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Objective: To evaluate the utility of Pulse index Contour Continuous Cardiac Output (PiCCO) monitoring in critically ill patients. Study Design: Cross-sectional study. Setting: Intensive Care Unti of Sindh Institute of Urology and Transplant, Karachi, Pakistan. Period: October 2022 to March 2023. Methods: Patients presenting with various types of shock, requiring high-dose vasopressors or inotropes, and not responding to initial fluid therapy were analyzed. Demographic details, SOFA score, APACHE score, and invasive hemodynamic parameters using the PiCCO system were documented. Results: Out of 142 ICU admissions, 38 patients were included in the study. Most patients were males (73%) with a median age of 39 years. Significant changes were observed in the cardiac index, cardiac performance index, global ejection fraction, and systemic vascular resistance index (SVRI), all with p-values less than 0.05. The interventions included the initiation of inotropes in 22 patients (57.8%), diuretics in 4 patients (10.5%), and intravenous fluids in 19 patients (50%). Additionally, vasopressor doses were adjusted in 18 patients (47.3%). Initially, patients were presumed to have pure septic shock based on CO2 gap, mixed venous saturation, and echocardiographic assessment. However, after applying PiCCO monitoring, the diagnosis was revised to mixed shock in 21 patients (55.2%). Conclusion: PiCCO monitoring appears to be a valuable tool in the ICU for managing patients with complex hemodynamic profiles, facilitating targeted interventions that lead to significant improvements in hemodynamic stability. [ABSTRACT FROM AUTHOR]

Aims: The viability of cardiac resynchronization therapy (CRT) in inotrope‐dependent heart failure (HF) has been a matter of debate. Methods and results: We searched Medline, EMBASE, Scopus, and the Cochrane Library until 31 December 2022. Studies were included if (i) HF patients required inotropic support at CRT implantation; (ii) patients were ≥18 years old; and (iii) they provided a clear definition of 'inotrope dependence' or 'inability to wean'. A meta‐analysis was performed in R (Version 3.5.1). Nineteen studies comprising 386 inotrope‐dependent HF patients who received CRT (mean age 64.4 years, 76.9% male) were included. A large majority survived until discharge at 91.1% [95% confidence interval (CI): 81.2% to 97.6%], 89.3% were weaned off inotropes (95% CI: 77.6% to 97.0%), and mean discharge time post‐CRT was 7.8 days (95% CI: 3.9 to 11.7). After 1 year of follow‐up, 69.7% survived (95% CI: 58.4% to 79.8%). During follow‐up, the mean number of HF hospitalizations was reduced by 1.87 (95% CI: 1.04 to 2.70, P < 0.00001). Post‐CRT mean QRS duration was reduced by 29.0 ms (95% CI: −41.3 to 16.7, P < 0.00001), and mean left ventricular ejection fraction increased by 4.8% (95% CI: 3.1% to 6.6%, P < 0.00001). The mean New York Heart Association (NYHA) class post‐CRT was 2.7 (95% CI: 2.5 to 3.0), with a pronounced reduction of individuals in NYHA IV (risk ratio = 0.27, 95% CI: 0.18 to 0.41, P < 0.00001). On univariate analysis, there was a higher prevalence of males (85.7% vs. 40%), a history of left bundle branch block (71.4% vs. 30%), and more pronounced left ventricular end‐diastolic dilation (274.3 ± 7.2 vs. 225.9 ± 6.1 mL). Conclusions: CRT appears to be a viable option for inotrope‐dependent HF, with some of these patients seeming more likely to respond. [ABSTRACT FROM AUTHOR]

Abstract Aims The viability of cardiac resynchronization therapy (CRT) in inotrope‐dependent heart failure (HF) has been a matter of debate. Methods and results We searched Medline, EMBASE, Scopus, and the Cochrane Library until 31 December 2022. Studies were included if (i) HF patients required inotropic support at CRT implantation; (ii) patients were ≥18 years old; and (iii) they provided a clear definition of ‘inotrope dependence’ or ‘inability to wean’. A meta‐analysis was performed in R (Version 3.5.1). Nineteen studies comprising 386 inotrope‐dependent HF patients who received CRT (mean age 64.4 years, 76.9% male) were included. A large majority survived until discharge at 91.1% [95% confidence interval (CI): 81.2% to 97.6%], 89.3% were weaned off inotropes (95% CI: 77.6% to 97.0%), and mean discharge time post‐CRT was 7.8 days (95% CI: 3.9 to 11.7). After 1 year of follow‐up, 69.7% survived (95% CI: 58.4% to 79.8%). During follow‐up, the mean number of HF hospitalizations was reduced by 1.87 (95% CI: 1.04 to 2.70, P

AIM: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

The optimal administration of inotrope after cardiac surgery is unknown. This study aimed to investigate the impact of postoperative inotrope on clinical outcomes in adult elective cardiac surgery patients. Data from the Blood Pressure and Relative Optimal Target after Heart Surgery in Epidemiologic Registry study were analyzed, employing propensity score considering the hospital of admission. The primary outcome was the length of hospital stay evaluated using quantile regression. Secondary outcomes were kidney injury progression, renal replacement therapy, atrial fibrillation, mortality, mechanical ventilation duration, and length of intensive care unit (ICU) stay. Among 870 patients from 14 ICUs in Japan, 535 received inotropes within 24 h of ICU admission, with usage rates ranging from 40 to 100% among facilities. After propensity score matching, 218 patients were included in each group. The inotrope group had a significantly longer hospital stay compared to the control group (16 days vs. 14 days; median difference 1.78 [95% confidence interval [CI] 0.31–3.24]; p = 0.018). However, no significant differences were observed in the secondary outcomes, except for mechanical ventilation duration. The results of the sensitivity analysis using a mixed-effects quantile regression analysis considering the hospital of admission for length of hospital stay in the original cohort were consistent with the results of the propensity analyses (median difference in days, 2.35 [95% CI, 0.35–4.36]; p = 0.022). The use of inotropes within 24 h of ICU admission in adult elective cardiac surgery patients was associated with an extended hospitalization period of approximately 2 days, without offering any prognostic benefit. Clinical trial registration: UMIN-CTR, https://www.umin.ac.jp/ctr/index-j.htm, UMIN000037074. [ABSTRACT FROM AUTHOR]

