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loop diuretics are a mainstay of the pharmacological treatment of AHF&#46; Despite the ubiquitous use of these agents&#44; uncertainties about appropriate dosing and overall safety profile persist&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">6&#44;7</span></a> As a result&#44; clinical practice varies widely across sites and countries with regard to both mode of administration and dosing&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Theoretically&#44; continuous infusion of a loop diuretic&#44; maintaining stable blood levels&#44; should allow more sustained diuresis&#44; avoiding large swings in intravascular volume and secondary neurohormonal activation&#46; Continuous IV infusion with appropriate dosing may also prevent high or even toxic levels being reached&#44; thereby causing fewer and less severe side effects&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Studies comparing the efficacy and safety of continuous and intermittent IV infusion of loop diuretics in AHF have yielded conflicting results and have been underpowered to address clinical questions&#44; and thus no specific recommendations can be made&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">8</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A recent randomized trial&#44; the Diuretic Optimization Strategies Evaluation &#40;DOSE&#41; trial&#44; challenged the existing clinical dogma concerning the optimal method of IV diuretic administration in hospitalized patients&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> However&#44; criticisms have been made due to the low dosage of the diuretic regimens used&#46; Also&#44; more than 25&#37; of patients included in this trial had left ventricular ejection fraction &#40;LVEF&#41; of 50&#37; or greater&#44; and exclusion criteria included systolic blood pressure &#40;BP&#41; &#60;90 mmHg&#44; serum creatinine &#62;3&#46;0 mg&#47;dl &#40;265 &#956;mol&#47;l&#41; and need for IV vasodilators or inotropic agents&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> thus excluding the most critically ill patients with AHF&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In the present study&#44; we sought to compare the clinical efficacy and safety of continuous and intermittent administration of IV furosemide in a less selected&#44; real-world clinical setting&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Population and study design</span><p id="par0105" class="elsevierStylePara elsevierViewall">Consecutive patients admitted between January 2010 and November 2012 to a cardiac intensive care unit for AHF were selected&#46; Diagnosis of AHF was made according to the definition in the European Society of Cardiology guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> Patients with acute coronary syndromes and end-stage renal disease on a regular hemodialysis program were excluded&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">For this analysis&#44; patients were divided into two groups according to the diuretic protocol selected by the admitting team&#58; group A included patients receiving furosemide by continuous infusion&#59; group B included patients who received only IV bolus furosemide therapy&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In group A furosemide infusion was titrated by the nursing team to achieve and maintain an hourly diuresis of 100&#8211;150 ml as a goal&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">All patients had controlled fluid intake &#40;1 l&#47;day&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Data collection</span><p id="par0130" class="elsevierStylePara elsevierViewall">Data collected from patients&#8217; medical records included history of ischemic heart disease&#44; hypertension&#44; diabetes&#44; chronic renal failure and&#47;or obstructive sleep apnea&#59; time-course and etiology of HF&#59; admission heart rate&#44; BP&#44; and oxygen saturation&#59; electrocardiogram&#59; blood urea nitrogen &#40;BUN&#41;&#44; creatinine&#44; troponin I&#44; NT-pro-BNP&#44; hemoglobin&#44; sodium&#44; potassium&#44; total bilirubin&#44; alkaline phosphatase&#44; aspartate transaminase &#40;AST&#41;&#44; alanine transaminase &#40;ALT&#41; and cystatin C&#46; Particular attention was paid to the evolution of renal function by determining maximum and discharge BUN and creatinine&#46; Estimated glomerular filtration rate &#40;eGFR&#41; was calculated using the Modification of Diet in Renal Disease &#40;MDRD&#41; formula&#44; which has been shown to be the best method of indirect renal function assessment in patients with HF&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The incidence of acute renal injury or cardiorenal syndrome &#40;CRS&#41;&#44; defined as an increase of &#8805;26&#46;5 &#956;mol&#47;l in serum creatinine relative to the admission value&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">12&#44;13</span></a> was also assessed&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The mean difference in serum creatinine at discharge compared to baseline was defined as a safety endpoint&#44; chosen to reflect whether either strategy was associated with lasting effects on renal function&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">All patients underwent transthoracic echocardiography and assessment of LVEF&#44; diastolic function and pulmonary artery systolic pressure &#40;PASP&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Treatments considered for the analysis were maximum daily furosemide dose&#59; use of IV isosorbide dinitrate&#44; dobutamine&#44; dopamine&#44; levosimendan and&#47;or norepinephrine&#59; renal support therapy and mechanical ventilation &#40;both non-invasive and invasive&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In-hospital mortality&#44; incidence of nosocomial infection and length of hospital stay &#40;LOS&#41; were