Diuretic Protocol Research Articles

P246 URINARY SODIUM–GUIDED I.V. DIURETIC THERAPY IN ACUTE HEART FAILURE: APPLICATION OF THE YALE DIURETIC PROTOCOL IN A REAL–WORLD ITALIAN SETTING

Abstract Background Loop diuretics are the cornerstone of acutely decompensated heart failure (ADHF) treatment, but evidences on doses and administration modalities are still lacking. Veena S. et al have recently validated the Natriuretic Response Prediction Equation and applied it with the Yale Diuretic Protocol (YDP) in a clinical implementation cohort demonstrating its safety. Objectives Our purpose is to test the applicability and safety of YDP for titration of diuretic therapy in a real–world in–hospital setting, as compared to standard diuretic therapy. METHODS From 15th September 2021 patients hospitalized with ADHF, almost one sign of congestion and need of i.v. diuretics were enrolled. Patients with active bleeding, hematocrit < 21%, or on dialysis were excluded. Patients were treated with i.v. diuretic therapy guided by urinary sodium (YDP–group) or by weight changes and urinary output (control group) based on logistic in–hospital reasons. Results Thirty patients were included. Median age was 76.4 [IQR 68.3; 82.7] years old; median EF and glomerular filtration rate were 40% [IQR 30; 55] and 57.2 ml/min/m2 [IQR 44.9; 79.9], respectively. Nineteen (63.3%) patients were on chronic loop diuretic treatment. Ten (33.3%) patients were treated according to YDP. Main results are shown in the Table attached. YDP patients were younger (p = 0.02) and received shorter treatment with i.v. diuretics (YDP 36 [IQR 27; 48] hours, controls 48 [IQRS 38; 88] hours; p = 0.03). No differences in terms of total diuresis, weight loss at the end of i.v. diuretic therapy and length of hospitalization were shown. YDP patients experienced significant lower increase in creatinine during i.v. diuretic therapy (p = 0.02). The incidence of adverse events was comparable between groups, with equal hypotension rate (10%), and similar plasma levels of electrolytes at the end of i.v. diuretic therapy; YDP patients required less potassium supplementation. Reasons for i.v. diuretic therapy suspension were comparable between groups; 7 (70%) YDP patients concluded i.v. diuretic therapy for satisfactory decongestion, while only one patient because of hypotension and none because of worsening of renal function. Conclusion In our reality the YDP appeared to be applicable, safe and comparable to the standard i.v. diuretic therapy in terms of in–hospital outcomes. These preliminary results need to be confirmed in a larger cohort and longer term outcomes still need to be explored.

Standardization of Care Reduces Length of Stay for Postoperative Congenital Heart Disease Patients.

This single-center study utilized the Institute for Healthcare Improvement model to achieve the project aim. A diuretic wean protocol implemented in April 2018 entailed weaning to a homegoing diuretic regimen upon transfer from the cardiac intensive care unit to the inpatient step-down unit. A discharge milestone checklist implemented in September 2018 contained milestones necessary for discharge and an anticipated date of discharge. Outcome measures included aggregate median postoperative LOS and ∆LOS. Balancing measures included cardiac intensive care unit bounce back, pleural chest tube replacement, and readmission rates. Our baseline aggregate median postoperative LOS for the lesions studied was 6.2 days. Following diuretic protocol implementation, the aggregate median LOS decreased to 4.4 days. Baseline ∆LOS decreased from 5.5 to 0.42 days. Postoperative cost fell by an average of $11,874. Balancing measures demonstrated no unintended consequences. Implementation of a diuretic wean protocol led to sustained improvement in postoperative LOS, and ∆LOS in a subset of CHD patients with no unintended consequences supporting that standardization of postoperative care is effective for improvement efforts and can reduce overall practice variation.

Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study.

AimsAlthough acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step‐wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively.Methods and resultsThe Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT‐HF) study is an international, multicentre, non‐randomized, open‐label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N‐terminal pro‐B‐type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in‐hospital mortality, and length of hospitalization.ConclusionsThe ENACT‐HF study will investigate whether a step‐wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.

