Veno-venous extra-corporeal membrane oxygenation in a COVID-19 patient with cold-agglutinin haemolytic anaemia: A case report.

OVERVIEW: The use of extra-corporeal membrane oxygenation (ECMO) therapy to treat severe COVID-19 patients with acute respiratory failure is increasing worldwide. We reported herein the use of veno-venous ECMO in a patient with cold agglutinin haemolytic anaemia (CAHA) who suffered from severe COVID-19 infection. DESCRIPTION: A 64-year-old man presented to the emergency department (ED) with incremental complaints of dyspnoea and cough since one week. His history consisted of CAHA, which responded well to corticosteroid treatment. Because of severe hypoxemia, urgent intubation and mechanical ventilation were necessary. Despite deep sedation, muscle paralysis and prone ventilation, P/F ratio remained low. Though his history of CAHA, he still was considered for VV-ECMO. As lab results pointed to recurrence of CAHA, corticosteroids and rituximab were started. The VV-ECMO run was short and rather uncomplicated. Although, despite treatment, CAHA persisted and caused important complications of intestinal ischemia, which needed multiple surgical interventions. Finally, the patient suffered from progressive liver failure, thought to be secondary to ischemic cholangitis. One month after admission, therapy was stopped and patient passed away. CONCLUSION: Our case report shows that CAHA is no contraindication for VV-ECMO, even when both titre and thermal amplitude are high. Although, the aetiology of CAHA and its response to therapy will determine the final outcome of those patients.

Utility of Urine Biomarkers and Electrolytes for the Management of Heart Failure.

PURPOSE OF REVIEW: To provide insight into the role of urine biomarkers and electrolytes for the management of heart failure. RECENT FINDINGS: The age-dependent decrease in glomerular filtration rate due to loss of functional nephrons occurs at a faster pace in heart failure, potentially exacerbated by episodes of acute kidney injury. Urine biomarkers have not convincingly demonstrated to improve detection of irreversible renal damage and predict long-term renal trajectories, compared with serial creatinine measurements. Recent data show that natriuresis and diuretic response track poorly with glomerular filtration, but strongly with prognosis. Urine sodium concentration > 50-70 mmol/L was recently put forward through expert consensus as an adequate diuretic response. The value of urine biomarkers to detect structural renal damage in heart failure remains unsure and the latter is probably uncommon, especially over short-term follow-up. Urine electrolytes on the other hand predict diuretic response accurately and may allow better diuretic titration.

Renal sodium avidity in heart failure: from pathophysiology to treatment strategies.

Increased neurohumoral stimulation resulting in excessive sodium avidity and extracellular volume overload are hallmark features of decompensated heart failure. Especially in case of concomitant renal dysfunction, the kidneys often fail to elicit effective natriuresis. While assessment of renal function is generally performed by measuring serum creatinine-a surrogate for glomerular filtration-, this only represents part of the nephron's function. Alterations in tubular sodium handling are at least equally important in the development of volume overload and congestion. Venous congestion and neurohumoral activation in advanced HF further promote renal sodium and water retention. Interestingly, early on, before clinical signs of heart failure are evident, intrinsic renal derangements already impair natriuresis. This clinical review discusses the importance of heart failure (HF) induced changes in different nephron segments. A better understanding of cardiorenal interactions which ultimately result in sodium avidity in HF might help to treat and prevent congestion in chronic and acute HF.

Prognostic value of glomerular filtration changes versus natriuretic response in decompensated heart failure with reduced ejection.

BACKGROUND: Glomerular filtration rate (GFR) and natriuretic response to diuretics represent important treatment targets in acute decompensated heart failure (ADHF). METHODS AND RESULTS: Consecutive ADHF patients (n = 50) with ejection fraction ≤ 45% and clinical signs of volume overload received protocol-driven decongestive therapy. Serum creatinine (Cr), cystatin C (CysC), and ß-trace protein (ßTP) were measured on admission and three subsequent days of treatment. Worsening renal function (WRF) was defined as a ≥ 0.3 increase in absolute biomarker levels or ≥ 20% decrease in estimated GFR. Consecutive 24-hour urinary collections were simultaneously performed to measure Cr clearance and natriuresis. Serum Cr, CysC, and ßTP were strongly correlated at admission (ρ = 0.788-0.909) and during decongestive treatment (ρ = 0.884-888). Moreover, derived GFR estimates correlated well with Cr clearance (ρ = 0.820-0.908). Nevertheless, WRF incidence differed markedly according to Cr- (26%-30%), CysC- (46%-54%), or ßTP-based definitions (31%-48%). WRF by any definition was not associated with all-cause mortality or ADHF readmission, in contrast to stronger natriuresis per loop diuretic dose [hazard ratio 0.20 (95% confidence interval 0.06-0.64); P = .007]. CONCLUSIONS: Serial measurements of CysC/ßTP, compared with serum Cr, more frequently indicate WRF during decongestive treatment in ADHF. However, adverse clinical outcome in such patients might be better predicted by the natriuretic response to diuretic therapy.

