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Effectiveness of continuous infusions of loop diuretics for severe heart failure.

Heart failure is a growing worldwide epidemic resulting in frequent hospitalizations and increased resource utilization. A major cause of hospitalization is congestive symptoms and impaired functional capacity due to sodium and water retention. Diuretic resistance, which is common among patients with severe heart failure, may inhibit diuresis, thus prolonging hospitalizations. The current evidence suggests that continuous infusions are a potentially effective method for delivering high daily doses of diuretics and rapidly removing large amounts of excess sodium and water. In our experience, continuous intravenous infusions of furosemide are well tolerated and may shorten hospitalizations, which in turn reduces overall costs. Although the current evidence is largely limited to observational reports and small uncontrolled studies, the consistent findings of efficacy and safety warrant the further investigation of this treatment strategy in randomized controlled trials.

Diuretics↗

Norepinephrine-induced diuresis in chronically ethanol-treated rats.

Previous research from this laboratory indicated that noradrenergic mechanisms might mediate ethanol diuresis. Experiments described here examined changes in sensitivity of noradrenergic mechanisms in animals chronically treated with ethanol. Norepinephrine hydrochloride (0-12 micrograms intracerebroventricularly) produced dose-dependent diuresis in control (dextrin maltose) and ethanol (8-11 g/kg/day) treated rats on the first day of treatment. Tolerance to ethanol diuresis was present after 10 days of ethanol treatment. Lack of responsiveness to norepinephrine-induced diuresis was evident only on the 20th day of treatment in both the ethanol and dextrin-maltose groups of rats. These results indicate a temporal dissociation between the tolerance to ethanol-induced and norepinephrine-induced diuresis and suggest that norepinephrine may not play a primary role in the development of tolerance to the diuretic action of ethanol.

Animals↗

The effect of muzolimine on the tubuloglomerular feedback mechanism in the rat kidney.

Inhibition of tubuloglomerular feedback (TGF) by loop diuretics can enhance the diuretic response by attenuating the fall in GFR to be expected with the diuretic-induced rise in distal salt delivery. To establish whether such a mechanism contributes to muzolimine (M)-induced diuresis, TGF activity was tested in male Wistar rats by measuring early proximal flow rate in nephrons, the loops of Henle of which were perfused with M at various concentrations in the presence or absence of M systemically. Since M inhibited TGF only at concentrations far in excess of those adequate to produce substantial diuresis, it is concluded that TGF inhibition by M plays no significant role in the diuretic response to this agent.

Animals↗

Low dose loop diuretics in essential hypertension. Experience with torasemide.

Diuretics belong to the class of antihypertensive drugs recommended for first-line therapy of essential hypertension. Although they are widely and effectively used for the treatment of hypertension, the question remains whether their possible negative influence on metabolic and electrolyte parameters could partly offset the benefit of blood pressure reduction with respect to reduction of coronary artery disease. Recently published data demonstrate that much lower doses of thiazides exert the same antihypertensive effect as the higher doses used in the past and even prescribed today. These lower doses produce relatively little change in biochemical parameters. Thus, the postulated risks can be avoided by using the lowest effective dose. Traditionally, loop diuretics of the furosemide (frusemide) type are rarely used as first-line antihypertensive agents. They seem to display less efficacy coupled with an intense diuresis when used in standard available doses. However, there is evidence that newly developed loop diuretics, in lower doses than used in congestive heart failure, are effective antihypertensive agents. For example, torasemide 2.5mg once daily, which does not exert a significant diuresis over 24 hours compared with placebo, lowers elevated blood pressure to a similar extent than thiazides or related compounds. This antihypertensive effect is accompanied by less, if any, changes in metabolic or electrolyte parameters compared with widely used standard diuretics such as hydrochlorothiazide, indapamide or chlorthalidone. The influence on serum potassium and magnesium is similar to or even less than fixed combinations of hydrochlorothiazide and triamterene or amiloride. Thus, low-dose torasemide constitutes an alternative to established thiazide antihypertensive therapy.