Temporal trends in tolvaptan use after revision of national heart failure guidelines in Japan

Within no definite diuretic protocol for acute heart failure (AHF) patients and its variation in regional clinical guidelines, the latest national guidelines in Japan commends use of tolvaptan in diuretic-resistant patients. This study aimed to examine trends in tolvaptan usage and associated outcomes of AHF patients requiring hospitalization. Between April, 2018 and October, 2019, 1343 consecutive AHF patients (median 78 [69–85] year-old) were enrolled in a prospective, multicenter registry in Japan. Trends over time in tolvaptan usage, along with the severity of heart failure status based on the Get With The Guideline-Heart Failure [GWTG-HF] risk score, and in-hospital outcomes were investigated. During the study period, tolvaptan usage has increased from 13.0 to 28.7% over time (p for trend = 0.07), and 49.4% started tolvaptan within 3 days after admission. The GWTG-HF risk score in the tolvaptan group has significantly decreased over time, while that in the non-tolvaptan group has unchanged. There were no differences in the in-hospital mortality rate between the patients with and without tolvaptan (6.7% vs. 5.8%). After revision of the Japanese clinical practice guidelines for AHF in March 2018, tolvaptan usage for AHF patients has steadily increased. However, in-hospital outcomes including mortality do not seem to be affected.

Patients with acute heart failure treated with the CARRESS-HF diuretic protocol in association with canrenoate potassium: Tolerance of high doses of canrenoate potassium

Oral mineralocorticoid receptor antagonists have failed to prove their efficacy for decongestion and potassium homeostasis in acute heart failure. Intravenous mineralocorticoid receptor antagonists have yet to be studied. The aim of this study was to confirm the safety of high-dose potassium canrenoate in association with classic diuretics in acute heart failure. This retrospective single-centre study included consecutive patients who were hospitalized with acute heart failure between 2013 and 2018. One hundred patients with overload treated with the standardized diuretic protocol from the CARRESS-HF trial were included. There were no exclusion criteria relating to creatinine or kalaemia at the time of admission. Two groups were constituted on the basis of potassium canrenoate posology: a low-dose group (<300mg/day) and a high-dose group (≥300mg/day); the groups were similar in terms of baseline characteristics. Mean daily potassium canrenoate doses were 198mg/day (range 100-280mg/day) in the low-dose group and 360mg/day (range 300-600mg/day) in the high-dose group. There was no significant difference between the high-dose and low-dose groups in terms of mortality, dialysis, renal function, hyperkalaemia, haemorrhage, sepsis or confusion. Potassium canrenoate at high doses can be used safely in association with standard diuretics in acute heart failure, even in patients with altered renal function. A prospective study is required to evaluate the efficacy of high-dose potassium canrenoate in preventing hypokalaemia and improving decongestion.

Use of ReDS Technology to Treat Heart Failure in the Home Health Setting

Background Volume overload is a major determinant in the physical symptoms and quality of life in patients with heart failure (HF), as well as the predominant factor leading to HF admissions. Accurate assessment of a patient's volume status can be difficult. The Remote Dielectric Sensing (ReDS) Wearable System is an FDA-approved device developed by Sensible Medical Innovations that allows a health care provider to accurately, quickly and non-invasively measure lung fluid. In this study, we used the ReDS system to facilitate a nurse-led care transitions program to improve outcomes and reduce HF readmission rate in a rural hospital lacking an onsite HF program. Methods Randolph Hospital (RH) is a non-profit facility in central North Carolina with a 30-day HF readmission rate ≥ 25%. Medicare patients admitted for HF were enrolled into a nurse-led care transitions program. Patients received telephone follow up or home visit by a nurse within 3 days of discharge. Patients were instructed to call the care transitions nurse with any signs or symptoms of worsening HF during the follow-up period. If the patient complained of volume overload or increased dyspnea a nurse would travel to the patient's home to assess the patient and obtain a ReDS measurement. If the ReDS reading was consistent with volume overload (lung fluid > 35%), a specifically-designed diuretic protocol was initiated. Daily ReDS readings were performed and treatment protocol followed until the reading was below 35% or the protocol was stopped by the medical director. Renal function and electrolytes were monitored and replaced following pre-specified protocol. Results The Care Transitions Team has evaluated 61 patients thus far. There have been 32 elevated readings (ReDS > 35%) which triggered implementation of treatment using the diuretic-protocol. It took an average of 2.5 visits to titrate diuretics and obtain a reading Conclusions A nurse-led care transitions program employing ReDS technology and a specifically-designed diuretic protocol to manage HF patients post hospital discharge, was successful in reducing 30-day HF readmission and reduce overall resource utilization in a community hospital without a dedicated HF clinic.