Asymptomatic episodes of device-registered atrial tachyarrhythmia are not associated with worse cardiac resynchronization therapy response.

AIMS: To assess the influence of device-registered episodes of atrial tachyarrhythmia (AT) on the response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Consecutive CRT patients without history of atrial fibrillation (AF; n = 118) were followed prospectively. AT was defined as a device-registered episode of atrial rate >190 b.p.m. for ≥30 s. Episodes of electrocardiographically documented AF, accompanied by symptoms, or need for cardioversion, were classified as clinical AF. During mean follow-up of 26 ± 9 months, 39 patients (33%) had ≥1 episode of asymptomatic device-registered AT. Twenty-one patients (18%) developed clinical AF of whom seven had previously experienced episodes of asymptomatic device-registered AT. Patients with asymptomatic AT or AF had a higher body mass index, but otherwise similar baseline characteristics, compared with the subjects without AT. Reverse remodelling after CRT was similar among the groups. While clinical AF was significantly associated with the composite endpoint of all-cause mortality or unplanned hospital admission (hazard ratio = 2.43, 95% confidence interval: 1.40-4.24), this correlation was not observed in patients with asymptomatic device-registered AT (P value = 0.540). CONCLUSION: Episodes of asymptomatic device-registered AT are frequent in CRT patients, but are not associated with impaired reverse remodelling. In contrast to clinical AF, such episodes are not associated with worse clinical outcome.

New insights into combinational drug therapy to manage congestion in heart failure.

Congestion is the most important contributor to morbidity and mortality in heart failure. In patients without congestion, maintaining a neutral sodium balance is imperative to prevent evolving volume overload. Adequate use of neurohumoral blockers, in combination with dietary sodium restriction, is essential and may preclude the need for maintenance diuretic therapy. If volume overload still prevails, loop diuretics remain the mainstay treatment to reduce excessive extracellular volume. However, combinational drug therapy might offer a more attractive alternative to achieve a balanced natriuresis, instead of further uptitration of loop diuretics. Importantly, elevated cardiac filling pressures may be caused by volume misdistribution and impaired venous capacitance, rather than absolute volume overload. Vasodilator therapy to unload the heart, increase venous capacitance, and lower arterial impedance might be interesting in such cases. This review offers a practical approach into current and potential future pharmacologic therapies for managing congestion, focusing on combinational and targeted therapy.

Hyponatraemia in heart failure: time for new solutions?

Hyponatraemia is very common in heart failure (HF), especially in decompensated patients. It is associated with increased mortality and morbidity and considered a marker of advanced disease. Recognition of hyponatraemia and its causes may help guide treatment strategy. Historically, therapy has primarily focused on water restriction, decongestion with loop diuretics in case of volume overload (dilutional hyponatraemia) and sodium repletion in case of depletion. In this review, we summarise the potential benefits of established and emerging HF therapies on sodium homeostasis, with a focus on dual vasopressin antagonists, angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors and hypertonic saline, and propose a potential therapeutic approach for hyponatraemia in HF.

Measures of Loop Diuretic Efficiency and Prognosis in Chronic Kidney Disease.

