Aims To evaluate whether the addition of hydrochlorothiazide (HCTZ) to intravenous furosemide is a safe and effective strategy for improving diuretic response in acute heart failure (AHF). Methods and results A prospective, double-blind, placebo-controlled trial, including patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The coprimary endpoints were changes in body weight and patient-reported dyspnoea 72 h after randomization. Secondary outcomes included metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. Safety outcomes (changes in renal function and/or electrolytes) were also assessed. Two hundred and thirty patients (48% women, 83 years) were randomized. Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo [−2.3 vs. −1.5 kg; adjusted estimated difference (notionally 95% confidence interval) −1.14 (−1.84 to −0.42); P = 0.002], but there were no significant differences in patient-reported dyspnoea (area under the curve for visual analogue scale: 960 vs. 720; P = 0.497). These results were similar 96 h after randomization. Patients allocated to HCTZ showed greater 24 h diuresis (1775 vs. 1400 mL; P = 0.05) and weight loss for each 40 mg of furosemide (at 72 and at 96 h) (P < 0.001). Patients assigned to HCTZ more frequently presented impaired renal function (increase in creatinine >26.5 μmoL/L or decrease in eGFR >50%; 46.5 vs. 17.2%; P < 0.001), but hypokalaemia and hypokalaemia were similar between groups. There were no differences in mortality or rehospitalizations. Conclusion The addition of HCTZ to loop diuretic therapy improved diuretic response in patients with AHF.

High plasma and CSF ferritin concentrations within the first 24 hours from the onset of ischemic stroke are associated with early neurologic deterioration. Increased body iron stores may contribute to stroke progression by enhancing the cytotoxic mechanisms in cerebral ischemia.

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Summary:There are no useful markers in blood of nitric oxide (NO)-mediated brain damage. Because L-arginine (L-arg) is the only known substrate for NO generation, the authors investigated the plasma profile of L-arg after cerebral ischemia, and the relationship of L-arg concentrations in blood with stroke outcome and infarct volume in a clinical and experimental study. L-Arg levels were determined with high-performance liquid chromatography in blood and CSF samples obtained on admission, and in blood 48 hours after inclusion, in 268 patients admitted with a hemispheric ischemic stroke lasting 8.2 ± 5.9 hours. Infarct volume was measured by days 4 to 7 using computed tomography. Plasma L-arg profiles were analyzed in a separate group of 29 patients seen within 8 hours of onset (median, 4.5 hours) and in 24 male Fischer rats treated with subcutaneous vehicle or 20-mg/kg 1400W (a specific inducible NO synthase inhibitor) every 8 hours for 3 days after performing sham or permanent middle cerebral artery occlusion. Plasma L-arg concentrations decreased after the ischemic event, both in patients and rats, and peaked between 6 and 24 hours.In patients, there was a highly correlation between L-arg levels in CSF and plasma at 48 hours (r ‫ס‬ 0.85, P<0.001). CSF and plasma L-arg concentrations negatively correlated with infarct volume (r ‫ס‬ −0.40 and r ‫ס‬ −0.35, respectively, P<0.001), and were significantly lower in patients with early neurologic deterioration and in those with poor outcome (Barthel index <85) at 90 days (P<0.001). In rats, the administration of 1400W resulted in a 55% significant reduction of infarct volume measured 72 hours after permanent middle cerebral artery occlusion, an effect that correlated with the inhibition caused by 1400W on the ischemia-induced decrease of plasma L-arg concentrations at 6 to 24 hours after the onset of the ischemia. Taken together, these data indicate that determination of L-arg levels in blood might be useful to evaluate the neurotoxic effects of NO generation. These findings might be helpful to guide future neuroprotective strategies in patients with ischemic stroke.

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