Diuretics↗

Alterations in neurogenically mediated contractile responses of urinary bladder in rats with diabetes.

Diabetic bladder dysfunction (DBD) is among the most common and bothersome complications of diabetes mellitus. Autonomic neuropathy has been counted as the cause of DBD. In the present study, we compared the alterations in the neurogenically mediated contractile responses of urinary bladder in rats with streptozocin-induced diabetes, 5% sucrose-induced diuresis, and age-matched controls. Male Sprague-Dawley rats were divided into three groups: 9-wk diabetic rats, diuretic rats, and age-matched controls. Micturition and morphometric characteristics were evaluated using metabolic cage and gross examination of the bladder. Bladder detrusor muscle strips were exposed to either periodic electrical field stimulation (EFS) or to EFS in the presence of atropine, alpha,beta-methylene adrenasine 5'-triphosphate, or tetrodotoxin. The proportions of cholinergic, purinergic, and residual nonadrenergic-noncholinergic (NANC) components of contractile response were compared among the three groups of animals. Diabetes caused a significant reduction of body weight compared with diuresis and controls, although the bladders of diabetic and diuretic rats weighed more than the controls. Both diabetes and diuresis caused significant increase in fluid intake, urine output, and bladder size. Diabetes and diuresis caused similarly increased response to EFS and reduced response to cholinergic component compared with controls. However, the purinergic response was significantly smaller in diuretic bladder strips compared with controls but not in diabetic rats. A residual NANC of unknown origin increased significantly but differently in diabetics and diuretics compared with controls. In conclusion, neurogenically mediated bladder contraction is altered in the diabetic rat. Diabetic-related changes do not parallel diuretic-induced changes, indicating that the pathogenesis of DBD needs further exploration.

Acetylcholine↗

[Use of diuretics in the treatment of patients with viral hepatitis].

The effectiveness of intensification of diuresis by means of hypothiaside and furosemide has been studied during treatment of 135 patients with viral hepatitis A and B. Both these agents were found to posses the same effect which was manifested by lessening of the intoxication syndrome, total blood toxicity and convalescence terms. A therapeutic effect of diuretics is most pronounced in moderately severe form of the disease.

Adolescent↗

Diuresis with continuous infusion of furosemide after cardiac surgery.

We prospectively evaluated the diuretic effect of furosemide administered by bolus injection and by continuous infusion in 18 cardiac surgery patients. Nine patients were randomly assigned to receive 0.3 mg/kg of furosemide as a bolus injection at time 0 and again 6 hours later (nine patients) or 0.05 mg/kg per hour of furosemide as a constant infusion for 12 hours (nine patients). There were no significant differences between groups with respect to age, weight, creatinine clearance, changes in serum sodium and potassium levels, total urinary concentrations of sodium and potassium, or total urine volume for 12 hours. Diuresis during continuous infusion of furosemide was less variable from hour to hour than after bolus injection of furosemide and was sustained throughout the infusion period. Although the continuous infusion of furosemide will not provide the rapid and vigorous diuresis that is necessary in some clinical situations, it may be useful whenever a gentle, sustained diuresis is desired.

Cardiac Surgical Procedures↗

Treatment of adult respiratory distress syndrome with diuretics, dialysis, and positive end-expiratory pressure.

Twelve patients were treated prospectively for adult respiratory distress syndrome with diuresis and low levels (less than or equal to 20 mm Hg) of positive end-expiratory pressure. Eight patients responded to diuretics and two to dialysis by an increase in static compliance of the respiratory system, improvement in arterial oxygen tension and an increased urine output. Two patients did not respond with an improvement in these tests. Responses were transient and multiple doses were required to produce a sustained effect. Even with improvement of pulmonary function after treatment, the mortality was 67%, similar to that reported from other centers since 1975. Recently a new treatment protocol has been proposed that uses high positive end-expiratory pressure (greater than or equal to 20 mm Hg) early in the course of adult repiratory distress syndrome; mortality using this technique was 20%. The difference in survival may be more apparent than real since each center has a unique population of patients and time of initial therapeutic intervention. A randomized collaborative study comparing treatment protocols is needed.