The authors investigated the role of early venoarterial extracorporeal membrane oxygenation (VA ECMO) implantation in patients with postcardiotomy cardiogenic shock (PCS) on mortality and morbidity when integrating vasoactive-inotropic score (VIS) and type of catecholamine support. A retrospective, multicenter, observational study with propensity-weight matching. Four university-affiliated intensive care units. Patients with PCS in the operating room. Early VA ECMO support. Of 2,742 patients screened during the study period, 424 (16%) patients were treated with inotropic drugs, and 75 (3%) patients were supported by VA ECMO in the operating room. Patients supported by VA ECMO had a higher use of vasopressor and inotropic drugs, with a higher VIS score. After propensity matching (integrating VIS and catecholamines type), mortality (56% v 20%, p < 0.001) and morbidity (cardiac, renal, transfusion) were higher in patients supported by VA ECMO than in a matched control group. When matching integrated the pre-ECMO VIS and the type of catecholamines, VA ECMO remained associated with high mortality and morbidity, suggesting that VIS alone should not be used as a main determinant of VA ECMO implantation. [ABSTRACT FROM AUTHOR]

Abstract Aim Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular‐pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right‐sided haemodynamics in HFrEF assessed by RVPAC. Methods and results The Karolinska Acyl ghrelin Trial was a randomized double‐blind placebo‐controlled trial of acyl ghrelin versus placebo (120‐min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5–4.6) to 4.6 (3.9–6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3–7.6) to 6.3 (4.8–7.5) mm·(m/s)−1, P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3–6.4) to 4.8 (4.2–5.8) mm·(m/s)−1, P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged. Conclusion Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure.

To evaluate milrinone's impact on pediatric cardiac function, focusing on its specific role as an inotrope and lusitrope, while considering its systemic and pulmonary vasodilatory effects. Search of PubMed, EMBASE, and the Cochrane Library up to August 2023. We included all studies that evaluated milrinone in children under 18 years old in neonatal, pediatric, or cardiac intensive care units. We excluded case reports, studies that did not provide tabular information on milrinone's outcomes, and studies focused on non-intensive care populations. We extracted data on the research design, objectives, study sample, and results of each study, including the impact of milrinone and any associated factors. We screened a total of 9423 abstracts and 41 studies were ultimately included. Milrinone significantly improved left ventricular ejection fraction (WMD 3.41 [95% CI 0.61 – 6.21]), left ventricle shortening fraction (WMD 4.25 [95% CI 3.43 – 5.08]), cardiac index (WMD 0.50 [95% CI 0.32 to 0.68]), left ventricle output (WMD 55.81 [95% CI 4.91 to 106.72]), serum lactate (WMD -0.59 [95% CI -1.15 to -0.02]), and stroke volume index (WMD 2.95 [95% CI 0.09 – 5.82]). However, milrinone was not associated with improvements in ventricular myocardial performance index (WMD -0.01 [95% CI -0.06 to 0.04]) and ventricular longitudinal strain (WMD -2.14 [95% CI -4.56 to 0.28]). Furthermore, milrinone was not associated with isovolumetric relaxation time reduction (WMD -8.87 [95% CI -21.40 to 3.66]). Conclusion: Our meta-analysis suggests potential clinical benefits of milrinone by improving cardiac function, likely driven by its systemic vasodilatory effects. However, questions arise about its inotropic influence and the presence of a lusitropic effect. Moreover, milrinone's pulmonary vasodilatory effect appears relatively weaker compared to its systemic actions. Further research is needed to elucidate milrinone's precise mechanisms and refine its clinical applications in pediatric practice. What is Known: • Milrinone is a phosphodiesterase III inhibitor that has been used to treat a variety of pediatric and neonatal conditions. • Milrinone is believed to exert its therapeutic effects by enhancing cardiac contractility and promoting vascular relaxation. What is New: • Milrinone may not have a significant inotropic effect. • Milrinone's pulmonary vasodilatory effect is less robust than its systemic vasodilatory effect. [ABSTRACT FROM AUTHOR]

