呋塞米联合小剂量多巴胺间歇静脉泵入治疗终末期心力衰竭合并利尿剂抵抗

目的观察比较间歇微量泵静脉泵入呋塞米和多巴胺与分次静脉推注呋塞米治疗终末期心衰伴利尿剂抵抗患者的疗效。方法将56例利尿剂抵抗性心力衰竭患者随机分为两组,对照组28例患者在进行常规抗心力衰竭治疗基础上,单纯分次静脉推注呋塞米治疗;观察组28例患者在常规抗心力衰竭治疗的基础上同时给予呋塞米和多巴胺间歇静脉泵入治疗。两组患者均治疗5 d。观察治疗前后两组患者在心功能分级（NYHA）、心功能指标、肾功能、尿量和体重等方面的变化。结果与对照组比较,观察组患者心功能分级（NYHA）明显改善,LVEF增加,6 min步行试验距离延长,尿量明显增加（P均〈0.05）。结论对终末期心衰伴利尿剂抵抗的患者,间歇静脉泵入呋塞米和多巴胺治疗的疗效优于单纯静脉推注呋塞米治疗。     

Diuretika bei kardiorenalen Syndromen

Cardiorenal syndromes are well-defined diseases of the heart and kidneys and five forms can be distinguished which are divided into acute and chronic, as well as primary cardiac and primary renal forms. Triggering and predisposing factors contribute to the development of acute renal failure. Diuretics are necessary and indispensible drugs in cases of fluid overload in acute cardiorenal syndromes. In acute decompensated heart failure diuretics are recommended for the symptomatic treatment of hyperhydration. A benefit of diuretics with respect to hard endpoints (e.g. cardiovascular events and mortality) has not been demonstrated in chronic heart failure and chronic cardiorenal syndromes. Loop diuretics, thiazide diuretics, potassium-sparing diuretics and vasopressin V2 antagonist are available with varying mechanisms and sites of action. The maximum recommended dose of diuretics depends on renal function. Major side effects include electrolyte disturbances (e.g. hypokalemia, hyponatremia and hypomagnesemia), disorders of acid-base balance, increased insulin resistance and ototoxicity. The use of diuretics in cases of renal failure reduces the chance of recovery of renal function. A sequential nephron blockade and/or transient ultrafiltration or renal replacement therapy (e.g. hemodialysis and peritoneal dialysis) might be of benefit in cardiorenal syndromes and resistance to conventional treatment but evidence from controlled studies is still lacking.     

Disposition and response to bumetanide and furosemide

Bumetanide and furosemide are potent loop diuretics; the former is 40 to 50 times more potent than the latter on a weight basis. Bumetanide is absorbed more quickly than furosemide and is twice as bioavailable. Both drugs exhibit changes in elimination in the presence of renal insufficiency as well as changes in the time course of absorption in congestive heart failure. More data are needed to assess potential differences between them in various clinical conditions.     

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m² will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).     

Effect of intrarenal furosemide on renal function and intrarenal hemodynamics in acute renal failure

The ability of short-term furosemide administration to alter intrarenal hemodynamics and to modify the clinical course of acute renal failure was assessed in six patients 2 to 9 days after the onset of acute renal failure. Following renal arterial catheterization, the intraarterial administration of furosemide at a dose of 9.6 mg/min for 30 minutes failed to improve renal function as assessed either by an increase in urine output or a decrease in serum creatinine during the 4 days after administration in the five oliguric patients. In a sixth patient with nonoliguric acute renal failure, urine volume increased with a gradual decrease in blood urea nitrogen and creatinine during the week after study. Furosemide failed to alter either mean renal blood flow or its intrarenal distribution as determined at intervals of 3 to 40 minutes after its infusion. These studies demonstrate that the short-term administration of furosemide in large doses does not improve renal hemodynamics or alter the clinical course of patients with established acute oliguric renal failure.     