BACKGROUND: The evolution and prognostic impact of loop diuretic efficiency according to chronic kidney disease (CKD) severity is unclear. METHODS: This retrospective cohort study includes 783 CKD patients on oral loop diuretic therapy with a 24-h urine collection available. Acute kidney injury and history of renal replacement therapy were exclusion criteria. Patients were stratified according to Kidney Disease Improving Global Outcomes (KDIGO) glomerular filtration rate class. Loop diuretic efficiency was calculated as urine output, natriuresis, and chloruresis, each adjusted for loop diuretic dose, and compared among strata. Risk for onset of dialysis and all-cause mortality was evaluated. RESULTS: Loop diuretic efficiency metrics decreased from KDIGO class IIIB to IV in furosemide users and from KDIGO class IV to V with all loop diuretics (p value <0.05 for all comparisons). The correlation between loop diuretic efficiency and creatinine clearance was moderate at best (Spearman's ρ 0.298-0.436; p value <0.001 for all correlations). During median follow-up of 45 months, 457 patients died (58%) and 63 received kidney transplantation (8%), while dialysis was started before in 328 (42%). All loop diuretic efficiency metrics were significantly and independently associated with both the risk for dialysis and all-cause mortality. In KDIGO class IV/V patients, low loop diuretic efficiency (i.e., urine output adjusted for loop diuretic dose ≤1,000 mL) shortened median time to dialysis with 24 months and median time to all-cause mortality with 23 months. CONCLUSION: Low loop diuretic efficiency is independently associated with a shorter time to dialysis initiation and a higher risk for all-cause mortality in CKD.

Impact of oral anticoagulation in patients with atrial fibrillation at very low thromboembolic risk.

OBJECTIVE: To investigate reasons for and impact of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) at very low thromboembolic risk. METHODS: Individuals with CHA2DS2-VASc score 0 (men) or 1 (women) from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) were studied. Baseline characteristics according to OAC use were evaluated by logistic regression analysis. Non-haemorrhagic stroke or systemic embolism, major bleeding, cardiovascular and all-cause mortality were compared. RESULTS: From 2224 low CHA2DS2-VASc patients in GARFIELD-AF, 44% received OAC. In an adjusted model, increasing age up to 65 years (OR (95% CI)=1.31 (1.19 to 1.44)) and persistent AF (OR (95% CI)=3.25 (2.44 to 4.34)) or permanent AF (OR (95% CI)=2.29 (1.59 to 3.30)) versus paroxysmal/unclassified AF were associated with OAC use. Concomitant antiplatelet therapy (OR (95% CI)=0.21 (0.17 to 0.27)) was inversely associated. Crude incidence rates per 100 person-years over 2 years in patients on OAC versus not on OAC were 0.32 (95% CI 0.14 to 0.71) vs 0.30 (95% CI 0.14 to 0.63) for non-haemorrhagic stroke or systemic embolism, 0.21 (95% CI 0.08 to 0.57) vs 0.17 (95% CI 0.06 to 0.46) for major bleeding, 0.26 (95% CI 0.11 to 0.64) vs 0.26 (95% CI 0.12 to 0.57) for cardiovascular mortality and 0.74 (95% CI 0.44 to 1.25) vs 0.99 (95% CI 0.66 to 1.49) for all-cause mortality. CONCLUSIONS: In contrast to guideline recommendations, almost half of real-world patients with AF at a very low thromboembolic risk according to the CHA2DS2-VASc score receive OAC. Persistent or permanent AF and increasing age up to 65 years are associated with OAC use, while concomitant antiplatelet therapy shows an inverse association. Regardless whether patients received OAC therapy, few thromboembolic and bleeding events occur, highlighting the low risk of this population.

Urinary Sodium Profiling in Chronic Heart Failure to Detect Development of Acute Decompensated Heart Failure.