• Inotrope formulations avoiding the burdens of continuous IV infusion are needed. • We tested a novel, concentrated formulation of milrinone for inhalation. • Nebulized milrinone was well tolerated and without adverse events. • Intermittent inhalation of milrinone produced therapeutic serum concentrations. • Nebulized milrinone improved invasive hemodynamic parameters. Nonintravenous inotropic-delivery options are needed for patients with inotropic-dependent heart failure (HF) to reduce the costs, infections and thrombotic risks associated with chronic central venous catheters and home infusion services. We developed a novel, concentrated formulation of nebulized milrinone for inhalation and evaluated the feasibility, safety and pharmacokinetic profile in a prospective, single-arm, phase I clinical trial. We enrolled 10 patients with stage D HF requiring inotropic therapy during a hospital admission for acute HF. Milrinone 60 mg/4 mL was inhaled via nebulization 3 times daily for 48 hours. The coprimary outcomes were adverse events and pharmacokinetic profiles of inhaled milrinone. Acute changes in hemodynamic parameters were secondary outcomes. A concentrated nebulized milrinone formulation was well tolerated, without hypotensive events, arrhythmias or inhalation-related adverse events requiring discontinuation. Nebulized milrinone produced serum concentrations in the goal therapeutic range with a median plasma milrinone trough concentration of 39 (17–66) ng/mL and a median peak concentration of 207 (134–293) ng/mL. There were no serious adverse events. From baseline to 24 hours, mean pulmonary artery saturation increased (60% ± 7%–65 ± 5%; P = 0.001), and mean cardiac index increased (2.0 ± 0.5 mL/min/1.73m2–2.5 ± 0.1 mL/min/1.73m2; P = 0.001) with nebulized milrinone. In a proof-of-concept study, a concentrated, nebulized milrinone formulation for inhalation was safe and produced therapeutic serum milrinone concentrations. Nebulized milrinone was associated with improved hemodynamic parameters of cardiac output in a population with advanced HF. These promising results require further investigation in a longer-term trial in patients with inotrope-dependent advanced HF. [ABSTRACT FROM AUTHOR]

Aim: Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular‐pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right‐sided haemodynamics in HFrEF assessed by RVPAC. Methods and results: The Karolinska Acyl ghrelin Trial was a randomized double‐blind placebo‐controlled trial of acyl ghrelin versus placebo (120‐min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5–4.6) to 4.6 (3.9–6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3–7.6) to 6.3 (4.8–7.5) mm·(m/s)−1, P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3–6.4) to 4.8 (4.2–5.8) mm·(m/s)−1, P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged. Conclusion: Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism. [ABSTRACT FROM AUTHOR]

This was a single center, retrospective cohort study designed to evaluate the association between the administration of inotropes to hypotensive very low gestational age infants (VLGAI) and prenatal and neonatal risk factors. Inpatient medical records were reviewed to identify neonates treated with inotropes (treated group) and a control group for comparison. Two hundred and twenty two (222) VLGAI (less than 32 weeks' gestation) were included in the final analysis and were stratified based on timing of treatment with 83 infants (37.4%) and 139 infants (62.6%) in the treated and control groups, respectively. A total of 56/83 (67%) received inotropes for arterial hypotension during the first 3 days (early treatment subgroup) and 27/83 (32.5%) after 3 days of life (late-treated subgroup). Fentanyl, severe intraventricular hemorrhage (IVH), and gestational age (GA) were the risk factors most significantly associated with the need for inotrope use both during the first 3 days of life and the whole NICU stay, before and after adjustment for confounders. In conclusion, fentanyl, severe IVH, and GA are the risk factors most strongly associated with the need for inotrope treatment in VLGAI. Measures to modify these risk factors may decrease the need for cardiovascular medications and improve outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: In anesthetized dogs, hypotension, defined as a mean arterial pressure (MAP) of <60–70 mmHg, has an incidence of up to 60%. It is therefore imperative to avoid the occurrence of hypotension and undertake immediate strategies to treat it. Treatment protocols for the correction of isoflurane-mediated hypotension include lowering or terminating isoflurane administration; lowering isoflurane requirement by using anesthetic adjuncts and analgesics; intravenous crystalloid and/or colloid bolus; and delivering anticholinergics, positive inotropes, and vasopressor drugs. The present study evaluated and compared the hemodynamic effects of dobutamine (DOB), norepinephrine (NEP), vasopressin (VAS), and hetastarch (HES) for the treatment of isoflurane-induced hypotension and established the most effective dosage regimen for the correction of hypotension. In healthy, anesthetized Beagle dogs undergoing acute, severe isoflurane-induced hypotension, NEP administered as an infusion was the most efficient therapy for correcting MAP. However, the DOB, VAS, and HES treatments were unsuccessful in stabilizing the MAP to >65 mmHg, even at maximum doses. Isoflurane is a commonly used inhalation anesthetic in species undergoing veterinary care that induces hypotension, impacting organ perfusion, making it imperative to minimize its occurrence or identify effective strategies for treating it. This study evaluated and compared the hemodynamic effects of DOB, NEP, VAS, and HES in twelve isoflurane-anesthetized Beagle dogs. The order of the first three treatments was randomized. HES was administered last. Data were collected before treatments (baseline) and after 10 min of a sustained MAP of <45 mmHg induced by a high end-tidal isoflurane concentration (T0). Once treatment was initiated and the target MAP was achieved (65 to 80 mmHg) or the maximum dose reached, data were collected after 15 min of stabilization (T1) and 15 min after (T2). A 15 min washout period with a MAP of ≥65 mmHg was allowed between treatments. The intravenous dosage regimens started and were increased by 50% every five minutes until the target MAP or maximum dose was reached. The dosages were as follows: DOB, 5–15 μg/kg/min; NEP, 0.1–2 μg/kg/min; VAS, 0.5–5 mU/kg/min; and HET, 6% 1–20 mL/kg/min. DOB improved CO, DO2, and VO2, but reduced SVR. VAS elevated SVR, but decreased CO, DO2, and VO2. HES minimally changed BP and mildly augmented CO, DO2, and VO2. These treatments failed to reach the target MAP. NEP increased the arterial BP, CO, MPAP, and PAWP, but reduced HR. Norepinephrine infusion at 0.44 ± 0.19 μg/kg/min was the most efficient therapy for correcting isoflurane-induced hypotension. [ABSTRACT FROM AUTHOR]