assessed&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Readmission for AHF and mortality during follow-up were analyzed&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0165" class="elsevierStylePara elsevierViewall">The statistical analysis was performed using SPSS for Windows&#44; version 17&#46;0&#46; Categorical variables are expressed as a percentage of the total sample and compared using the chi-square test or Fisher&#39;s exact test&#44; as appropriate&#46; Continuous variables are expressed as mean &#177; standard deviation&#59; the Student&#39;s t-test &#40;two-tailed&#41; was used to compare normally distributed variables and the Mann&#8211;Whitney U test to compare variables without a normal distribution&#46; Survival analysis was performed with Kaplan&#8211;Meier curve analysis&#46; For the purpose of this study&#44; p values &#8804;0&#46;05 were considered significant&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Patient population</span><p id="par0170" class="elsevierStylePara elsevierViewall">A total of 110 patients were included in the study&#46; Mean age was 68&#46;5&#177;14&#46;5 years and 77&#37; were male&#46; Their baseline characteristics are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">Less frequent etiologies of heart failure were valvular disease &#40;17&#46;3&#37;&#41; and alcohol abuse &#40;13&#46;6&#37;&#41;&#46; At least moderate systolic dysfunction &#40;LVEF &#8804;40&#37;&#41; was observed in 79&#46;0&#37; of patients&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Continuous furosemide infusion was used in 56 &#40;50&#46;9&#37;&#41; patients&#44; while IV bolus was chosen in the remaining 54 &#40;49&#46;1&#37;&#41;&#46; The mean maximum daily dose of furosemide was 163&#177;126 mg&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows concomitant cardiovascular medical therapy and major in-hospital endpoints&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Comparison of baseline characteristics</span><p id="par0190" class="elsevierStylePara elsevierViewall">No differences were found between the groups concerning gender &#40;male&#58; 78&#46;6&#37; vs&#46; 75&#46;9&#37;&#59; p&#61;0&#46;741&#41;&#44; age &#40;69&#46;1&#177;13&#46;2 vs&#46; 67&#46;9&#177;15&#46;9 years&#59; p&#61;0&#46;657&#41;&#44; history of hypertension &#40;64&#46;3&#37; vs&#46; 72&#46;2&#37;&#59; p&#61;0&#46;372&#41;&#44; diabetes &#40;35&#46;7&#37; vs&#46; 25&#46;9&#37;&#59; p&#61;0&#46;267&#41;&#44; chronic renal disease &#40;46&#46;3&#37; vs&#46; 38&#46;9&#37;&#59; p&#61;0&#46;473&#41; or obstructive sleep apnea &#40;14&#46;3&#37; vs&#46; 13&#46;0&#37;&#59; p&#61;0&#46;840&#41;&#46; There were no differences concerning HF etiology &#40;p&#61;0&#46;209&#44; coronary artery disease being the most frequent in both groups &#91;25&#46;0&#37; vs&#46; 25&#46;9&#37;&#93;&#41;&#44; decompensating factors&#44; or NYHA class on admission &#40;NYHA IV&#58; 67&#46;9&#37; vs&#46; 66&#46;7&#37;&#59; p&#61;0&#46;894&#41;&#46; The incidence of atrial fibrillation at admission was also similar between groups &#40;43&#46;0&#37; vs&#46; 46&#46;3&#37;&#59; p&#61;0&#46;432&#41;&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Group A more often presented with decompensated chronic HF &#40;78&#46;6&#37; vs&#46; 59&#46;3&#37;&#59; p&#61;0&#46;028&#41; rather than new-onset HF&#44; and had more previous admissions for AHF &#40;58&#46;9&#37; vs&#46; 24&#46;1&#37;&#59; p&#60;0&#46;001&#41;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows some of the vital signs and laboratory data in the two groups at admission&#46; No differences were found in respect to heart rate &#40;94&#177;28 vs&#46; 96&#177;29 bpm&#59; p&#61;0&#46;618&#41;&#59; hemoglobin &#40;12&#46;3&#177;1&#46;9 vs&#46; 12&#46;7&#177;2&#46;1 g&#47;dl&#59; p&#61;0&#46;337&#41;&#59; potassium &#40;4&#46;6&#177;1&#46;0 vs&#46; 4&#46;6&#177;0&#46;7 mmol&#47;l&#59; p&#61;0&#46;992&#41;&#59; troponin I &#40;0&#46;53&#177;1&#46;5 vs&#46; 0&#46;63&#177;1&#46;8 ng&#47;ml&#59; p&#61;0&#46;759&#41;&#59; NT-pro-BNP &#40;20 688&#177;26 910 vs&#46; 13 784&#177;15 510 pg&#47;ml&#59; p&#61;0&#46;115&#41;&#59; AST &#40;131&#177;454 vs&#46; 123&#177;421 U&#47;l&#59; p&#61;0&#46;930&#41; or ALT &#40;101&#177;242 vs&#46; 103&#177;279 U&#47;l&#59; p&#61;0&#46;974&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0205" class="elsevierStylePara elsevierViewall">Echocardiographic findings included lower LVEF in group A &#40;30&#46;2&#177;11&#46;2&#37; vs&#46; 34&#46;8&#177;12&#46;6&#37;&#59; p&#61;0&#46;046&#41;&#44; with a higher incidence of moderate to severe impairment of systolic function &#40;LVEF &#60;40&#37;&#41; &#40;87&#46;5&#37; vs&#46; 68&#46;5&#37;&#59; p&#61;0&#46;016&#41;&#59; they also more often presented type 3 diastolic dysfunction &#40;restrictive filling pattern&#41; &#40;41&#46;8&#37; vs&#46; 20&#46;4&#37;&#59; p&#61;0&#46;032&#41; and a trend towards higher PASP &#40;51&#177;17 mmHg vs&#46; 45&#177;13 mmHg&#59; p&#61;0&#46;063&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Comparison of therapeutic strategies</span><p id="par0210" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> shows the main differences between groups concerning therapeutic strategies&#46; No differences were found in the use of isosorbide dinitrate &#40;25&#46;0&#37; vs&#46; 38&#46;9&#37;&#59; p&#61;0&#46;118&#41; or invasive ventilation &#40;17&#46;9&#37; vs&#46; 13&#46;0&#37;&#59; p&#61;0&#46;478&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Safety endpoints</span><p id="par0215" class="elsevierStylePara elsevierViewall">The incidence of CRS was higher in group A &#40;76&#46;8&#37; vs&#46; 51&#46;9&#37;&#59; p&#61;0&#46;009&#41;&#46; <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> show the course of renal dysfunction during hospitalization in both groups&#46; There were no differences in changes in creatinine &#40;&#8211;4&#46;0&#177;76&#46;4 