Drug therapy in the management of acute renal failure

Pharmacologic intervention aimed at altering the natural history of acute renal failure is a routine practice without scientific support of efficacy. Oliguria has become a separate disease entity with an apparent disregard for the underlying condition that caused it. Volume expansion is clearly beneficial in preventing many volume depleted patients from progressing to acute renal failure. While mannitol and furosemide have been used to "convert" oliguric acute renal failure to the more easy to manage non-oliguric acute renal failure, published reports suggest that responders were not as ill as non-responders. The use of dopamine to increase urine flow in patients with established acute renal failure is the current fashion, but there is little evidence that this drug raises the glomerular filtration rate or shortens the course of acute renal failure. These pharmacologic therapies increase the complexity and cost of care with little tangible evidence of benefit to the patient or the physician caring for the patient.     

Changes in Pharmacokinetics and in Effect of Furosemide in the Elderly

In this paper the general changes in the pharmacokinetics of drugs in the elderly are summarized. The suggestion is proposed, that in the case of diuretics - which act after renal excretion -the results of these changes are totally different: contrary to other drugs the standard dose of a diuretic must have less sali-uretic effect instead of more effect.

This thesis is supported by the results of experiments with furo-semide in old patients: the kinetics are changed as expected, leading to higher plasma levels and increased Area Under the (plasma level versus time) Curve (AUC), but the effects are -dependent on renal function - decreased. To a certain degree kinetics and dynamics of furosemide can be explained and predicted on the basis of simple patient parameters. If diuretics are used in old people to treat congestive heart failure, the normal adult dose has to be used, and occasionally a larger dose has to be given.     

The rational use of diuretics in the treatment of arterial hypertension.

The development of modern pharmacologic diuretic agents has revolutionized the therapy of arterial hypertension. The diuretics currently available are easily administered orally, are effective in the presence of alkalosis or acidosis, are non-toxic and have a low incidence of side effects which are readily circumvented or treated. Loop diuretics such as furosemide have the capacity to be effective in patients with diminished renal function or clinical situations that have a powerful stimulus to sodium retention. In clinical circumstances when renal potassium loss is to be prevented such as in patients receiving digitalis, the addition of a potassium-sparing diuretic to either a thiazide or furosemide will achieve the clinical goal of providing an effective diuresis while inhibiting potassium excretion. The mechanism of antihypertensive activity of the diuretic agents appears to be the reduction of extracellular fluid volumes and plasma volumes. Hence, the clinical dictum that to be effective as an antihypertensive agent, diuretics should be administered in diuretic doses. Besides being the cornerstone of initial antihypertensive therapy, diuretics also play an important role in antihypertensive therapy of patients with moderate to severe hypertension who are receiving potent antihypertensive drugs of the vasodilator or sympatholytic class of compounds. Indeed, one of the most important steps in the successful therapy of these patients receiving multiple drugs, is the re-assessment of the diuretic agent. The sodium retention and consequent fluid volume expansion associated with the administration of these potent antihypertensive agents may often cause these patients to develop apparent drug resistance since the thiazide diuretics are not potent enough to counteract the powerful stimulus to sodium retention caused by these antihypertensive agents. The re-evaluation of the diuretic agent at this point will usually necessitate the substitution of furosemide for thiazide or the doubling of the dose of the present loop diuretic. A working knowledge of the physiology of urine formation and the sites of action of currently available diuretic agents will enable the clinician to tailor the diuretic agent to the clinical circumstances of an individual patient and allow the clinician to rationally select a diuretic for the treatment of arterial hypertension.     

Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites

To investigate if lysine acetylsalicylate influences the hemodynamic and diuretic responses to furosemide in cirrhosis, 21 nonazotemic patients with ascites were studied. In 8 patients (group 1), the renal plasma flow and glomerular filtration rate were serially measured before and during three 30-min periods after the i.v. administration of lysine acetylsalicylate (450 mg). In 7 patients (group 2), renal plasma flow, glomerular filtration rate, urine volume, and sodium excretion were measured before and during three 20-min periods after the i.v. administration of furosemide (40 mg). After a 45-min period in which urinary losses were restored, a similar study was performed before and after a second injection of furosemide (40 mg). Six patients (group 3) were studied with an identical protocol as group 2, except that the second injection of furosemide was preceded by the administration of lysine acetylsalicylate (450 mg). In 6 patients of group 1, lysine acetylsalicylate caused a marked and reversible reduction of renal plasma flow and glomerular filtration rate. In groups 2 and 3, the i.v. injections of furosemide alone produced a significant increase in renal plasma flow and glomerular filtration rate, and a marked diuresis and natriuresis. In patients of group 3, pretreatment with lysine acetylsalicylate suppressed the renal hemodynamic effect and markedly reduced the diuretic effect of the second injection of furosemide. Lysine acetylsalicylate did not cause the appearance of renal insufficiency in any of these patients. These results suggest that prostaglandins are involved in the renal response to furosemide in cirrhosis with ascites and that furosemide protects these patients from developing renal insufficiency after acute administration of nonsteroidal antiinflammatory agents.     

Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites

Nonselective inhibition of cyclooxygenase (COX) by nonsteroidal anti-inflammatory drugs frequently induces renal failure in decompensated cirrhosis. Studies in experimental cirrhosis suggest that selective inhibitors of the inducible isoform COX-2 do not adversely affect renal function. However, very limited information is available on the effects of these compounds on renal function in human cirrhosis. This investigation consists of a double-blind, randomized, placebo-controlled trial aimed at comparing the effects of the selective COX-2 inhibitor celecoxib (200 mg every 12 hours for a total of 5 doses) on platelet and renal function and the renal response to furosemide (40 mg intravenously) with those of naproxen (500 mg every 12 hours for a total of 5 doses) and placebo in 28 patients with cirrhosis and ascites. A significant reduction (P < .05) in glomerular filtration rate (113 +/- 27 to 84 +/- 22 mL/min), renal plasma flow (592 +/- 158 to 429 +/- 106 mL/min) and urinary prostaglandin E(2) excretion (3430 +/- 430 to 2068 +/- 549 pg/min) and suppression of the diuretic (urine volume: 561 +/- 128 to 414 +/- 107 mL/h) and natriuretic (urine sodium: 53 +/- 13 to 34 +/- 10 mEq/h) responses to furosemide were observed in the group of patients treated with naproxen but not in the other two groups. Naproxen, but not celecoxib or placebo, significantly inhibited platelet aggregation (72% +/- 8% to 47% +/- 8%, P < .05) and thromboxane B(2) production (41 +/- 12 to 14 +/- 5 pg/mL, P < .05). In conclusion, our results indicate that short-term administration of celecoxib does not impair platelet and renal function and the response to diuretics in decompensated cirrhosis. Further studies are needed to evaluate the long-term safety of this drug in cirrhosis.     