Simple Summary: Cardiac output (CO) measurement devices are classified as invasive, minimally invasive, or noninvasive depending on their level of invasiveness for CO data acquisition. Pulmonary artery thermodilution is the 'gold standard' CO technique. This method is more accurate, but its invasiveness possesses risks. Minimally invasive lithium dilution (LiD) is slowly replacing thermodilution as a reference standard in animal research due to its excellent agreement and acceptable performance. Monitoring CO with standard cardiovascular parameters (i.e., blood pressure and heart rate) in anesthetized animals can potentially improve patient care and case outcomes. Hence, we evaluated noninvasive electrical cardiometry (EC)-measured CO and other EC-acquired hemodynamic variables, and analyzed them against CO measured using LiD in healthy, anesthetized dogs during different treatments (dobutamine, esmolol, phenylephrine, and high-dose isoflurane) impacting CO values. Overall, EC showed good agreement with LiD, but it exhibited consistent underestimation when the CO values were higher. The percentage error was low and within published standards, and a good trending pattern was exhibited by EC. The acquired EC variables followed the trends in CO obtained by LiD. EC may be a pivotal tool for monitoring trends in hemodynamics and guiding treatments for cardiovascular anesthetic complications in clinical settings. Numerous cardiac output (CO) technologies were developed to replace the 'gold standard' pulmonary artery thermodilution due to its invasiveness and the risks associated with it. Minimally invasive lithium dilution (LiD) shows excellent agreement with thermodilution and can be used as a reference standard in animals. This study evaluated CO via noninvasive electrical cardiometry (EC) and acquired hemodynamic variables against CO measured using LiD in six healthy, anesthetized dogs administered different treatments (dobutamine, esmolol, phenylephrine, and high-dose isoflurane) impacting CO values. These treatments were chosen to cause drastic variations in CO, so that fair comparisons between EC and LiD across a wide range of CO values (low, intermediate, and high) could be made. Statistical analysis included linear regression, Bland–Altman plots, Lin's concordance correlation coefficient (ρc), and polar plots. Values of p < 0.05 represented significance. Good agreement was observed between EC and LiD, but consistent underestimation was noted when the CO values were high. The good trending ability, ρc of 0.88, and low percentage error of ±31% signified EC's favorable performance. Other EC-acquired variables successfully tracked changes in CO measured using LiD. EC may be a pivotal hemodynamic tool for continuously monitoring circulatory changes, as well as guiding and treating cardiovascular anesthetic complications in clinical settings. [ABSTRACT FROM AUTHOR]

Background and Aims Ghrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes. Methods and results In a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3. Conclusion In patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT05277415 [ABSTRACT FROM AUTHOR]

Vasopressor use in patients undergoing autologous free tissue transfer is generally discouraged by surgeons perioperatively. This stems from concerns about the increased risk of flap failure with their use. The aim of this systematic review was to investigate the evidence and quantify any harm or benefits associated with vasopressor use. A systematic review of the literature was undertaken using OVID Medline to search 13 databases. The search strategy used Boolean operators, text word searches, truncation symbols, and adjacency searching. Terms such as "free flap," "free tissue graft," and "free tissue transfer" were used along with a list of appropriate vasopressors. The primary outcome was free flap failure, on which a meta-analysis was performed. The search initially identified 1029 unique articles, which after title and abstract screening was reduced to 112, of which 15 remained after full-text screening for inclusion in the review and analysis. We analyzed data from 8427 flaps, with 6695 having received a vasopressor. Meta-analysis demonstrated that vasopressor use reduced the relative risk (RR) of free flap failure (RR: 0.70; 95% CI: 0.50–0.97; p = 0.03) but did not affect rates of other adverse events (RR: 0.81; 95% CI: 0.63–1.05; p = 0.11). Vasopressor use appears beneficial for autologous free tissue transfer, with evidence that it reduced the risk of flap failure without impacting the rates of other adverse events. The use of vasopressors should, therefore, be encouraged on a case-by-case basis, depending upon the general physiological needs of the patient. [ABSTRACT FROM AUTHOR]

This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline‐directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end‐of‐life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support). [ABSTRACT FROM AUTHOR]

Cardiogenic shock is characterized by tissue hypoxia caused by circulatory failure arising from inadequate cardiac output. In addition to treating the pathologic process causing impaired cardiac function, prompt hemodynamic support is essential to reduce the risk of developing multiorgan dysfunction and to preserve cellular metabolism. Pharmacologic therapy with the use of vasopressors and inotropes is a key component of this treatment strategy, improving perfusion by increasing cardiac output, altering systemic vascular resistance, or both, while allowing time and hemodynamic stability to treat the underlying disease process implicated in the development of cardiogenic shock. Despite the use of mechanical circulatory support recently garnering significant interest, pharmacologic hemodynamic support remains a cornerstone of cardiogenic shock management, with over 90% of patients receiving at least 1 vasoactive agent. This review aims to describe the pharmacology and hemodynamic effects of current pharmacotherapies and provide a practical approach to their use, while highlighting important future research directions.