vs&#46; &#8211;0&#46;3&#177;52&#46;7&#59; p&#61;0&#46;784&#41;&#44; BUN &#40;2&#46;3&#177;9&#46;5 vs&#46; 0&#46;6&#177;8&#46;3 mmol&#47;l&#59; p&#61;0&#46;361&#41; or eGFR &#40;&#8211;2&#46;9&#177;28&#46;0 vs&#46; &#8211;0&#46;2&#177;23&#46;4 ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#59; p&#61;0&#46;611&#41; from admission to discharge&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0220" class="elsevierStylePara elsevierViewall">Group A had longer LOS &#40;16&#46;0&#177;12&#46;3 vs&#46; 11&#46;0&#177;8&#46;3 days&#59; p&#61;0&#46;014&#41; and a higher incidence of nosocomial infections &#40;57&#46;1&#37; vs&#46; 31&#46;5&#37;&#59; p&#61;0&#46;005&#41;&#59; however&#44; in-hospital mortality was similar &#40;19&#46;6&#37; vs&#46; 11&#46;1&#37;&#59; p&#61;0&#46;216&#41;&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Follow-up</span><p id="par0225" class="elsevierStylePara elsevierViewall">In the first 30 days no differences were found in readmissions for AHF &#40;16&#46;3&#37; vs&#46; 14&#46;6&#37;&#59; p&#61;0&#46;823&#41; or mortality &#40;15&#46;9&#37; vs&#46; 4&#46;2&#37;&#59; p&#61;0&#46;081&#41;&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">These results persisted during a mean follow-up of 11&#46;2&#177;9&#46;8 months&#44; with a high rate of readmissions for AHF &#40;58&#46;1&#37; vs&#46; 45&#46;8&#37;&#59; p&#61;0&#46;241&#41;&#44; and mortality barely reaching statistical significance &#40;38&#46;6&#37; vs&#46; 25&#46;0&#37;&#59; p&#61;0&#46;057&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a> shows the Kaplan&#8211;Meier survival curves during follow-up&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0235" class="elsevierStylePara elsevierViewall">Congestion and volume retention are the hallmark of AHF&#44; a condition with high morbidity and mortality for which there is no optimal treatment&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">In current clinical practice&#44; loop diuretics are the first-line therapy for AHF&#46; Despite their familiarity&#44; there remain many unanswered questions about their efficacy&#44; outcomes&#44; and safety&#46; Determination of the optimal mode for diuretic therapy in the management of fluid volume in patients with AHF remains an ongoing issue&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">In our study&#44; which aims to describe a real-world severe AHF population&#44; continuous infusion of furosemide was preferred by the attending team in patients presenting with more criteria of dire prognosis on admission&#46; This tendency could relate to the perception that infusion allows for better monitoring and more stable urinary output&#44; while avoiding falls in BP&#46; Although there was greater deterioration in renal function during hospitalization in the continuous infusion group&#44; at discharge there were no significant differences between the groups in creatinine or BUN&#46; In theory&#44; continuous infusion of a loop diuretic could maintain levels above the natriuretic threshold and provide more constant diuresis without swings in intravascular volume&#46; A pooled analysis of prospective randomized controlled studies prior to 2004 concluded that continuous infusion was beneficial in terms of increased urine output and a better safety profile&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">8</span></a> However&#44; the studies included in the analysis were quite small &#40;254 patients in total&#41; and heterogeneous in design&#44; and the advantage disappeared when two studies using hypertonic saline were excluded&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Recent studies have failed to reach a consensus&#46; Allen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a> found no advantage with continuous infusion&#44; whereas Thomson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">15</span></a> did find a significant increase in urine output with equivalent doses of furosemide administered via continuous infusion compared to intermittent boluses&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">In fact&#44; there is limited evidence to guide diuretic use&#44; as reflected in practice guidelines<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> in which diuretic therapy is given a class I recommendation&#44; with a level of evidence based on a single randomized trial &#40;the DOSE trial&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> This trial&#44; in a well-matched baseline population&#44; found no differences in patients&#8217; global assessment of symptoms&#44; net fluid loss&#44; change in weight&#44; renal safety&#44; or LOS based on the mode of diuretic administration&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Although the DOSE trial was well-designed and is widely considered a landmark study&#44; it excluded patients with systolic BP &#60;90 mmHg and those requiring IV vasodilators or inotropic agents&#44; and thus in our opinion does not reflect the severe AHF population of daily clinical practice&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Our study&#44; albeit retrospective in design&#44; has the advantage of including many patients with severe AHF&#46; Compared with the DOSE trial our patients were older&#44; had lower LVEF&#44; and presented at admission with higher creatinine and NT-pro-BNP levels&#46; The severity of the AHF episode was also reflected in the use of very high furosemide doses&#44; need for renal support in 8&#46;2&#37;&#44; and high use of inotropes&#44; vasopressors&#44; and mechanical ventilation&#46; Hospital stay was complicated by CRS and nosocomial infection in around half of the population&#44; which caused longer LOS than described in the literature&#46; These factors may also explain our high in-hospital mortality&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Clinicians tended to choose IV furosemide infusion rather than bolus in patients presenting with decompensated