Adolescent↗

Diuretic and natriuretic effect of ebelactone B in anesthetized rats by inhibition of a urinary carboxypeptidase Y-like kininase.

Ebelactone B (EB) (10(-7)-10(-5) M) inhibited dose-dependently carboxypeptidase (CP) Y-like exopeptidase, one of the major kininases separated from rat urine, whereas it inhibited neither CPA, CPB or neutral endopeptidase (NEP). Degradation of bradykinin (BK) to BK-(1-8) in rat urine was completely inhibited by EB (10(-5) M) with the increased generation of BK-(1-7). Intraduodenal administration of EB (3 mg/kg) to anesthetized rats caused marked diuresis (by 110%) and natriuresis (130%), in parallel with the increase in urinary kinin levels (110%). Intravenous infusion of a BK antagonist, Hoe140 (3 mg/kg/hr), strongly blocked both EB-induced diuresis and natriuresis. EB may be a novel type of diuretic and natriuretic agent that acts by increasing urinary kinin levels.

Amino Acid Sequence↗

Intraoperative management of renal function in the surgical patient at risk. Focus on aortic surgery.

Although the search for effective methods of renal prophylaxis during aortic surgery spans many decades, definitive answers are scarce. The literature is voluminous, yet the amount of work clearly relevant to the specific clinical situation of perioperative prophylaxis is small. Given the significant morbidity and subsequent mortality involved with perioperative ARF, it is difficult to sit back and do nothing when pharmacologic agents empirically are believed to possibly benefit the patient. Care must be taken to apply data from different clinical scenarios in the literature to the situation at hand. Drugs felt to be innocuous, even in low doses, may be insidiously counterproductive or damaging if they are not managed properly. Maintaining an adequate preload and stable hemodynamics seems to be the most logical universal approach at this time. Furosemide treatment without maintaining an adequate volume status once diuresis commences may be detrimental, which is true with the diuretic effects induced by mannitol or dopamine. The tachycardia resulting from a relative hypovolemia and from the beta effects of dopamine can cause myocardial ischemia from increased oxygen demand. Low urine output does not portend a negative outcome in the face of an adequate intravascular volume any more than an induced diuresis prevents renal injury. Currently, minimization of renal ischemia and maintenance of an adequate intravascular volume and renal hemodynamics are the keys to optimizing renal outcome during aortic surgery. Other maneuvers are not definitive and should be cautiously undertaken.

Acute Kidney Injury↗

Diuretic effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) in anesthetized rats.

A synthetic amino acid, L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), can be converted to (-)-norepinephrine (NE) by aromatic L-amino acid decarboxylase (AADC) in various mammalian tissues. Recent studies have indicated the pressor and diuretic effects of L-threo-DOPS. In this study, we examined the effects of L-threo-DOPS on renal hemodynamics and function in anesthetized rats, and evaluated possible mechanisms of the diuresis. Intravenous infusion of L-threo-DOPS at 120 micrograms/kg/min exerted a significant increase in mean arterial pressure (MAP). There was a slight but nonsignificant decrease in renal blood flow (RBF). Although the glomerular filtration rate (GFR) remained at a constant level, urine flow (UF) and urinary sodium excretion (UNaV) increased significantly during the drug infusion. Pretreatment with AADC inhibitor, benserazide, completely blocked both the pressor and diuretic effects of L-threo-DOPS. When the renal perfusion pressure was protected from the pressor effect of the drug by using a Blalock clamp, the drug-induced diuresis was abolished. The diuretic effect of L-threo-DOPS was markedly attenuated by the administration of phentolamine. There was a positive correlation between plasma NE concentration and UF during the infusion of L-threo-DOPS. Intrarenal arterial infusion of L-threo-DOPS at 20 micrograms/kg/min was without effect on renal function. These results indicate that diuresis and natriuresis induced by L-threo-DOPS are dependent on the pressor effect of NE via peripheral alpha-adrenoceptor activation.

Anesthesia↗