Background: Although many improvements in neonatal care have been achieved, mortality rates for sepsis and septic shock in newborns are still high. The vasoactive inotropic score (VIS) was designed and studied to predict mortality in different settings. There are currently no data on the predictive ability of the VIS for mortality in newborn patients with septic shock.Methods: Patients with late-onset neonatal sepsis who required inotropes because of fluid-refractory septic shock during the study period were included in the study. Four distinct VIS values were calculated for each septic shock episode after inotropic treatment had begun, that is, at the initiation of inotropic treatment and at 24 and 48 h after inotropic treatment had begun, and the highest VIS (VISmax) at any time after initiation of inotropic agents.Results: The 98 episodes studied were divided into two groups according to the outcomes of their sepsis episodes as survivors (n = 39) or nonsurvivors (n = 59). The areas under the curve of the VIS values for the prediction of mortality were the VISmax (0.819, p < 0.001), followed by the VIS48 (0.802, p < 0.001), VIS24 (0.762, p = 0.001) and VIS0 (0.699, p = 0.015). Patients with a VISmax of greater than 20 had significantly higher odds of mortality (p < 0.001, β = 14.7, 95% confidence interval [4.7-45.9]).Conclusion: We found that the VISmax was an easy-to-use and helpful tool for predicting a poor outcome in neonatal sepsis. Physicians should be aware that the prognosis is poor for any newborn with a VIS of 20 or greater at any point after the onset of sepsis. [ABSTRACT FROM AUTHOR]

This was a single center, retrospective cohort study designed to evaluate the association between the administration of inotropes to hypotensive very low gestational age infants (VLGAI) and prenatal and neonatal risk factors. Inpatient medical records were reviewed to identify neonates treated with inotropes (treated group) and a control group for comparison. Two hundred and twenty two (222) VLGAI (less than 32 weeks’ gestation) were included in the final analysis and were stratified based on timing of treatment with 83 infants (37.4%) and 139 infants (62.6%) in the treated and control groups, respectively. A total of 56/83 (67%) received inotropes for arterial hypotension during the first 3 days (early treatment subgroup) and 27/83 (32.5%) after 3 days of life (late-treated subgroup). Fentanyl, severe intraventricular hemorrhage (IVH), and gestational age (GA) were the risk factors most significantly associated with the need for inotrope use both during the first 3 days of life and the whole NICU stay, before and after adjustment for confounders. In conclusion, fentanyl, severe IVH, and GA are the risk factors most strongly associated with the need for inotrope treatment in VLGAI. Measures to modify these risk factors may decrease the need for cardiovascular medications and improve outcomes.

Abstract The inodilator levosimendan, in clinical use for over two decades, has been the subject of extensive clinical and experimental evaluation in various clinical settings beyond its principal indication in the management of acutely decompensated chronic heart failure. Critical care and emergency medicine applications for levosimendan have included postoperative settings, septic shock, and cardiogenic shock. As the experience in these areas continues to expand, an international task force of experts from 15 countries (Austria, Belgium, China, Croatia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Spain, Sweden, Switzerland, and the USA) reviewed and appraised the latest additions to the database of levosimendan use in critical care, considering all the clinical studies, meta-analyses, and guidelines published from September 2019 to November 2021. Overall, the authors of this opinion paper give levosimendan a “should be considered” recommendation in critical care and emergency medicine settings, with different levels of evidence in postoperative settings, septic shock, weaning from mechanical ventilation, weaning from veno-arterial extracorporeal membrane oxygenation, cardiogenic shock, and Takotsubo syndrome, in all cases when an inodilator is needed to restore acute severely reduced left or right ventricular ejection fraction and overall haemodynamic balance, and also in the presence of renal dysfunction/failure.

Background: Aortic stenosis (AS) increases left ventricular afterload, leading to cardiac damage and heart failure (HF). Transcatheter aortic valve replacement (TAVR) is an effective therapy for AS. No inotropic agents including levosimendan have been evaluated in patients undergoing TAVR. Methods: A total of 285 patients underwent TAVR between 2014 and 2019; 210 were included in the matched analysis and 105 received 0.1 µg/kg body weight/min levosimendan immediately after the prosthesis had been successfully implanted. Medical history, laboratory tests, and echocardiography results were analyzed. Endpoints including 2-year allcause mortality, stroke, or HF-related hospitalization, and a combination of the above were analyzed by Cox proportional hazard models. Results: The levosimendan group had no difference in 2-year mortality compared with the control group (hazard ratio [HR]: 0.603, 95% confidence interval [CI]: 0.197-1.844; p = 0.375). However, levosimendan reduced stroke or HF-related hospitalization (HR: 0.346; 95% CI: 0.135-0.884; p = 0.027) and the combined endpoint (HR: 0.459, 95% CI: 0.215-0.980; p = 0.044). After adjusting for multiple variants, levosimendan still reduced stroke or HFrelated hospitalization (HR: 0.346, 95% CI: 0.134-0.944; p = 0.038). Conclusion: Prophylactic levosimendan administration immediately after valve implantation in patients undergoing TAVR can reduce stroke or HF-related hospitalization but does not lower all-cause mortality. [ABSTRACT FROM AUTHOR]