chronic HF&#44; rather than new-onset HF&#44; in particular if BP was low&#46; This coincided with other well-known parameters of poor prognosis&#44; such as higher cystatin C levels&#44; hyponatremia and hepatic&#47;cholestatic jaundice&#46; Not surprisingly&#44; group A was more often treated with inotropes&#44; vasopressors and non-invasive ventilation&#46; The maximum daily furosemide dose was also significantly higher&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">As expected for a more severe HF population&#44; the incidence of CRS was higher&#44; with higher peak creatinine values&#44; requiring renal support therapy in 16&#46;1&#37; of patients&#46; However&#44; their improvement in renal function was such that they were discharged with similar eGFR to group B&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Unlike previous studies in which the endpoint was acute renal injury&#44; in our study we used discharge renal function as a safety endpoint&#46; By doing so we demonstrated that continuous infusion can be safe in critically ill patients&#46; One possible explanation for the considerable improvement in renal function may be decreased fluctuations in intravascular volume due to relatively constant urine output associated with continuous infusion&#44; as well as effective decongestion&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">When treating patients with AHF&#44; physicians should bear in mind that persistent congestion is itself a predictor of adverse outcomes&#59; transient worsening of renal function may be an acceptable price to pay in order to achieve better short-term fluid removal and symptomatic relief&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">It is of course impossible to determine whether it was the mode of administration or the higher dose of diuretics that was responsible for the similar results between the groups concerning the safety endpoint&#46; Recent data<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">9&#44;16&#44;17</span></a> have suggested that higher doses of diuretics are likely to be more efficacious in relieving congestion&#44; at the cost of transient worsening of renal function&#44; apparently with no long-term consequences&#46; Previous observations linking high-dose diuretics with poor outcomes may reflect the severity of the illness &#40;more advanced cardiac and renal disease&#41; rather than the harmful effect of high doses&#46; Whether repeated episodes of transient worsening of renal function may have permanent harmful effects in the long term cannot be determined from this study&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">Also&#44; the longer LOS in the continuous infusion group may have contributed to the similar outcomes in follow-up&#46; The literature suggests that there may be a tradeoff in HF care between increased LOS and readmission rates&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">18&#44;19</span></a> Many believe that longer LOS allows care teams more time to educate&#44; prepare&#44; and treat the patient&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Although the continuous infusion group contained patients with more severe episodes of AHF&#44; there was no evidence of worse short- or long-term prognosis in terms of in-hospital mortality&#44; readmissions for AHF or follow-up mortality&#46; It should however be noted that the differences are close to statistical significance&#44; and the population was probably too small to have the statistical power to detect differences&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">In the authors&#8217; opinion it would be difficult to prove that a single drug or strategy improves outcomes in patients with severe AHF&#46; As shown in a recent trial&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">20</span></a> in the case of diuretics&#44; a stepped algorithmic approach to dose titration and tailored addition of thiazide&#44; vasodilators&#44; and inotropic support may help guide pharmacological treatment and prevent diuretic resistance&#46; Another study<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">21</span></a> showed that a diuretic protocol can reduce admissions for AHF&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">The authors believe that an algorithm for treatment that closely monitors response with constant fine-tuning of dosages allows safer and more effective administration of drugs with potentially dangerous adverse effects&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Limitations</span><p id="par0315" class="elsevierStylePara elsevierViewall">Our study has a number of limitations that should be recognized&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">First&#44; the observational nature of the study means that doses and mode of administration of furosemide were at the discretion of the admitting physician&#46; The lack of randomization to parallel treatment strategies also created two populations that were clearly different in severity on admission&#44; which precludes firm conclusions regarding the superiority or inferiority of continuous infusion over intermittent bolus administration&#46; We were unable to control for unknown factors that may have confounded our clinical outcomes&#44; a known limitation of observational studies&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Second&#44; body weight was not routinely measured on a daily basis&#44; because a significant proportion of patients were bedridden due to the severity of AHF&#44; and thus weight loss could not be used as a surrogate marker of better decongestion&#46; However&#44; recent studies indicate that total weight loss during hospitalization for AHF is not associated with improvements in recurrent HF or mortality&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">Third&#44; the only loop diuretic included in the analysis was furosemide&#44; and so the conclusions