David J. Wang

Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine

Background—Nesiritide (synthetic human brain natriuretic peptide) is approved for the treatment of symptomatic heart failure. However, studies of brain natriuretic peptide in patients with heart failure have come to conflicting conclusions about effects on glomerular filtration rate (GFR), effective renal plasma flow, natriuresis, and diuresis. Methods and Results—To identify a population at high risk of renal dysfunction with conventional treatment, we selected patients with a creatinine level increased from baseline (within 6 months). We examined the effects of nesiritide on GFR (measured by iothalamate clearance), renal plasma flow (measured by para-amino hippurate clearance), urinary sodium excretion, and urine output in a double-blind, placebo-controlled, crossover study. Patients received nesiritide (2 &mgr;g/kg IV bolus followed by an infusion of 0.01 &mgr;g/kg per minute) or placebo for 24 hours on consecutive days. Nesiritide and placebo data were compared by repeated-measures analysis and Student t test. We studied 15 patients with a recent mean baseline creatinine of 1.5±0.4 mg/dL and serum creatinine of 1.8±0.8 mg/dL on admission to the study. There were no differences in GFR, effective renal plasma flow, urine output, or sodium excretion for any time interval or for the entire 24-hour period between the nesiritide and placebo study days. For 24 hours, urine output was 113±51 mL/h with placebo and 110±56 mL/h with nesiritide. GFR during placebo was 40.9±25.9 mL/min and with nesiritide was 40.9±25.8. Conclusions—Nesiritide did not improve renal function in patients with decompensated heart failure, mild chronic renal insufficiency, and renal function that had worsened compared with baseline. The lack of effect may be related to renal insufficiency, hemodynamic alterations, sodium balance, severity of heart failure, or drug dose. Understanding the importance of these issues will permit effective and appropriate use of nesiritide.

Diuretics: still the mainstay of treatment.

The mainstay of treatment of acute decompensated heart failure is diuretic therapy. While there are no data showing a morbidity or mortality benefit from the use of chronic diuretic therapy, diuretics rapidly improve symptoms associated with volume overload. Thus, despite concerns that some diuretics may cause harm by neurohormonal activation, these agents continue to be the first-line treatment for patients with heart failure. There is no conclusive evidence that one means of diuresis is better than another. When administration of moderate doses of loop diuretics is not sufficient, patients can be treated with higher doses, continuous infusions, or the addition of a thiazide diuretic or aldosterone antagonist. Diuretics improve symptoms but should be used in addition to other agents that improve the long-term outcome of patients with heart failure.

Impedance cardiography: more questions than answers.

Thoracic electrical bioimpedance, also known as impedance cardiography (ICG), is a noninvasive method to obtain hemodynamic measurements, including cardiac output. Recently, there has been a flurry of reports on the clinical use of ICG. Authors have suggested that ICG measurements are useful for a myriad of situations, including diagnosis of heart failure, monitoring of a patient’s clinical status, and assisting in medicine titration decisions. However, data continue to suggest poor correlation between current generation ICG devices and invasive measurements of cardiac output, especially in heart failure patients. ICG is also not able to accurately measure left ventricular filling pressures. There are limited data demonstrating any improved outcomes using ICG in the clinical setting. Given the available data, ICG use should be limited to the research setting.

Fructose-1,6-diphosphate attenuates acute lung injury induced by ischemia-reperfusion in rats.

Objective To determine whether fructose-1,6-diphosphate (FDP) pretreatment can attenuate acute lung injury induced by ischemia-reperfusion in our isolated lung model in rats. Design Randomized, controlled study. Setting Animal care facility procedure room. Subjects Twenty-four adult male Sprague-Dawley rats each weighing 250–350 g. Interventions Typical acute lung injury in rats was induced successfully by 10 mins of hypoxia followed by 75 mins of ischemia and 50 mins of reperfusion. Ischemia-reper-fusion significantly increased microvascular permeability as measured by the capillary filtration coefficient, lung weight gain, lung weight to body weight ratio, pulmonary arterial pressure, and protein concentration of bronchoalveolar lav-age fluid. Measurements and Main Results Pretreatment with FDP significantly attenuated the acute lung injury induced by ischemia-reperfusion as shown by a significant decrease in all of the assessed variables (p < .05 p < .001). The protective effect of FDP was nearly undetectable when promazine (an ecto-adenosine 5-triphosphatase inhibitor) was added before FDP pretreatment. Conclusions Pretreatment with FDP significantly ameliorates acute lung injury induced by ischemia-reperfusion in rats.

Protective effect of lipophilic antioxidants on phorbol-induced acute lung injury in rats.

ObjectiveTo determine whether the lipophilic antioxidant U-74389G can ameliorate the acute lung injury induced by phorbol myristate acetate (PMA) in our isolated lung model in rats, and to compare its activity with the intracellular enzymes superoxide dismutase (SOD) or catalase. DesignRandomized, controlled study. SettingAnimal-care facility procedure room. SubjectsForty-two adult male Sprague-Dawley rats each weighing 250–350 g. InterventionsTypical acute lung injury was induced successfully by PMA during 60 mins of observation. PMA (2 &mgr;g/kg) elicited a significant increase in microvascular permeability (measured by using the capillary filtration coefficient Kfc), lung weight gain, the lung weight/body weight ratio, pulmonary arterial pressure, and the protein concentration of the bronchoalveolar lavage fluid. Measurements and Main Results Pretreatment with 1 mg of U-74389G significantly attenuated the acute lung injury induced by PMA, all parameters having decreased significantly (p < .001). The protective effect of U-74389G was dose dependent, but SOD (6,000 U/kg) or catalase (50,000 U/kg) exhibited no protective effect. ConclusionsU-74389G significantly ameliorates acute lung injury induced by PMA in rats.

Dimethylthiourea ameliorates acute lung injury induced by phorbol myristate acetate in dogs

Background and Methods:The protective effects of dimethylthiourea, a potent scavenger of hydroxy radical (·OH) and hydrogen peroxide, in experimental lung injury in large animals remain controversial. The present study was designed to determine whether dimethylthiourea can ameliorate the acute lung injury produced in dogs by phorbol myristate acetate. Six dogs were infused with dimethylthiourea (0.75 μg/kg in saline) for 1.5 hrs, beginning 1 hr before an iv bolus injection of phorbol myristate acetate (17 μg/kg); six dogs received phorbol myristate acetate (17 μg/kg) alone; and six dogs were infused with saline alone. Hemodynamic changes, arterial oxygenation, and the development of lung edema were monitored for 4 hrs after phorbol myristate acetate injection to assess the extent of lung damage. Results:As compared with the dogs that received phorbol myristate acetate alone, the edematous lung damage was significantly reduced in those dogs that received dimethylthiourea as well as phorbol myristate acetate. In the dimethylthiourea-treated dogs, the lung wet/dry weight ratios were smaller (p < .01); protein concentrations in lung lavage fluid were lower (p < .01); the decrease in Pao2 was significantly reduced (p < .01); and there were significant reductions in the alveolar-arterial oxygen tension difference (P[A-a]o2) (p < .01) and shunt (Qsp/Qt) (p < .05). Also, dimethylthiourea significantly lowered the increased mean pulmonary arterial pressure levels during the second half of the experiment. Conclusions:These experimental data suggest that dimethylthiourea is capable of reducing the neutrophil-mediated lung injury produced by the release of hydroxy radical and/or hydrogen peroxide in dogs exposed to phorbol myristate acetate.