How to use diuretics in heart failure

Systemic and pulmonary congestion is a central aspect of both acute and chronic heart failure and directly leads to many of the clinical manifestations of these syndromes. Therefore, diuretic therapy to treat congestion plays a fundamental role in heart failure management. However, although diuretics are the most common drugs prescribed for heart failure, there is limited quality evidence to guide their use. Unlike other components of the heart failure armamentarium, such as β-blockers and angiotensin-converting enzyme inhibitors, diuretics (with the exception of aldosterone antagonists) have not been shown to decrease heart failure progression or improve mortality. Additionally, some observational data suggest that diuretics may actually be harmful in heart failure, contributing to neurohormonal activation, renal dysfunction, and potentially mortality. Despite these concerns, diuretics remain ubiquitous in heart failure management because of the need to address symptoms of congestion and the lack of alternative strategies. Recently, the development of a variety of potential adjuncts or alternatives to diuretic therapy has suggested the need for an active reappraisal of diuretic therapy for heart failure. The main classes of diuretics are the loop diuretics, potassium-sparing diuretics, and thiazides. Loop diuretics, the mainstay of acute and chronic therapy for heart failure, are “threshold drugs”; therefore, an adequate dose to achieve a pharmacodynamic effect (ie, to increase urine output) must be prescribed for effective therapy. The minimum dose to achieve diuresis and manage congestion should be used to minimize adverse effects. For patients refractory to initial dosing of intravenous diuretics, options include dose escalation, use of continuous infusion rather than intermittent boluses, or combination therapy with the addition of a thiazide or thiazide-like diuretic (eg, metolazone). Management of chronic heart failure often includes patient-directed titration of diuretics based on changes in symptoms or body weight in an attempt to decrease hospitalizations, although the efficacy of this strategy has not been tested in well-designed trials. Aldosterone antagonists, which are used primarily as neurohormonal agents rather than for their diuretic effects, are indicated for patients with systolic failure and moderate to severe symptoms, as long as renal function and serum potassium are stable and monitored closely. All diuretic therapy requires careful monitoring of electrolytes and renal function. Whether newer modalities for managing congestion (vasopressin antagonists, adenosine A1 antagonists, and ultrafiltration therapy) will be an improvement over diuretic therapy will be determined by the results of multiple ongoing clinical trials.     

The aldosterone antagonist and facultative diuretic eplerenone: A critical review

Eplerenone is a new aldosterone-receptor blocker that differs from spironolactone by virtue of higher selectivity for the aldosterone receptor. Therefore, eplerenone treatment is associated with comparative and absolute low incidences of gynecomastia, mastodynia, and abnormal vaginal bleeding. Similarly, a lower incidence of sexual impotence than that associated with spironolactone administration may be anticipated. Eplerenone and spironolactone increase natriuresis and cause renal retention of potassium when plasma aldosterone is high, i.e., both agents are facultative diuretics. Eplerenone reduces high blood pressure effectively. The results of a recent large study and an ensuing meta-analysis on antihypertensive treatment suggest that a diuretic should be the first-choice agent in most circumstances. Low-dose eplerenone combinations with a low-dose thiazide-type diuretic appear to be options worth investigating, since the overall cardiovascular benefit brought about by reducing blood pressure with the thiazide would be increased, inter alia, by the antikaliuretic action and by the blockade of extrarenal aldosterone receptors provoked by eplerenone. Eplerenone should replace spironolactone as a natriuretic and antikaliuretic in heart failure and as add-on treatment in severe systolic cardiac insufficiency, and it is indicated after an acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The finding that hypertension control with diuretic-based pharmacotherapy results in better prevention of heart failure than pressure reduction with other drugs makes it pertinent to investigate whether diuretics in general, and eplerenone in particular, should constitute part of the initial pharmacotherapy for heart failure when there is no overt fluid retention and independent of the etiology. Eplerenone may cause hyperkalemia, and it might favor the development of metabolic acidosis or hyponatraemia in some circumstances.     

The aldosterone antagonist and facultative diuretic eplerenone: a critical review

Eplerenone is a new aldosterone-receptor blocker that differs from spironolactone by virtue of higher selectivity for the aldosterone receptor. Therefore, eplerenone treatment is associated with comparative and absolute low incidences of gynecomastia, mastodynia, and abnormal vaginal bleeding. Similarly, a lower incidence of sexual impotence than that associated with spironolactone administration may be anticipated. Eplerenone and spironolactone increase natriuresis and cause renal retention of potassium when plasma aldosterone is high, i.e., both agents are facultative diuretics. Eplerenone reduces high blood pressure effectively. The results of a recent large study and an ensuing meta-analysis on antihypertensive treatment suggest that a diuretic should be the first-choice agent in most circumstances. Low-dose eplerenone combinations with a low-dose thiazide-type diuretic appear to be options worth investigating, since the overall cardiovascular benefit brought about by reducing blood pressure with the thiazide would be increased, inter alia, by the antikaliuretic action and by the blockade of extrarenal aldosterone receptors provoked by eplerenone. Eplerenone should replace spironolactone as a natriuretic and antikaliuretic in heart failure and as add-on treatment in severe systolic cardiac insufficiency, and it is indicated after an acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The finding that hypertension control with diuretic-based pharmacotherapy results in better prevention of heart failure than pressure reduction with other drugs makes it pertinent to investigate whether diuretics in general, and eplerenone in particular, should constitute part of the initial pharmacotherapy for heart failure when there is no overt fluid retention and independent of the etiology. Eplerenone may cause hyperkalemia, and it might favor the development of metabolic acidosis or hyponatraemia in some circumstances.     