Aim: Noradrenaline (NA) has been used in preterm and term infants for circulatory support due to conditions including sepsis and pulmonary hypertension of the newborn. Treatment in neonates varies widely between institutions and respective neonatologists. The aim of this study is to determine the indications, use and effects of NA in preterm and term infants requiring circulatory support at the Royal Brisbane and Women's Hospital neonatal intensive care unit. We also aim to determine whether there were any differences between neonates who survived versus those who died after NA treatment. Methods: Data were collected from Royal Brisbane and Women's Hospital neonatal unit database including preterm and term infants between 1 January 2016 and 31 May 2021. Analysis included indication for use, blood pressure response, perfusion parameters, haemodynamic indicators and adverse effects. Results: NA treatment was documented in 37 patients requiring treatment of cardiovascular compromise. In 11 (30%) of these infants the indication for use was due to sepsis, 19 (51%) infants had pulmonary hypertension of the newborn, and 7 (19%) infants were diagnosed with hypotension prior to NA administration. Infants who subsequently died (49%) represented a younger gestational age population and exhibited worse cardiac compromise prior to NA administration. Tachycardia occurred in 15 (31%) infants and 1 (2.7%) infant developed transient hypertension. Overall improvement in poor tissue perfusion was seen after NA use. Conclusion: NA use in treating neonates requiring circulatory support appears to be effective. Further prospective trials into NA use as a first‐ or second‐line inotropic agent would be valuable. [ABSTRACT FROM AUTHOR]

Cardiogenic shock (CS) remains a leading cause of morbidity and mortality among patients with cardiovascular disease. In the past, acute myocardial infarction was the leading cause of CS. However, in recent years, other etiologies, such as decompensated chronic heart failure, arrhythmia, valvular disease, and post-cardiotomy, each with distinct hemodynamic profiles, have risen in prevalence. The number of treatment options, particularly with regard to device-mediated therapy has also increased. In this review, we sought to survey the medical literature and provide an update on current practices. [ABSTRACT FROM AUTHOR]

Aims: Cardiogenic shock (CS) is linked to high morbidity and mortality rates, posing a challenge for clinicians. Interventions to improve tissue perfusion and blood pressure are crucial to prevent further deterioration. Unfortunately, current inotropes, which act through adrenergic receptor stimulation, are associated with malignant arrhythmias and poorer outcomes. Due to its unique mechanism of action, istaroxime should improve haemodynamics without adrenergic overactivation. The SEISMiC study is designed to examine the safety and efficacy (haemodynamic effect) of istaroxime administrated in pre-CS patients., Methods and Results: The SEISMiC study is a multinational, multicentre, randomized, double-blind, placebo-controlled safety and efficacy study with two parts (A and B). The study enrols patients hospitalized for decompensated heart failure (pre-CS, not related to myocardial ischaemia) with persistent hypotension [systolic blood pressure (SBP) 70-100 mmHg for at least 2 h] and clinically confirmed congestion, NT-proBNP ≥1400 pg/mL, and LVEF≤40%. Subjects must not have taken intravenous (iv) vasopressors, inotropes or digoxin in the past 6 h. Eligible patients are randomized to receive IV infusion of istaroxime (different doses and regimens in Parts A and B) or placebo for up to 60 h. Central haemodynamics, ECG Holter monitoring, cardiac ultrasound and biomarkers are recorded at predefined time points during the trial. The study's primary efficacy endpoint is the SBP area under the curve from baseline curve from baseline to 6 and 24 h in the combined SEISMiC Parts A and B population. Key secondary efficacy endpoints include haemodynamic, laboratory and clinical measures in SEISMiC B alone in the combined SEISMiC A and B studies., Conclusions: The study results will contribute to our understanding of the role of istaroxime in pre-CS patients and potentially provide insight into the drug's haemodynamic effects and safety in this population., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In patients with newly diagnosed heart failure with reduced ejection fraction (HFrEF) who are on a downward clinical trajectory, options are mostly limited to left ventricular assist device and transplantation. However, in those with factors favorable for reverse remodeling, every effort should be made to promote native myocardial recovery. We present three patients with newly diagnosed severe HFrEF, NYHA Class 3-4 symptoms, and low cardiac output with and without organ malperfusion. Ivabradine and/or home milrinone were used during their tenuous hemodynamic period as a bridge to optimize guideline-directed medical therapy (GDMT), device therapy, and eventual reverse remodeling. Evidence of structural heart improvement continued far beyond 1 year., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Lekha Racharla et al.)

Cardiogenic shock (CS) is a hemodynamically complex and highly morbid syndrome characterized by circulatory collapse and inadequate end-organ perfusion due to impaired cardiac output. It is usually associated with multiorgan failure and death. Mortality rate is still high despite advancement in treatment. CS has been conceptualised as a vicious cycle of injury and decompensation, both cardiac and systemic. Interrupting the vicious cycle and restoring the hemodynamic stability is a fundamental treatment of CS. Acute coronary syndrome (ACS) is the most frequent cause of CS. Early coronary revascularization is a cornerstone therapy that reduces mortality in patients with ACS complicated by CS. Early diagnosis of CS accompanied with invasive hemodynamics, helps in identification of CS phenotype, classification of CS severity, stratification of risk and prognostication. This can guide a tailored and optimized therapeutic approach. Inotropes and vasopressors are considered the first-line pharmacological option for hemodynamic instability. The current availability of the mechanical circulatory support devices has broadened the therapeutic choices for hemodynamic support. To date there is no pharmacological or nonpharmacological intervention for CS that showed a mortality benefit. The clinical practices in CS management remain inconsistent. Herein, this review discusses the current evidence in the diagnosis and management of CS complicating ACS, and features the changes in CS definition and classification.