OBJECTIVES: This study sought to determine the relationship between urinary sodium (Una) concentration and the pathophysiologic interaction with the development of acute heart failure (AHF) hospitalization. BACKGROUND: No data are available on the longitudinal dynamics of Una concentration in patients with chronic heart failure (HF), including its temporal relationship with AHF hospitalization. METHODS: Stable, chronic HF patients with either reduced or preserved ejection fraction were prospectively included to undergo prospective collection of morning spot Una samples for 30 consecutive weeks. Linear mixed modeling was used to assess the longitudinal changes in Una concentration. Patients were followed for the development of the clinical endpoint of AHF. RESULTS: A total of 80 chronic HF patients (71 ± 11 years of age; an N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentration of 771 [interquartile range: 221 to 1,906] ng/l; left ventricular ejection fraction [LVEF] 33 ± 7%) prospectively submitted weekly pre-diuretic first void morning Una samples for 30 weeks. A total of 1,970 Una samples were collected, with mean Una concentration of 81.6 ± 41 mmol/l. Sodium excretion remained stable over time on a population level (time effect p = 0.663). However, interindividual differences revealed the presence of high (88 mmol/l Una [n = 39]) and low (73 mmol/l Una [n = 41]) sodium excreters. Only younger age was an independent predictor of high sodium excretion (odds ratio [OR]: 0.91; 95% confidence interval [CI]: 0.83 to 1.00; p = 0.045 per year). During 587 ± 54 days of follow-up, 21 patients were admitted for AHF. Patients who developed AHF had significantly lower Una concentrations (F[1.80] = 24.063; p < 0.001). The discriminating capacity of Una concentration to detect AHF persisted after inclusion of NT-proBNP and estimated glomerular filtration rate (eGFR) measurements as random effects (p = 0.041). Furthermore, Una concentration dropped (Una = 46 ± 16 mmol/l vs. 70 ± 32 mmol/l, respectively; p = 0.003) in the week preceding the hospitalization and returned to the individual's baseline (Una = 71 ± 22 mmol/l; p = 0.002) following recompensation, while such early longitudinal changes in weight and dyspnea scores were not apparent in the week preceding decompensation. CONCLUSIONS: Overall, Una concentration remained relatively stable over time, but large interindividual differences existed in stable, chronic HF patients. Patients who developed AHF exhibited a chronically lower Una concentration and exhibited a further drop in Una concentration during the week preceding hospitalization. Ambulatory Una sample collection is feasible and may offer additional prognostic and therapeutic information.

Hyponatremia in Acute Heart Failure in Relation to Hematocrit Levels: Clinical Relevance and Prognostic Implication.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality found in hospitalized patients with acute heart failure (AHF) and is related to poor prognosis. This study sought to evaluate: (1) the different prognostic impact of dilutional versus depletional hyponatremia, evaluating short- and long-term outcome; (2) the relationship between both types of hyponatremia and intravenous furosemide dose, renal function changes, and persistent congestion at discharge. METHODS: This retrospective single-center study included 233 consecutive patients with a primary diagnosis of AHF. Hyponatremia was defined as serum sodium < 135 mEq/L, which could be either dilutional (hematocrit < 35%) or depletional (hematocrit ≥35%). Persistent congestion was defined as a congestion score ≥2 at discharge. Patients were followed 180 days for occurrence of death or rehospitalization for AHF. RESULTS: Hyponatremia was present in 68/233 patients with 27 cases classified as dilutional hyponatremia versus 41 as depletional. The proportion of patients with persistent congestion was higher in the dilutional hyponatremia group, but similar in the depletional hyponatremia group (52 vs. 81 vs. 58%; p = 0.02). After adjustment for important baseline characteristics, dilutional hyponatremia was significantly associated with the risk of death or rehospitalization for AHF at 60 days (HR 2.17 [1.08-4.37]; p = 0.03) and 180 days (HR 1.88 [1.10-3.21]; p = 0.02). In contrast, depletional hyponatremia was only significantly associated with the same endpoint at 180 days (HR 1.64 [1.05-2.57]; p = 0.03). CONCLUSIONS: Low hematocrit levels in AHF patients with hyponatremia characterize a population that is more difficult to decongest and has poor clinical outcome. In contrast, patients with hyponatremia but normal hematocrit are better decongested and have better short-term outcome.

Optimizing CRT - Do We Need More Leads and Delivery Methods.