Combined aquaretic and diuretic therapy in acute heart failure.

IntroductionAcute heart failure (AHF) is a leading cause of hospitalization and readmission in the US. The present study evaluated maximum diuresis while minimizing electrolyte imbalances, hemodynamic instability, and kidney dysfunction, to achieve a euvolemic state safely in a shorter period of time.Methods and resultsA protocol of combined therapy with furosemide, metolazone, and spironolactone, with or without tolvaptan and acetazolamide, was used in 17 hospitalized patients with AHF. The mean number of days on combination diuretic protocol was 3.8 days. The mean daily fluid balance was 3.0±2.1 L negative. The mean daily urine output (UOP) was 4.1±2.0 L (range 1.8–10.5 L). There were minimal fluctuations in serum electrolyte levels and serum creatinine over the duration of diuretic therapy. There was no statistically significant change in patients’ creatinine from immediately prior to therapy to the last day of therapy, with a mean increase in creatinine of 0.14 mg/dL (95% CI −0.03, +0.30, p=0.10).ConclusionOur strategy of treating AHF by achieving high UOP, while maintaining stable electrolytes and creatinine in a short period to euvolemic state, is safe.

Evaluation of 2 diuretic 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography imaging protocols for intrapelvic cancer.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) plays an important part in the oncological evaluation of the abdomen and pelvis, but the interpretation and quantification is often hampered by intense physiological urinary activity. We evaluate 2 different diuretic imaging protocols by comparing intensity of urinary activity and we look at the impact of multiple variables on the final urinary activity. Comparative analysis of 102 patients (median age: 64) having intrapelvic carcinoma. After full body acquisition, 58 patients were administered 20 mg of furosemide 90 min post injection of FDG (P90). For 44 patients, 20 mg of furosemide was administered 30 min post injection of FDG (P30). Comparisons between groups were performed using the Mann-Whitney Test and χ2. The BMI, creatinine, clearance, age, injected activity, diuretic protocol, gender and glycemia were evaluated with multivariate analysis for their impact on the final urinary activity. Concerning the comparison of the urinary activity we observe a significant difference (P=0.0029) between P90 and P30 for the SUVmax (median 4.3 [range 1.6: 17.7] vs. 6.0 [range 2.9: 15.1]), and for the SUVmean (P<0.001) (median 2.4 [range 1.1; 9.9] vs. 3.8 [range 2.0; 10.1]). For 2 patients of P30, the acquisition was interrupted because the patient needed to void. Multivariate analysis shows that creatinine and creatinine clearance do not have a significant independent impact on the final bladder activity. By comparing the 2 diuretic imaging protocols, we found a significant lower urinary activity for the P90 protocol and the regression decision tree shows that the P90 protocol is mostly superior. The P30 protocol, which seems to be less well tolerated, is adequate in the group of patients with an injected activity of less than 240 MBq and older than 65 years, if P90 is not feasible. For most patients with injected activity ≥240 MBq or BMI of ≥25 and a glycemia >120 mg/dL, a significant amount of residual urinary activity remains for both protocols.

Optimizing Prescribing Practices of High-Cost Medications With Computerized Alerts in the Inpatient Setting.