cannot be extrapolated to the more potent loop diuretics torsemide and bumetanide&#46; Although furosemide is the most widely used loop diuretic&#44; it remains controversial whether the more potent loop diuretics should be first-line treatment&#46; The rationale for the use of these diuretics is related to their potential superiority in achieving diuresis without increased adverse events&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">Finally&#44; we were unable to analyze the dose and the mode of administration separately&#46; The higher doses of furosemide in the continuous infusion group probably also affected our results&#44; contributing to better decongestion&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusions</span><p id="par0340" class="elsevierStylePara elsevierViewall">Until more effective strategies for volume removal are available&#44; appropriate diuretic administration is a major component in the care of AHF patients&#46;</p><p id="par0345" class="elsevierStylePara elsevierViewall">Loop diuretics should be used with constant dosage adjustment and with regular clinical assessment&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">Although a conclusion has not yet been reached as to the best mode of IV diuretic administration&#44; our non-randomized study certainly contributes to the evidence of efficacy and safety of very high doses of furosemide administered in continuous infusion to a seriously ill AHF population&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">Renal function is both a limiting factor and an indication of the efficacy and safety of any treatment of heart failure&#46; The fact that more severe AHF patients with worse admission renal function as assessed by cystatin C were discharged with similar creatinine levels to less severely ill patients is certainly reassuring for continuous IV furosemide protocols&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Ethical disclosures</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Protection of human and animal subjects</span><p id="par0360" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association &#40;Declaration of Helsinki&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Confidentiality of data</span><p id="par0365" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Right to privacy and informed consent</span><p id="par0370" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflicts of interest</span><p id="par0375" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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              "identificador" => "abst0005"
              "titulo" => "Introduction and Objectives"
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            0 => array:2 [
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              "titulo" => "Population and study design"
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              "titulo" => "Patient population"
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          "titulo" => "Comparison of baseline characteristics"
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          "titulo" => "Comparison of therapeutic strategies"
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          "titulo" => "Safety endpoints"
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              "titulo" => "Follow-up"
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          "titulo" => "Limitations"
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          "titulo" => "Ethical disclosures"
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              "titulo" => "Protection of human and animal subjects"
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              "titulo" => "Confidentiality of data"
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              "identificador" => "sec0090"
              "titulo" => "Right to privacy and informed consent"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-11-25"
    "fechaAceptado" => "2014-08-16"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec462595"
          "palabras" => array:4 [
            0 => "Diuretics"
            1 => "Intravenous infusion"
            2 => "Acute renal injury"
            3 => "Heart failure"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec462594"
          "palabras" => array:4 [
            0 => "Diur&#233;ticos"
            1 => "Perfus&#227;o intravenosa"
            2 => "Les&#227;o renal aguda"
            3 => "Insufici&#234;ncia card&#237;aca"
          ]
        ]
      ]
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    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Intravenous loop diuretics are an essential part of acute heart failure management&#59; however&#44; data to guide their use is sparse&#46; Our aim was to compare continuous intravenous infusion of loop diuretics with intravenous bolus administration in terms of efficacy and adverse events in patients admitted with severe acute heart failure&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Over a period of three years&#44; 110 patients were admitted to our cardiac intensive care unit with acute heart failure&#46; Clinical&#44; laboratory and prognostic parameters were compared according to the diuretic strategy used and mortality and readmission for acute heart failure during follow-up were analyzed&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Previous medical history was similar in the two groups&#46; At admission&#44; the continuous infusion group met criteria for worse prognosis&#58; lower systolic blood pressure &#40;p&#61;0&#46;011&#41;&#44; more severe renal injury &#40;p&#61;0&#46;008&#41;&#44; lower left ventricular ejection fraction &#40;p&#61;0&#46;016&#41; and higher incidence of restrictive pattern of diastolic dysfunction &#40;p&#61;0&#46;032&#41;&#46; They were more often treated with vasopressors &#40;p&#61;0&#46;003&#41;&#44; inotropes &#40;p&#61;0&#46;010&#41;&#44; renal support therapy &#40;p&#61;0&#46;003&#41; and non-invasive ventilation &#40;p&#60;0&#46;001&#41;&#46; They had longer hospitalizations &#40;p&#61;0&#46;014&#41; and a higher incidence of cardiorenal syndrome &#40;p&#61;0&#46;009&#41;&#59; however&#44; at discharge&#44; there were no differences in renal function between the groups&#46; In-hospital mortality was similar&#44; and during follow-up there were no differences in mortality or readmission for acute heart failure&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Continuous infusion was preferred in patients presenting with worse clinical status&#44; in whom renal dysfunction was transiently worse&#46; However&#44; in-hospital mortality and creatinine at discharge were similar&#46; Continuous infusion thus appears to counteract the initial dire prognosis of more unstable patients&#46;</p></span>"
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            "identificador" => "abst0005"
            "titulo" => "Introduction and Objectives"
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            "titulo" => "Methods"
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      "pt" => array:3 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdu&#231;&#227;o&#47;objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O uso de diur&#233;ticos da ansa &#233; essencial no tratamento de doentes com insufici&#234;ncia card&#237;aca aguda&#59; contudo existe pouca evid&#234;ncia para guiar o seu uso&#46; Neste trabalho compar&#225;mos a efic&#225;cia e efeitos adversos do uso de diur&#233;ticos em perfus&#227;o cont&#237;nua com b&#243;lus em doentes com insufici&#234;ncia card&#237;aca aguda&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">An&#225;lise de 110 doentes admitidos por insufici&#234;ncia card&#237;aca aguda&#44; ao longo de tr&#234;s anos&#44; numa unidade de cuidados intensivos card&#237;acos&#46; Par&#226;metros cl&#237;nicos&#44; anal&#237;ticos e progn&#243;sticos foram comparados de acordo com a estrat&#233;gia diur&#233;tica utilizada&#46; Realizado seguimento referente a mortalidade e reinternamento por insufici&#234;ncia card&#237;aca aguda&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A hist&#243;ria m&#233;dica pr&#233;via era semelhante&#46; &#192; admiss&#227;o&#44; o grupo da perfus&#227;o cont&#237;nua reunia crit&#233;rios de maior gravidade&#58; press&#227;o arterial sist&#243;lica mais baixa &#40;p&#61;0&#44;011&#41;&#44; les&#227;o renal mais grave &#40;p&#61;0&#44;008&#41;&#44; menor fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo &#40;p&#61;0&#44;016&#41; e maior incid&#234;ncia de padr&#227;o restritivo de disfun&#231;&#227;o diast&#243;lica &#40;p&#61;0&#44;032&#41;&#46; Foram tratados mais frequentemente com vasopressores &#40;p&#61;0&#44;003&#41;&#44; inotr&#243;picos &#40;p&#61;0&#44;010&#41;&#44; terap&#234;utica de suporte renal &#40;p&#61;0&#44;003&#41; e ventila&#231;&#227;o n&#227;o invasiva &#40;p&#60;0&#44;001&#41;&#46; Tiveram internamentos mais prolongados &#40;p&#61;0&#44;014&#41; e maior incid&#234;ncia de s&#237;ndrome cardiorrenal &#40;p&#61;0&#44;009&#41;&#59; contudo &#224; alta n&#227;o houve diferen&#231;a na fun&#231;&#227;o renal entre os grupos&#46; A mortalidade hospitalar foi semelhante&#59; no seguimento n&#227;o houve diferen&#231;as na mortalidade ou nos reinternamentos por insufici&#234;ncia card&#237;aca&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#245;es</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A utiliza&#231;&#227;o de diur&#233;ticos da ansa em perfus&#227;o cont&#237;nua foi preferida em doentes com crit&#233;rios de maior gravidade &#224; admiss&#227;o&#46; Transitoriamente apresentaram maior agravamento da fun&#231;&#227;o renal&#59; contudo&#44; a mortalidade hospitalar e a fun&#231;&#227;o renal &#224; alta foram semelhantes&#46; Assim&#44; a perfus&#227;o cont&#237;nua poder&#225; ser uma op&#231;&#227;o em doentes mais inst&#225;veis&#46;</p></span>"
        "secciones" => array:4 [
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      0 => array:3 [
        "identificador" => "nom0005"
        "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0065">List of abbreviations</span>"
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          0 => array:1 [
            "definicion" => array:13 [
              0 => array:2 [
                "termino" => "AHF"
                "descripcion" => "<p id="par0005" class="elsevierStylePara elsevierViewall">acute heart failure</p>"
              ]
              1 => array:2 [
                "termino" => "ALT"
                "descripcion" => "<p id="par0010" class="elsevierStylePara elsevierViewall">alanine transaminase</p>"
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              2 => array:2 [
                "termino" => "AST"
                "descripcion" => "<p id="par0015" class="elsevierStylePara elsevierViewall">aspartate transaminase</p>"
              ]
              3 => array:2 [
                "termino" => "BUN"
                "descripcion" => "<p id="par0020" class="elsevierStylePara elsevierViewall">blood urea nitrogen</p>"
              ]
              4 => array:2 [
                "termino" => "CRS"
                "descripcion" => "<p id="par0025" class="elsevierStylePara elsevierViewall">cardiorenal syndrome</p>"
              ]
              5 => array:2 [
                "termino" => "eGFR"
                "descripcion" => "<p id="par0030" class="elsevierStylePara elsevierViewall">estimated glomerular filtration rate</p>"
              ]
              6 => array:2 [
                "termino" => "HF"
                "descripcion" => "<p id="par0035" class="elsevierStylePara elsevierViewall">heart failure</p>"
              ]
              7 => array:2 [
                "termino" => "IV"