Cardiac resynchronization therapy (CRT) is an established therapeutic option in symptomatic heart failure with reduced ejection fraction and evidence of left ventricular (LV) conduction delay (QRS width ≥120 ms), especially when typical left bundle branch block is present. The rationale behind CRT is restoration of aberrant LV electrical activation. As there is considerable heterogeneity of the LV electrical activation pattern among CRT candidates, an individualized approach with targeting of the LV lead in the region of latest electrical activation while avoiding scar tissue may enhance CRT response. Echocardiography, electro anatomic mapping, and cardiac magnetic resonance imaging with late gadolinium enhancement are helpful to guide such targeted LV lead placement. However, an important limitation remains the anatomy of the coronary sinus, which often does not allow concordant LV lead placement in the optimal region. Epicardial LV lead placement through minimal invasive surgery or endocardial LV lead placement through transseptal punction may overcome this limitation, obviously with an increased complication risk. Furthermore, recent pacing algorithms suggest superiority of LV-only versus biventricular pacing in patients with preserved atrio ventricular (AV) conduction and a typical LBBB pattern. Finally, pacing from only one LV site might not overcome the wide electrical dispersion often seen in patients with LV conduction delays. Therefore, multisite pacing has gained significant interest to improve CRT response. The use of multiple LV leads may potentially lead to more favorable reverse remodeling, improved functional capacity and quality of life in CRT candidates, but adverse events and a shorter battery span are more frequent because of the extra lead. The use of one multipolar LV lead increases the number of pacing configurations within the same coronary sinus side branch (within small distances from each other) without the use of an additional lead. Small observational studies suggest that more effective resynchronization can be achieved with this approach. Finally, there are many reasons for non effective CRT delivery in carefully selected patients with an adequately implanted device. Multidisciplinary, post implantation care inside a dedicated CRT clinic ensures optimal CRT delivery, improves response rate and should be considered standard of care.

Management of the cardiorenal syndrome in decompensated heart failure.

BACKGROUND: The management of the cardiorenal syndrome (CRS) in decompensated heart failure (HF) is challenging, with high-quality evidence lacking. SUMMARY: The pathophysiology of CRS in decompensated HF is complex, with glomerular filtration rate (GFR) and urine output representing different aspects of kidney function. GFR depends on structural factors (number of functional nephrons and integrity of the glomerular membrane) versus hemodynamic alterations (volume status, renal perfusion, arterial blood pressure, central venous pressure or intra-abdominal pressure) and neurohumoral activation. In contrast, urine output and volume homeostasis are mainly a function of the renal tubules. Treatment of CRS in decompensated HF patients should be individualized based on the underlying pathophysiological processes. KEY MESSAGES: Congestion, defined as elevated cardiac filling pressures, is not a surrogate for volume overload. Transient decreases in GFR might be accepted during decongestion, but hypotension must be avoided. Paracentesis and compression therapy are essential to remove fluid overload from third spaces. Increasing the effective circulatory volume improves renal function when cardiac output is depressed. As mechanical support is invasive and inotropes are related to increased mortality, afterload reduction through vasodilator therapy remains the preferred strategy in patients who are normo- or hypertensive. Specific therapies to augment renal perfusion (rolofylline, dopamine or nesiritide) have rendered disappointing results, but recently, serelaxin has been shown to improve renal function, even with a trend towards reduced all-cause mortality in selected patients. Diuretic resistance is associated with worse outcomes, independent of the underlying GFR. Combinational diuretic therapy, with ultrafiltration as a bail-out strategy, is indicated in case of diuretic resistance.

Time from emerging heart failure symptoms to cardiac resynchronisation therapy: impact on clinical response.

OBJECTIVE: To investigate whether time from onset of heart failure signs and/or symptoms (ie, progression to stage C/D heart failure) until implantation affects reverse remodelling and clinical outcome after cardiac resynchronisation therapy (CRT). DESIGN: Cohort study of consecutive CRT patients, implanted between 1 October 2008 and 30 April 2011. SETTING: Single tertiary care centre (Ziekenhuis Oost-Limburg, Genk, Belgium). PATIENTS: Consecutive CRT patients (n=172; 71±9 years), stratified into tertiles according to the time since first heart failure signs and/or symptoms at implantation. MAIN OUTCOME MEASURES: Change in left ventricular dimensions, New York Heart Association (NYHA) functional class and freedom from all-cause mortality or heart failure admission. RESULTS: Baseline renal function was better in patients implanted earlier after emerging heart failure symptoms (estimated glomerular filtration rate=73±20 vs 63±23 vs 58±26 ml/min/1.73 m(2) for tertiles, respectively). After 6 months, decreases in left ventricular end-diastolic/systolic diameter and improvement in NYHA functional class were similar among tertiles. Freedom from all-cause mortality or heart failure admission was better in patients with early implantation (p value=0.042). However, this was not the case in patients with preserved renal function (p value=0.794). Death from progressive heart failure was significantly more frequent in patients implanted later in their disease course. CONCLUSIONS: Reverse left ventricular remodelling after CRT is not affected by the duration of heart failure. However, clinical outcome is better in patients implanted earlier in their disease course, which probably relates to better renal preservation.