Isoflurane is a commonly used inhalation anesthetic in species undergoing veterinary care that induces hypotension, impacting organ perfusion, making it imperative to minimize its occurrence or identify effective strategies for treating it. This study evaluated and compared the hemodynamic effects of DOB, NEP, VAS, and HES in twelve isoflurane-anesthetized Beagle dogs. The order of the first three treatments was randomized. HES was administered last. Data were collected before treatments (baseline) and after 10 min of a sustained MAP of 2, and VO2, but reduced SVR. VAS elevated SVR, but decreased CO, DO2, and VO2. HES minimally changed BP and mildly augmented CO, DO2, and VO2. These treatments failed to reach the target MAP. NEP increased the arterial BP, CO, MPAP, and PAWP, but reduced HR. Norepinephrine infusion at 0.44 ± 0.19 μg/kg/min was the most efficient therapy for correcting isoflurane-induced hypotension.

Small molecule cardiac troponin activators could potentially enhance cardiac muscle contraction in the treatment of systolic heart failure. We designed a small molecule, RPI-194, to bind cardiac/slow skeletal muscle troponin (Cardiac muscle and slow skeletal muscle share a common isoform of the troponin C subunit.) Using solution NMR and stopped flow fluorescence spectroscopy, we determined that RPI-194 binds to cardiac troponin with a dissociation constant KD of 6–24 μM, stabilizing the activated complex between troponin C and the switch region of troponin I. The interaction between RPI-194 and troponin C is weak (KD 311 μM) in the absence of the switch region. RPI-194 acts as a calcium sensitizer, shifting the pCa50 of isometric contraction from 6.28 to 6.99 in mouse slow skeletal muscle fibers and from 5.68 to 5.96 in skinned cardiac trabeculae at 100 μM concentration. There is also some cross-reactivity with fast skeletal muscle fibers (pCa50 increases from 6.27 to 6.52). In the slack test performed on the same skinned skeletal muscle fibers, RPI-194 slowed the velocity of unloaded shortening at saturating calcium concentrations, suggesting that it slows the rate of actin-myosin cross-bridge cycling under these conditions. However, RPI-194 had no effect on the ATPase activity of purified actin-myosin. In isolated unloaded mouse cardiomyocytes, RPI-194 markedly decreased the velocity and amplitude of contractions. In contrast, cardiac function was preserved in mouse isolated perfused working hearts. In summary, the novel troponin activator RPI-194 acts as a calcium sensitizer in all striated muscle types. Surprisingly, it also slows the velocity of unloaded contraction, but the cause and significance of this is uncertain at this time. RPI-194 represents a new class of non-specific troponin activator that could potentially be used either to enhance cardiac muscle contractility in the setting of systolic heart failure or to enhance skeletal muscle contraction in neuromuscular disorders. [ABSTRACT FROM AUTHOR]

Low copeptin levels may indicate inadequate arginine-vasopressin release promoting arterial hypotension, whereas high copeptin concentrations may reflect disease severity. This single-center prospective non-randomized clinical trial analyzed the course of blood copeptin in critically ill normo- and hypotensive children and its association with disease severity. In 164 patients (median age 0.5 years (interquartile range 0.1, 2.9)), the mean copeptin concentration at baseline was 43.5 pmol/L. Though not significantly different after 61 h (primary outcome, mean individual change: −12%, p = 0.36, paired t-test), we detected 1.47-fold higher copeptin concentrations during arterial hypotension when compared to normotension (mixed-effect ANOVA, p = 0.01). In total, 8 out of 34 patients (23.5%) with low copeptin concentrations <10 pmol/L were hypotensive. Copeptin was highest in the adjusted mixed-effect regression analysis within the first day (+20% at 14 h) and decreased significantly at 108 h (−27%) compared to baseline (p = 0.002). Moreover, we found a significant association with vasopressor-inotrope treatment intensity, infancy (1–12 months) and cardiopulmonary bypass (all p ≤ 0.001). In conclusion, high copeptin values were associated with arterial hypotension and severity of disease in critically ill children. This study does not support the hypothesis that low copeptin values might be indicative of arginine-vasopressin deficiency. [ABSTRACT FROM AUTHOR]

Small molecule cardiac troponin activators could potentially enhance cardiac muscle contraction in the treatment of systolic heart failure. We designed a small molecule, RPI-194, to bind cardiac/slow skeletal muscle troponin (Cardiac muscle and slow skeletal muscle share a common isoform of the troponin C subunit.) Using solution NMR and stopped flow fluorescence spectroscopy, we determined that RPI-194 binds to cardiac troponin with a dissociation constant KD of 6–24 μM, stabilizing the activated complex between troponin C and the switch region of troponin I. The interaction between RPI-194 and troponin C is weak (KD 311 μM) in the absence of the switch region. RPI-194 acts as a calcium sensitizer, shifting the pCa50 of isometric contraction from 6.28 to 6.99 in mouse slow skeletal muscle fibers and from 5.68 to 5.96 in skinned cardiac trabeculae at 100 μM concentration. There is also some cross-reactivity with fast skeletal muscle fibers (pCa50 increases from 6.27 to 6.52). In the slack test performed on the same skinned skeletal muscle fibers, RPI-194 slowed the velocity of unloaded shortening at saturating calcium concentrations, suggesting that it slows the rate of actin-myosin cross-bridge cycling under these conditions. However, RPI-194 had no effect on the ATPase activity of purified actin-myosin. In isolated unloaded mouse cardiomyocytes, RPI-194 markedly decreased the velocity and amplitude of contractions. In contrast, cardiac function was preserved in mouse isolated perfused working hearts. In summary, the novel troponin activator RPI-194 acts as a calcium sensitizer in all striated muscle types. Surprisingly, it also slows the velocity of unloaded contraction, but the cause and significance of this is uncertain at this time. RPI-194 represents a new class of non-specific troponin activator that could potentially be used either to enhance cardiac muscle contractility in the setting of systolic heart failure or to enhance skeletal muscle contraction in neuromuscular disorders.