                "descripcion" => "<p id="par0040" class="elsevierStylePara elsevierViewall">intravenous</p>"
              ]
              8 => array:2 [
                "termino" => "LOS"
                "descripcion" => "<p id="par0045" class="elsevierStylePara elsevierViewall">length of hospital stay</p>"
              ]
              9 => array:2 [
                "termino" => "LVEF"
                "descripcion" => "<p id="par0050" class="elsevierStylePara elsevierViewall">left ventricular ejection fraction</p>"
              ]
              10 => array:2 [
                "termino" => "MDRD"
                "descripcion" => "<p id="par0055" class="elsevierStylePara elsevierViewall">Modification of Diet in Renal Disease</p>"
              ]
              11 => array:2 [
                "termino" => "PASP"
                "descripcion" => "<p id="par0060" class="elsevierStylePara elsevierViewall">pulmonary artery systolic pressure</p>"
              ]
              12 => array:2 [
                "termino" => "BP"
                "descripcion" => "<p id="par0065" class="elsevierStylePara elsevierViewall">blood pressure</p>"
              ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Evolution of creatinine &#40;in &#956;mol&#47;l&#41; and blood urea nitrogen &#40;in mmol&#47;l&#41; levels during hospitalization in both groups&#46; BUN&#58; blood urea nitrogen&#59; Group A&#58; continuous infusion&#59; Group B&#58; bolus administration&#46;</p>"
        ]
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      1 => array:7 [
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        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Kaplan&#8211;Meier survival curves during follow-up &#40;mean 11&#46;2&#177;9&#46;8 months&#41;&#46;</p>"
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      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">AHF&#58; acute heart failure&#59; ALT&#58; alanine transaminase&#59; AST&#58; aspartate transaminase&#59; BUN&#58; blood urea nitrogen&#59; eGFR&#58; estimated glomerular filtration rate &#40;Modification of Diet in Renal Disease formula&#41;&#59; LVEF&#58; left ventricular ejection fraction&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">History</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypertension &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">75 &#40;68&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diabetes &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34 &#40;30&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Chronic renal disease &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47 &#40;42&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Obstructive sleep apnea &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;13&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Heart failure indices</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Previous admissions for AHF &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46 &#40;41&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LVEF&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&#46;4&#177;12&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ischemic etiology &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28 &#40;25&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>NT-pro-BNP&#44; pg&#47;ml&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17<span class="elsevierStyleHsp" style=""></span>400&#177;22<span class="elsevierStyleHsp" style=""></span>391&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Troponin I&#44; ng&#47;ml&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;58&#177;1&#46;60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Renal function</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cystatin C&#44; mg&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;67&#177;0&#46;81&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">150&#46;3&#177;91&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BUN&#44; mmol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;6&#177;11&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>eGFR&#44; ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&#46;0&#177;30&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>eGFR &#60;30 ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25 &#40;22&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Other admission laboratory values</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hemoglobin&#44; g&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;5&#177;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sodium&#44; mmol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&#46;8&#177;4&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Potassium&#44; mmol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;6&#177;0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Total bilirubin&#44; &#956;mol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&#46;7&#177;14&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Alkaline phosphatase&#44; U&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">113&#177;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>AST&#47;ALT&#44; U&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">127&#177;436&#47;102&#177;260&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab685924.