An approach to the treatment of hypertension in the aged.

Because of the multiplicity of disease conditions and diminished tolerance for drugs in the aged, it is necessary to know concomitant pathologic conditions to determine which antihypertensive drug to use. In the Philadelphia Geriatric Center, there are about 1,000 residents, between 70 and 100 years of age. About 40% have hypertension; almost 50% have or once had depression; there are many cases of hiatal hernia and/or peptic ulcer; in one subdivision of residents, almost 40% have renal disease with BUN above 30 mg/100 ml. In antihypertensive treatment, some individuals respond fairly well to reassurance and weight reduction, when obese, even without drugs. All are given a low-salt diet. A diuretic is first used--thiazide in cases of good renal function, furosemide with impaired renal function. Liquid potassium supplements are given. If there is but little reduction in blood pressure in several weeks, methyldopa is added in ascending doses, in cases with or without renal impairment. In hypertension with impaired renal function, furosemide and/or methyldopa were especially valuable. Furosemide as an antihypertensive drug was also noted to delay the onset of congestive heart failure. Since reserpine can aggravate peptic ulcer and can precipitate or aggravate depression, it should seldom be used to treat hypertension in the aged. Guanethidine is rarely used, since it can cause cerebrovascular insufficiency and marked weakness. High blood pressure should be reduced slowly in the aged, to avoid untoward effects.     

Diuretic usage for protection against end‐organ damage in liver cirrhosis and heart failure

Volume overload is common in liver cirrhosis, heart failure, and chronic kidney disease, being an independent risk factor for mortality. Loop diuretics have been widely used for treating volume overload in these patients. However, there is a tendency to increase the dose of loop diuretics partly because of diuresis resistance. Neurohormonal factors are also enhanced in these patients, which play a role in volume overload and organ ischemia. Loop diuretics cannot improve neurohormonal factors and could result in end‐organ damage. The water diuretic tolvaptan has been approved for use for volume overload in heart failure and liver cirrhosis. Despite causing similar increases in urine volume, its characteristics differ from those of loop diuretics. Renal blood flow is maintained with tolvaptan but decreased with furosemide in heart failure patients. Neurohormonal factors and blood pressure are not markedly altered by tolvaptan administration. It is expected that these mechanisms of tolvaptan can protect against worsening renal function by volume overload diseases compared with loop diuretics. It has also been reported that some patients do not respond well to tolvaptan. Loop diuretics and tolvaptan share the same mechanism with regard to decreasing renal interstitial osmolality, which plays a fundamental role in water diuresis. Thus, a high dose of loop diuretics could result in resistance to tolvaptan, so tolvaptan should be administered before increasing the loop diuretic dose. Therefore, volume control without enhancing end‐organ damage can be achieved by adding tolvaptan to a tolerable dose of Na‐sparing diuretics.     

