Introduction
According to the definition of the European Society of Cardiology (ESC), heart failure (HF) is a clinical syndrome comprising various symptoms, such as dyspnea, swollen ankles, and fatigue. These symptoms are usually accompanied by clinical signs such as elevated pressure in the jugular veins, lung crepitations, and peripheral edema (1). HF can be caused by all diseases that lead to structural, mechanical, or electrical abnormalities in the heart (2). For many years, HF types have been determined based on left ventricular ejection fraction (LVEF). If LVEF values are up to 40%, it is classified as HF with reduced ejection fraction (HFrEF), which comprises half of all patients with HF. HFrEF also has the poorest survival prognosis. The importance of the LVEF-based division is especially relevant for choosing the treatment modality. The importance of diagnosing HF is clear from its prevalence, which is between 1% and 2% in adults, and above 10% in the age group above 70 years of age. Etiologically, the most important factors underlying HF in Western countries are coronary artery disease (CAD) and arterial hypertension. It is important to emphasize that acute manifestation of heart failure (AHF) is the leading cause of hospitalization in patients older than 65. According to individual studies, one-year mortality for all types of HF is approximately 20%, whereas five-year mortality is approximately 53% (3). This places HF on par with malignant diseases with very low survival rates. Given its high prevalence, it is clear why significant attention is focused on patient treatment modalities, especially in those with advanced HF. The ESC Guidelines for the treatment of advanced HF mention ultrafiltration (UF) as one mode of treatment.
Case report
In May 2021, the Clinic for Cardiovascular Diseases hospitalized a 67-year-old patient due to swelling in the abdomen and legs and breathing difficulties. According to the patient, the issues had manifested approximately a month before admission, during which he had also noted reduced urination. The patient was also suffering from psoriatic arthritis and hyperlipoproteinemia. Initial examination at the Integrated Emergency Hospital Admission (IEHP) found significantly elevated NT-proBNP (8515 ng/L), with hyponatremia (Na 116 mmol/L) and a liver lesion (AST 675 U/L, ALT 1051 U/L). Additionally, increased values of inflammatory parameters and kidney function were observed, whereas albumin values were normal (CRP 60.8 mg/L, urea 13.7 mmol/L, creatinine 105 μmol/L, albumins 46.9 g/L). Electrocardiography determined atrial fibrillation with unknown time of onset and ventricular frequencies of approximately 96/min with left branch block, while radiological examination showed venous congestion and interstitial edema over both sides of the lungs with more pronounced right-sided pleural effusion. The clinical status was notable for dyspnea, diminished breath sounds on both sides of the lungs, physical signs of ascites, and pitting edema on the upper and lower legs.
Treatment was commenced immediately upon presentation, with an emphasis on diuretic therapy, and hemoculture and urine culture were sampled. Cardiac ultrasounds showed enlargement of all the heart cavities (LVIDd 65 mm, LA 71 x 65 mm, RV 32 mm, RA 65 x 48 mm), with significantly reduced LVEF of 20-25%, as well global hypokinesis. Reduced systolic function of the right ventricle was also observed, and Doppler ultrasound found moderate mitral and tricuspid regurgitation (PG max 39 m/s, Vmax 3.6 m/s, IVC 22 mm without adequate inspiratory collapse, sPAP 54 mmHg, TAPSE 16 mm). Abdominal ultrasound was performed due to the previously mentioned liver lesion, followed by CT of the abdomen and pelvis, which showed morphological changes in the liver, most likely due to cirrhosis. Tumor processes were not observed. Despite gradually increasing the dose of the parenteral diuretic furosemide to 1 g, good diuresis was achieved, but with no improvement in the clinical state and no regression of peripheral congestion. Therefore, on the 18th day of hospitalization, intermittent slow ultrafiltration (SUF) was commenced using a dialysis catheter in the right internal jugular vein. This treatment, after a total of 9 procedures lasting three to four hours, significantly improved the clinical state of the patient and reduced peripheral congestion, with the evacuation of almost 25 liters of fluid. Body weight before the first SUF was 109 kg, and was 85 kg after the last SUF procedure. UF settings were 500 mL/h, and blood flow was 200 to 250 mL/h. During hospitalization, we also monitored stationary troponin T values, which were approximately 100 ng/L, while urea and creatinine values increased to 26.9 mmol/L and 213 μmol/L, respectively, whereas NT-proBNP increased to 17345 ng/L. Due to the increase in inflammatory parameters and urinary tract infection, the patient was also successfully treated with antimicrobial therapy. After almost a month of hospitalization, the clinical state of the patient was optimized as much as possible, and the patient was discharged to home care, with follow-up scheduled 5 days later and a coronarography scheduled 2 months after discharge. A few days before discharge, nearly normal kidney function and electrolyte parameters were observed. CAD was assumed as the main diagnosis, followed by the first manifestation of HF with a clinical picture of anasarca, and with other significant diagnoses including newly discovered atrial fibrillation and left branch block, as well as a liver lesion as a consequence of ischemic hepatitis. The patient was discharged with the following therapy: pantoprazole 40 mg, bisoprolol 10 mg, eplerenone 25 mg, amiodaron 200 mg, rivaroxaban 20 mg, sacubitril/valsartan 2 x 49/51 mg, furosemide 500 mg, potassium citrate / potassium bicarbonate 2 eff. and 1 eff. alternating daily, atorvastatin 20 mg, and sulfasalazine 2 x 500 mg.