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of the study population&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">LOS&#58; length of hospital stay&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Concomitant cardiovascular medical therapy</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Isosorbide dinitrate &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35 &#40;35&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Levosimendan &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49 &#40;44&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dobutamine &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21 &#40;19&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dopamine &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;14&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Noradrenaline &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;13&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Other therapeutic strategies</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-invasive ventilation &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48 &#40;43&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Invasive ventilation &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;15&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Renal support therapy &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">In-hospital endpoints</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cardiorenal syndrome &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71 &#40;64&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nosocomial infection &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49 &#40;44&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LOS&#44; days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;6&#177;10&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mortality &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;15&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Concomitant cardiovascular medical therapy and major in-hospital endpoints&#46;</p>"
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      4 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">BP&#58; blood pressure&#59; BUN&#58; blood urea nitrogen&#59; eGFR&#58; estimated glomerular filtration rate &#40;Modification of Diet in Renal Disease formula&#41;&#59; Group A&#58; continuous infusion&#59; Group B&#58; bolus administration&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group A &#40;n&#61;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group B &#40;n&#61;54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Vital signs</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Systolic BP&#44; mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">112&#177;28&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">128&#177;37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Oxygen saturation&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&#46;8&#177;6&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">88&#46;0&#177;9&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;078&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Renal function</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cystatin C&#44; mg&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;96&#177;0&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;42&#177;0&#46;63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Creatinine&#44; &#956;mol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">164&#46;2&#177;105&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">135&#46;9&#177;70&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;103&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BUN&#44; mmol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&#46;7&#177;12&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;4&#177;10&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;057&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>eGFR&#44; ml&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;2&#177;32&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&#46;8&#177;28&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;343&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Other laboratory data</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sodium&#44; mmol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136&#46;8&#177;5&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138&#46;8&#177;4&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;033&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Total bilirubin&#44; &#956;mol&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&#46;6&#177;16&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;7&#177;12&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;037&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Alkaline phosphatase&#44; U&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">125&#46;0&#177;68&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">99&#46;7&#177;42&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;024&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab685920.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Baseline vital signs and laboratory data&#58; comparison between groups&#46;</p>"
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      ]
      5 => array:7 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Group A&#58; continuous infusion&#59; Group B&#58; bolus administration&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic strategy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group A &#40;n&#61;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group B &#40;n&#61;54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Max&#46; daily furosemide dose&#44; mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">246&#177;127&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78&#177;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Dobutamine&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;28&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;9&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Dopamine&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13 &#40;23&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;5&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0005"
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                  "contribucion" => array:1 [
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                        0 => array:2 [
                          "etal" => true
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