Current literature does not consistently show a benefit to providing medication cost information to inpatient health care prescribers. This study assessed the effectiveness of computerized provider order entry alerts that displayed the cost of a high-cost medication alongside a lower cost alternative, targeting 3 high-cost medications. Medication utilization during the one year prior to the intervention was compared to usage in the year after implementation. Reduced utilization of high-cost medications was found when comparing pre to post. Ipratropium hydrofluoroalkane and fluticasone hydrofluoroalkane metered dose inhaler utilization were reduced by 29% and 62%, respectively ( P < .001 for both). A 71% decrease in intravenous chlorothiazide was observed ( P < .001); however, its effect was unable to be separated from implementation of a heart failure diuretic protocol during the study period. Overall, these results suggest computerized medication cost alerts that recommend a lower cost therapeutic alternative are effective in changing prescribing practices.

F+0 diuretic protocol is superior to F-15 and F+20 for nuclear renogram in children.

Introduction:We compare the outcomes of three different diuretic protocols for renograms in children with hydronephrosis.Materials and Methods:Between August 2011 and July 2013, 148 diuretic renograms were performed to evaluate unilateral grade 3–4 hydronephrosis (reflux, posterior urethral valves, post-pyeloplasty status excluded). Patients were allotted into three groups based on the timing of diuretic administration: Diuretic given 15 min before (F-15), at the same time as (F + 0) and 20 min after (F + 20) radionuclide administration. Dynamic images and renogram curves were inspected to identify in each group (1) number of equivocal curves and (2) number of interrupted studies due to patient movement/discomfort/voiding. Statistical significance was determined by the Fisher exact test.Results:There was no significant difference in age/sex distribution between groups F-15 (n = 35), F + 0 (n = 38) and F + 20 (n = 75). The number of equivocal curves was significantly less in F + 0 (2/38) and F-15 (3/35) compared with F + 20 (20/75). The number of interrupted studies was significantly less in F + 0 (2/38) compared with F-15 (9/35) and F + 20 (18/75).Conclusion:The F + 0 and F-15 protocols are superior to the F + 20 protocol in reducing the number of equivocal curves, while the F + 0 protocol is superior to the other two in reducing interruptions due to patient movement or voiding. F + 0 is the diuretic protocol of choice for renogram in children.

Home diuretic protocol for heart failure: partnering with home health to improve outcomes and reduce readmissions.

The management of heart failure (HF) is challenging, with high rates of readmission and no single solution. MaineHealth, a health care system serving southern Maine, has shown initial success with home health nurses partnering with physicians in the management of complex patients with HF using the MaineHealth Home Diuretic Protocol (HDP). To demonstrate that augmented diuretic therapy, both oral and intravenous, an evidence-based treatment for care of patients with HF experiencing fluid retention, can be delivered safely in the home setting using the HDP and can improve outcomes for recently hospitalized patients with HF. In late 2011, the MaineHealth HDP was implemented in two hospitals and in the home health agency serving those hospitals. The patient population included recently hospitalized patients with a diagnosis of advanced HF, eligible for home health services and telemonitoring. Home health nurses reported data on the patients managed using the protocol, including interventions made, physical findings, lab values, and patient disposition after each episode of care. Questionnaires were used to determine patient and clinician satisfaction. Sixty patients meeting the criteria above were enrolled between November 2011 and January 2014. The protocol was initiated 84 times for 30 of these patients. Sixteen patients had multiple activations. The readmission rate was 10% and no adverse outcomes were observed. Clinician and patient satisfaction was 97% or greater. The MaineHealth HDP can be delivered effectively and safely to improve outcomes, reducing readmissions and allowing patients to remain at home.