The next hospitalization took place only four days later due to iatrogenic hyperkalemia. This was caused by the patient mistakenly using 4 doses of potassium citrate powder in the solution daily. During this hospital stay, after correcting the electrolyte disbalance, the previously planned coronarography was performed, which found mild atherosclerotic disease of the left and right coronary arteries without significant stenosis. This excluded CAD as the etiology of HF and raised suspicion of tachycardiomyopathy. Given the still present atrial fibrillation with tachyarrhythmia of the ventricles with a wide left branch block, ablation of the AV node and CRT device implantation was indicated. After recovery of kidney parameters, the patient was discharged, cardialy compensated with the reduction of the bisoprolol dose to 1.25 mg, furosemide to 250 mg with potassium citrate / potassium bicarbonate 1 eff., and reduction of sacubitril/valsartan to 2 x 24/26 mg, and retention of rivaroxaban 20 mg, eplerenone 25 mg, atorvastatin 20 mg, and sulfasalazine 2 x 500 mg.
In July 2021, the patient presented for follow-up. He reported he was feeling well and had not been gaining weight, while kidney parameters had stationary values, and NT-proBNP was 7223 ng/L. The therapy was continued, with the correction of bisoprolol to 5 mg and reintroduction of amiodarone 100 mg.
The patient was hospitalized once again in September 2021 due to acute phase of HF, most likely being precipitated by right-sided pneumonia. Application of diuretic therapy achieved ample diuresis with the regression of physical symptoms of congestion, and antibiotic therapy achieved almost complete regression of subjective symptoms and initially significantly increased inflammatory parameter values. In addition, this time laboratory tests found mild hypothyreosis, which led to the introduction of supplements. Ultrasound examination found EF of 30%, with severe hypokinesia of the interventricular septum and the inferior wall, with preserved contractility of the basal segment of the inferolateral wall. Doppler ultrasound found mild to moderate mitral and tricuspid regurgitation. The patient was discharged with a correction of furosemide dosing to 250 + 250 mg, eplerenone to 50 mg, amiodarone to 200 mg, and sacubitril/valsartan to 2 x 49/51 mg. In addition to continuing previous therapies, dapagliflozin 10 mg and levothyroxine 25 μg were introduced.
Another follow-up examination took place at the end of November 2021. The patient was in a good general state, with well-compensated heart and lungs, and implantation of a CRT-D device was decided upon due to the issues described above. Current therapy was continued, with a correction in eplerenone to alternating between 25 mg and 50 mg, and amiodarone to 100 mg. At the end of December of the same year, the patient was invited to CRT-D device implantation in order to achieve resynchronization. After successful implantation, radiofrequency ablation of the AV node was also performed, and the device was reprogrammed to VVIR 70-110/min. The patient was discharged after three days, with no changes in therapy.
The next follow-up examination was in June 2022. The patient reported feeling relatively well, and there were no clinical signs of cardiac decompensation. Functional testing of the pacemaker was normal, with an increase in the stimulation threshold for the left ventricular lead, which lead to increased threshold and stimulus duration. Electrocardiographic examination found atrial fibrillation with biventricular pacing 70/min. Near the end of July, another echocardiographic examination was performed, showing that all four heart cavities were still enlarged, but significantly less in comparison with earlier findings (LVIDd 53 mm, LVIDs 38 mm, LA 60 mm, RV 23 mm). This time, LVEF significantly increased to 45%, with still present inferior basal akinesis and hypokinesis of the inferoseptal wall. Doppler examination showed mild mitral regurgitation and traces of tricuspid regurgitation (Vmax 2.4 m/s, PGmax 23 mmHg, sPAP 28 mmHg). After the ultrasound, the patient was examined twice more in the cardiological clinic, the last time being in December 2022, when he stated he was felling increasingly well, with good tolerance for moderate exertion.
Discussion
The ESC Guidelines for the treatment of HFrEF list pharmacotherapy as the foundation for the achievement of three main goals, these being: mortality reduction, preventing rehospitalizations, and improving clinical status (1). The three most important groups of medications are beta blockers, mineralocorticoid receptor antagonists (MRA), and angiotensin-converting enzyme inhibitors or angiotensin receptor/neprilysin inhibitors (ARNI). In addition to the above, notable medications include sodium-glucose transport protein 2 (SGLT-2) inhibitors and diuretics, especially loop diuretics. This last group of medications has an important role in the treatment of both acute and chronic HF and the associated fluid retention. For AHF, loop diuretics are most commonly applied intravenously, and the dose is increased until congestion regresses. Resistance to diuretic treatment occurs in some patients, leading to a lack of adequate congestion reduction, in which cases renal replacement therapy is recommended according to the ESC Guidelines, at recommendation grade IIa and level of evidence C.
