysate:plasma creatinine ratio. Diabetic patients (n = 12) also experienced improved glycaemic control (haemoglobin Alc decreased from 8.9 ± 0.7% to 7.9 ± 0.7%, p < 0.05). Overall PD technique survival was prolonged by a mean of 11.6 months (95% CI 6.0–17.3 months). On multivariate Cox proportional hazards analysis, extension of technique survival by icodextrin was only significantly predicted by baseline net daily peritoneal ultrafiltration (adjusted HR 2.52, 95% CI 1.13–5.62, p < 0.05).ConclusionsIcodextrin significantly improved peritoneal ultrafiltration and extended technique survival in PD patients with symptomatic fluid overload, especially those who had substantially impaired peritoneal ultrafiltration.

Management of Adult Heart Failure: Bolus versus Continuous Infusion Loop Diuretics, A Review of the Literature

In an aging population, decompensated heart failure accounts for a significant number of hospital admissions. The standard management for edema and congestion associated with heart failure is loop diuretic therapy. Traditionally, bolus-dosed furosemide has been used to manage the edema and congestion associated with heart failure. However, diuretic resistance can occur with bolus dosing, resulting in inadequate diuresis and further hemodynamic instability. Based on current literature, furosemide given by continuous infusion may now be the preferred agent and route for diuretic refractory heart failure. This article reviews the literature that compares bolus versus continuous infusion loop diuretics in adult heart failure.

HEART FAILURE COMPLICATING ACUTE MYOCARDIAL INFARCTION

Older people with congestive heart failure associated with acute myocardial infarction should be treated with loop diuretic therapy. Class I indications for the use of early intravenous beta blockade in patients with acute myocardial infarction are patients without a contraindication to beta blockers who can be treated within 12 hours of onset of myocardial infarction; patients with continuing or recurrent ischemic pain; and patients with tachyarrythmias, such as atrial fibrillation with a rapid ventricular rate. Class I indications for the use of angiotensin-converting enzyme inhibitors during acute myocardial infarction are (1) patients within the first 24 hours of onset of a suspected acute myocardial infarction with ST segment elevation in two or more anterior precordial leads or with clinical heart failure in the absence of significant hypotension or contraindications to the use of angiotensin-converting enzyme inhibitors, (2) patients with myocardial infarction and a left ventricular ejection fraction of less then 40%, (3) and patients with clinical heart failure on the basis of systolic pump dysfunction during and after convalescence from acute myocardial infarction. No class I indications exist for using calcium channel blockers or magnesium during acute myocardial infarction.

Evaluation of ACE Inhibitor Therapy for Congestive Heart Failure in an Outpatient Setting

Objective: Angiotensin-converting enzyme (ACE) inhibitor therapy is considered the standard of care for the treatment of congestive heart failure. Despite this, clinical experience suggests that not all patients may be receiving ACE inhibitor therapy or may be receiving low dosages. This study was performed to better understand the use of ACE inhibitor therapy in clinical practice. Design and Participants: We reviewed the medical therapy of 110 patients with a history of congestive heart failure referred to an outpatient heart failure clinic at a university teaching hospital. Outcome Measures: This observational study evaluated the use of ACE inhibitors, including dosage, as well as other drugs to treat congestive heart failure. Results: Approximately 85% (93/110) of patients were receiving an ACE inhibitor. Twenty percent (22/110) were receiving enalapril 20 mg/d or more, captopril 150 mg/d or more, lisinopril 20 mg/d or more, or quinapril 40 mg/d or more. The remaining patients (n = 71) were receiving these drugs at lower dosages. However, 21 of the remaining patients (19% of all patients) were receiving lower dosages based on patient-specific parameters; 47 of the remaining patients (43% of all patients) were eligible to have their dosage increased. Ten eligible patients were not receiving an ACE inhibitor. The majority of patients were also receiving digoxin (70%) and loop diuretic (80%) therapy. Conclusions: Approximately 85% of patients were receiving ACE inhibitor therapy, with 9% of eligible patients not receiving an ACE inhibitor. In the patients receiving ACE inhibitor therapy, approximately 50% (47/93) were receiving dosages below those suggested in the guidelines. Overall, the use of ACE inhibitor therapy is varied and intervention appears required to ensure that all patients receive appropriate therapy for the treatment of congestive heart failure.

Thiamin Status, Diuretic Medications, and the Management of Congestive Heart Failure

Objective To assess the prevalence of thiamin deficiency in patients with congestive heart failure who are treated with diuretics that inhibit sodium and chloride reabsorption in the thick ascending limb of the loop of Henle (loop diuretic therapy). Design A cross-sectional investigation of thiamin status of consecutive patients with congestive heart failure being treated with loop diuretic therapy. Setting Cardiology clinic of a midwestern tertiary-care medical center. Subjects Thirty-eight patients were recruited (mean age±standard deviation=55±14 years). Validation of methodology was conducted with nine age-matched control subjects. Main outcome measures Thiamin status was assessed biochemically by in vitro erythrocyte transketolase activity assay. Assessment of dietary intake of thiamin was accomplished with a semiquantitative food frequency questionnaire. Statistical analyses performed Fisher's exact test and logistic regression were used to evaluate relationships between thiamin status and variables of interest. Results Biochemical evidence of thiamin deficiency was found in 8 of 38 (21%) patients. Evidence of risk for dietary thiamin inadequacy was found in 10 of 38 patients (25%). Seven of the 8 patients with biochemical evidence of thiamin deficiency met study criteria for dietary adequacy, although quantified data suggested that only 4 of the patients achieved two thirds of the Recommended Dietary Allowance. Biochemical evidence of thiamin deficiency tended to be more common among patients with poor left ventricular ejection fractions ( P=.07). Conclusions Thiamin deficiency may occur in a substantial proportion of patients with congestive heart failure, and dietary inadequacy may contribute to increased risk. J Am DietAssoc. 1995; 95:541-544.