Efficacy and Safety of an Intravenous Diuretic Dosing Protocol for the Treatment of Decompensated Heart Failure in an Ambulatory Heart Failure Clinic

Efficacy and Safety of an Intravenous Diuretic Dosing Protocol for the Treatment of Decompensated Heart Failure in an Ambulatory Heart Failure Clinic

Renal Scintigraphy in the Acute Care Setting

Renal scintigraphy is a powerful imaging method that provides both functional and anatomic information, which is particularly useful in the acute care setting. In our institution, for the past 2 decades, we have used a 25-minute renal diuretic protocol, technetium-99m ((99m)Tc) mercaptoacetyltriglycine with simultaneous intravenous injection of furosemide, for all ages and indications, including both native and transplant kidneys. As such, this protocol has been widely used in the workup of acutely ill patients. In this setting, there are common clinical entities which affect patients with native and transplant kidneys. In adult patients with native kidneys one of the most frequent reasons for emergency room visits is renal colic due to urolithiasis. Although unenhanced computed tomography is useful to assess the anatomy in cases of renal colic, it does not provide functional information. Time zero furosemide renal scintigraphy can do both and we have shown that it can effectively stratify patients with renal colic. To this end, 4 characteristic patterns of scintirenography have been identified, standardized, and consistently applied: no obstruction, partial obstruction (mild vs high grade), complete obstruction, and stunned (postdecompressed) kidney. With the extensive use of this protocol over the past 2 decades, a pattern of "regional parenchymal dysfunction" indicative of acute pyelonephritis has also been delineated. This information has proved to be useful for patients presenting with urinary tract infection and suspected pyelonephritis, as well as for patients who were referred for workup of renal colic but were found to have acute pyelonephritis instead. In instances of abdominal trauma, renal scintigraphy is uniquely suited to identify urine leaks. This is also true in cases of suspected leak following renal transplant or from other iatrogenic/postsurgical causes. Patients presenting with acute renal failure can be evaluated with renal scintigraphy. A scintigraphic pattern of "relative preservation of flow as compared to function" has been identified as indicative of acute tubular necrosis, which is distinct from other potential causes of acute renal failure, such as nephrotoxicity and in the case of renal transplants, rejection.

A Diuretic Protocol Increases Volume Removal and Reduces Readmissions Among Hospitalized Patients With Acute Decompensated Heart Failure

Despite the widespread use of loop diuretics to treat acute decompensated heart failure (ADHF), robust data supporting their role and optimal dosing strategies are scarce. This analysis aimed to compare clinical outcomes of patients admitted with ADHF who received a diuretic dosing protocol with those who received the usual diuretic therapy. We performed an observational medical records review to compare the use of a nurse-driven diuretic dosing protocol with usual diuretic dosing for patients admitted with ADHF during a 1-year period. Using a propensity scoring model, comparisons were made between groups for total weight loss, length of stay (LOS), 30-day readmissions, in-hospital mortality, 30-day mortality, and acute kidney failure. Sixty-eight of the 596 patients admitted with ADHF during the study period received the diuretic protocol. Protocol use was associated with an additional 2.63-kg weight loss (P=.003) but a trend toward increased LOS compared with patients receiving usual care (P=.097). However, patients receiving the protocol had a significantly lower risk of 30-day readmission (odds ratio, 0.46, 95% confidence interval, 0.22-0.95). Protocol use was not associated with significant differences in kidney failure, inpatient mortality, or 30-day mortality. A diuretic dosing protocol for patients admitted with ADHF improves weight loss and may lower 30-day readmissions, at the cost of potentially increasing LOS.

The effect of furosemide dose timing on bladder activity in oncology imaging with 18F-fluorodeoxyglucose PET/CT

To compare the effects of two furosemide administration protocols on bladder activity during 18F-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) imaging. A total of 109 consecutive patients with known or suspected malignancy, meeting our inclusion criteria, were chosen over a discrete time period. Group 1 (n=39) received furosemide 20 mg intravenous 15 min before PET/CT imaging (i.e. approximately 45 min after 18F-FDG administration). Group 2 (n=45) received furosemide 20 mg intravenous 15 min after 18F-FDG. Group 3 (n=25) did not receive furosemide and served as controls. Bladder standard uptake values (SUVs) and volume, and liver SUV data were collected. Relative to the control group, both furosemide groups showed significantly lower mean and maximum SUV bladder activities (P<0.001), lower mean bladder-to-liver SUV ratios (P<0.001), larger mean bladder volumes (P<0.001) and higher proportions of bladder PET/CT image mis-registration. Patients tolerated earlier administration of furosemide (group 2) better relative to urinary urgency during imaging. The use of a relatively simple diuretic protocol can significantly lower bladder FDG activity and potentially improve image quality by reducing bladder activity artifacts and avoid invasive bladder catheterization. Administering furosemide earlier after FDG injection (i.e. 15 min) versus later (i.e. 15 min before imaging) appears to be better tolerated by patients.