Ultrafiltration is one of the most common forms of replacement therapy, and has thus been the topic of numerous studies. Randomized trials conducted thus far have often reported contradictory results. The prospective randomized study UNLOAD, published in 2007, examined two groups of patients with AHF (more than 70% of patients with HFrEF) (4). One group was treated only with UF up to 500 mL/h, while the other was treated with intravenous loop diuretics. UF was conducted over up to 8 hours, and an average of 2611 ± 1002 mL of fluid was removed per procedure. It is important to emphasize that this was one of the first studies of its type. In the conclusion, the authors stated that early UF led to higher fluid body weight loss than intravenous administration of loop diuretics, while also reducing the number of rehospitalizations and unscheduled visits to the physician.
A study on the same topic was published in 2012, additionally monitoring deterioration of renal function along with HF (5). The study results showed that, for patients with AHF, progressive application of intravenous diuretics was superior in comparison to UF. UF was applied with filtration settings at 200 mL/h, and the median duration was about 40 hours. Both patient groups had almost the same body weight loss and fluid elimination, but UF was associated with a large number of adverse events and a more significant deterioration of renal function. In the same year, a group from the Cleveland Clinic published the results of a study on the application of slow continuous ultrafiltration (SCUF) in patients with advanced HF (6). The study included 63 patients refractory to standard therapy, with progressive oliguria and deteriorated renal function. All patients had LVEF between 11% and 41%, with an average value of 26%. Diuretic therapy was continued in patients who maintained diuresis, and all patients underwent SCUF at 100-400 mL/h (average 200 mL/h), depending on the clinical and hemodynamic state of individual patients. In their conclusion, the authors stated that SCUF treatment led to significant hemodynamic improvement in their patients, although improvement in renal function was not present. Despite the above, the need to employ SCUF indicates the very severe state of the patient, and the results of this study show that almost a third of the patients died during observed hospitalization, and a one-year mortality was almost 70%. It is important to note that none of the deaths were the result of SCUF treatment complications, but were instead a consequence of further progression of HF as the underlying cause of death.
A group of Polish scientists published a metanalysis in 2021 that examined the more significant studies conducted thus far on UF in patients with AHF (7). They concluded that UF is a safe and effective method for achieving decongestion in patients. In addition to fluid elimination, this method significantly reduces the number of adverse events and hospitalizations. With the goal of optimal employment of the UF method, the authors highlight the need for the development of clear algorithms for its use, as well for the monitoring of certain biomarkers, given potential glomerular and tubular damage.
In a systemic literature review published in the Cochrane database, the authors analyzed randomized controlled trials that compared ultrafiltration and diuretic therapy in patients with AHF (8). The metanalysis included 14 studies with approximately 1200 patients. In 2 studies, UF was used as an additional treatment modality along with diuretic therapy, whereas the other studies treated patients with either diuretics or UF. Study results showed that UF can have little or no effect on all-cause mortality in the longest study period available. Despite the above, UF reduced the number of rehospitalization for HF and other causes, both in a 30-day period and in the longer term. As for potential complications of UF, it had little or no effect in a 30-day period on increasing serum creatinine, but it increased the likelihood of employing other advanced forms of renal replacement therapy.
Conclusion
As stated in the Introduction, HF is a common topic of scientific studies due to its high prevalence in the older population. ESC Guidelines clearly describe the various steps in the treatment, as well as adequate therapy, depending on clinical staging and patient presentation. The patient described herein received treatment based on the Guidelines, but, due to inadequate clinical response, we employed one of the forms of renal replacement treatment, namely ultrafiltration. This method is also present in the Guidelines, but with a recommendation grade C. In the present case, intermittent SUF successfully eliminated approximately 25 liters of fluid, leading to faster recovery and earlier discharge from the hospital. Medication therapy was continued based on the Guidelines, and a CRT-D device was implanted in order to achieve resynchronization. Due to the above, the patient experienced significant recovery 13 months after the first hospitalization, with LVEF improving from 20-25% to as high as 45%, fulfilling the criteria for changing the initial diagnosis of HFrEF to HF with improved ejection fraction (HFimpEF). Given the patient’s resistance to loop diuretics, UF was certainly one of the more important steps in the treatment process. Currently available literature on the treatment of UF in patients with AHF does not allow for non-ambiguous conclusions. Studies indicate that UF successfully leads to decongestion, fluid elimination, and hemodynamic stabilization. Additionally, most studies report that UF reduces the number of rehospitalizations and visits to the physician. Despite some positive effects of this method, patient mortality was unchanged and reached as high as 70% in the first year in individual studies. It is therefore necessary to continue research on the application of UF with the goal of creating treatment guidelines that will, in addition to improving quality of life, contribute to improved survival.