Hypertension and stenosis of the graft artery: effects of conversion enzyme inhibition

The use of angiotensin converting enzyme inhibitors may lead to reversible renal insufficiency in transplant patients with transplant renal artery stenosis (TRAS). We assessed acute effects of captopril (50 mg, p. os) in 7 cadaver kidney recipients (mean age: 35.6 +/- 4 yrs) with TRAS, 9 to 46 mo after transplantation. All patients were treated by prednisolone and azathioprine. After captopril administration, mean arterial pressure decreased from 127 +/- 6 to 119 +/- 7 mmHg, effective renal plasma flow from 152 +/- 19 to 118 +/- 19 ml/min/1.73 m2, glomerular filtration rate from 59 +/- 8 to 39 +/- 10 ml/min/1.73 m2 and filtration fraction from 0.39 +/- 0.02 to 0.32 +/- 0.07. Among the 7 patients, 2 developed immediate and transient anuria; 4 presented a net decrease of GFR, only one had stable GFR. This patient was chronically treated by captopril; as BP was not controlled, furosemide (40 mg p. os) was added. Serum creatinine increased from 180 to 250 mumol/l. Percutaneous angioplasty was done without decrease in BP; however, treatment by captopril and furosemide could be reinstitued without deterioration in renal function. We conclude that: acute renal failure in kidney graft recipients with TRAS is frequent, but not mandatory; sodium depletion induced by diuretics enhances the fall in GFR; acute effect of captopril must be assessed in patients with TRAS before the use of this product as long term antihypertensive treatment.     

Diuretics in postinfarction heart failure

Summary Severe left ventricular failure, as evidenced by radiographic pulmonary edema or raised left ventricular filling pressure, accompanying acute myocardial infarction, carries a high mortality risk. In this situation, the intravenous loopdiuretic furosemide induces a rapid reduction in the raised left ventricular filling pressure due to an immediate and substantial increase in systemic venous compliance accompanied by increasing diuresis. This diuretic-induced venodilatation is probably due to the release of prostaglandins. The transient systemic arterial constriction and small increase in systemic blood pressure that follows intravenous furosemide probably results from the release of renin and subsequent activation of angiotensin. These diuretic induced hemodynamic changes are accompanied by restoration of the vasodilator reflex, which enables the heart to accommodate an acute volume load. Orally administered loop diuretics achieve slower, but similar, directional hemodynamic changes. There is no information on hemodynamic or neuroendocrine dose-response effects of loop diuretics, and there is no information pertaining to the use of other diuretic groups in this situation. The hemodynamic changes induced by furosemide summate with the changes induced by other anti-heart-failure drugs. In this subset of patients with acute myocardial infarction and severe heart failure, the influence of the diuretics on morbidity incidence and mortality risk remains to be measured.     

Diuretic Dosing in Acute Decompensated Heart Failure: Lessons from DOSE

The mainstay of treatment for acute decompensated heart failure (ADHF) is intravenous (IV) diuretic therapy either as a bolus or via continuous infusion. Despite being available for decades, few randomized trials exist to guide dosing and administration of these drugs. In 2011, the Diuretic Optimization Strategies Evaluation (DOSE) trial used a prospective, randomized design to compare bolus versus continuous infusion of IV furosemide, as well as high-dose versus low-dose therapy. The study found no difference in the primary end point for continuous versus bolus infusion. High-dose diuretics were more effective than low dose without clinically important negative effects on renal function. Although limited by patient selection criteria and protocol design, the study challenges long-held beliefs that continuous infusion is more effective than bolus dosing. The study also challenges the notion that high-dose diuretics carry clinically important renal toxicity risks for patients.     

Effective Use of Loop Diuretics in Heart Failure Exacerbation: A Nephrologist's View

Unfortunately, patients with congestive heart failure suffer frequent admissions for the management of fluid overload. Loop diuretics are pivotal in the management of this common clinical problem. Although loop diuretics have been in clinical use since the 1960s, we still do not understand how to optimally administer these drugs. It is unknown why some decompensated heart failure patients exhibit improvements in renal function with diuresis, whereas others display renal function deterioration, limiting attainment of euvolemia. Here the physiologic interactions between the failing heart and kidneys are reviewed. A conceptual framework is presented that emphasizes the balance between tubuloglomerular feedback and venous congestion in determining renal function during loop diuretic use in heart failure. within this framework, guidelines are derived that seek to maximize the chance for achieving adequate volume removal while maintaining stable or improved renal function during the treatment of acute decompensated heart failure.