Nesiritide Following Maze and Mitral Valve Surgery

Fluid retention following "maze" and mitral valve surgery has been associated with diminished levels of atrial natriuretic peptide (ANP). We hypothesized prophylactic administration of nesiritide (human recombinant brain natriuretic peptide, NES, Natrecor, Scios, Fremont, CA, USA), which has similar physiologic properties to ANP and would promote diuresis in maze and mitral patients postoperatively. Randomized, blinded, prospective pilot study comparing patients undergoing maze and mitral surgery including excision of the left atrial appendage. Three hours after cardiopulmonary bypass, patients received either a 72-hour infusion of NES at 0.01 mcg/kg/min (n = 9) or placebo (n = 10). Diuresis, diuretics, time to extubation, oxygenation, ANP, and serum Endothelin-1 levels were measured. Nonparametric analysis with Mann-Whitney test was performed with SPSS (SPSS Inc., Chicago, IL, USA). In both groups, postoperative ANP levels fell from baseline (NES 330 to 280 ng/mL and control 220 to 150 ng/mL). There were no significant differences in patients receiving NES compared to controls in diuresis (1.33 mL/kg/hour urine output NES vs. 1.68 mL/kg/hour controls, p = 0.14); furosemide dosage (0.04 mg/kg/hour NES vs. 0.04 mg/kg/hour controls, p = 0.08); time to extubation (17.5 hours NES vs. 19.5 control, p = 0.42) or PaO2/FiO2 ratio at 48 hours (NES 200 vs. 273 control, p > 0.05). Endothelin-1 levels were higher at baseline with NES but not at 1 and 72 hours after cardiopulmonary bypass (NES 3.1, 3.8, 2.9 pg/mL vs. control 1.85, 4.05, 2.75 pg/mL; p = 0.01, 0.77, 0.47). This pilot study did not demonstrate additional diuresis with nesiritide in postoperative mitral/maze patients already following a loop diuretic protocol.

The Effects of a Sliding Scale Diuretic Titration Protocol in Patients With Heart Failure

Patients with heart failure (HF) are often instructed to temporarily adjust their diuretic dose. This approach has become routine in some HF management programs; however, no study has specifically examined the effects of a patient-directed flexible diuretic protocol. For the purposes of this study, patients were randomized into a usual care (UC) group (n = 31) or a flexible diuretic titration (DT) group (n = 35). The DT group completed a 6-item diuretic titration protocol once a day, for 3 months. The 6-minute walk distance, plasma B-type natriuretic peptide (NT-BNP), plasma norepinephrine (NE), and quality of life (QOL) were measured at baseline and at 3 months. Hospitalizations, emergency department (ED) visits, and mortality rates were measured at 3 months. Compared to baseline, at 3 months, there was a significant increase in the DT group's 6-minute walk distance (646 +/- 60 ft vs 761 +/- 61 ft, P = .01) and total QOL score (53 +/- 5 vs 38 +/- 5, P = .001), whereas these parameters remained unchanged within the UC group. There were significantly less ED visits in the DT group compared with those in the UC group (3% vs 23%, P = .015). No differences were found between the groups in HF-related hospitalizations or mortality. Within both groups, no differences were found between baseline and 3-month NE or NT-BNP plasma values. Patients with heart failure who used a sliding scale diuretic titration protocol had significant improvements in their exercise tolerance and QOL, had fewer ED visits, and had no change in plasma NE or NT-BNP levels.