IntroductionTwo parallel paradigms of cardiovascular efficiency and haemodynamic optimisation coexist in haemodynamic research. Targeting ventriculo-arterial (VA) coupling [i.e., the ratio between arterial and ventricular elastance (EV)] and electromechanical coupling are two promising approaches in acute circulatory failure. However, validation of the parameters of electromechanical coupling in critically ill patients is ongoing. Furthermore, a unifying link between VA and electromechanical coupling may exist, as EV is correlated with different times of the cardiac cycle.Materials and MethodsThis study was a retrospective analysis of a prospectively collected observational database from one tertiary center ICU. We analyzed the relationship between electromechanical dyssynchrony and acute circulatory failure hemodynamics before and after treatment (i.e., fluid expansion, dobutamine, or norepinephrine infusion). The relationship between electromechanical coupling and VA coupling was also investigated. Adult patients with haemodynamic instability were included. Haemodynamic parameters, including arterial pressure, cardiac index, VA coupling, stroke work index/pressure–volume area (SWI/PVA), t-IVT, and Tei's index, were collected before and after treatment. A t-IVT of >12 s/min was classified as intraventricular dyssynchrony.ResultsWe included 54 patients; 39 (72.2%) were classified as having intraventricular dyssynchrony at baseline. These patients with baseline dyssynchrony showed a statistically significant amelioration of t-IVT (from 18 ± 4 s to 14 ± 6 s, p = 0.001), left ventricular EV [from 1.1 (0.72–1.52) to 1.33 (0.84–1.67) mmHg mL−1, p = 0.001], VA coupling [from 2 (1.67–2.59) to 1.80 (1.40–2.21), p = 0.001], and SWI/PVA [from 0.58 (0.49–0.65) to 0.64 (0.51–0.68), p = 0.007]. Patients without baseline dyssynchrony showed no statistically significant results. The improvement in VA coupling was mediated by an amelioration of EV. All patients improved their arterial pressure and cardiac index with treatment. The haemodynamic treatment group exhibited no effect on changing t-IVT.ConclusionAcute circulatory failure is associated with electromechanical dyssynchrony. Cardiac electromechanical coupling was improved by haemodynamic treatment only if altered at baseline. The improvement of cardiac electromechanical coupling was associated with the improvement of markers of cardiocirculatory efficacy and efficiency (i.e., SWI/PVA and VA coupling). This study was the first to demonstrate a possible link between cardiac electromechanical coupling and VA coupling in patients with acute circulatory failure.

Background and Aims: We hypothesized that maintaining a patient on moderate–high doses of potent inhalational agent for greater than 30 min during the post-bypass period would be an independent predictor of initiation and usage of either inotropic and/or vasopressor infusions. Setting and Design: This study is a retrospective design and approved by the institutional review board. The setting was a single-center, academic tertiary care hospital in Detroit, Michigan. Materials and Methods: Three-hundred, ninety-seven elective cardiac surgery patients were identified for chart review. Electronic medical records were reviewed to collect demographics and perioperative data. Statistics used include a propensity score regression adjusted analysis utilizing logistic regression models and a multivariable model. Results: A propensity score regression adjusted analysis was performed and then applied in both univariate and multivariate logistic regression models with a p value of ISO ≥ 0.5MAC, 30 min) in the post-bypass period. After adjusting for propensity score, this was found to be a significant predictor of inotrope and/or vasoconstrictor use post-bypass (OR 2.49, 95% CI 1.15–5.38, p = 0.021). In the multivariate model, pulmonary hypertension (OR 5.9; 95% CI 1.33–26.28; p = 0.02), Euroscore II (2.73; 95% CI 1.35–5.5; p = 0.005), and cardiopulmonary bypass hours (OR 1.86; 95% CI 1.02–3.4; p = 0.042) emerged as significant. Conclusions: This study showed that an ETISO ≥ 0.5MAC, 30 min exposure during the immediate post-bypass period during elective cardiac surgery was an independent predictor of a patient being started on inotrope or vasoconstrictor infusions. Further research should consider a prospective design and examine depth of anesthesia during the post-bypass period.

Patients with cardiac amyloidosis (CA) often experience heart failure (HF) episodes. No evidence is available on inotropic therapy. This study aims to fill this gap by examining the safety and efficacy of levosimendan. We retrieved all HF patients receiving ≥1 levosimendan infusion from 2013 to 2023. CA patients were matched with HF patients without CA (controls) based on sex, age, and left ventricular ejection fraction (LVEF). The response to levosimendan was measured as changes in daily urinary output, body weight, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR). CA patients (median age 77 years, 73% men, 59% with ATTR-CA) and controls were compared. Levosimendan infusion was stopped because of hypotension in 2 cases with CA and (in 1 case) worsening renal function, and in 2 controls because of ventricular tachycardia episodes and (in 1 case) hypotension. CA patients showed a trend toward increased daily urinary output (p = 0.078) and a significant decrease in body weight (p < 0.001), without significant changes in NT-proBNP (p = 0.497) and eGFR (p = 0.732). Both CA patients and controls displayed similar changes in urinary output, weight, and eGFR, but NT-proBNP decreased more significantly among controls (p < 0.001). No differences were noted in rehospitalization rates, but CA patients experienced higher mortality at 6 and 12 months (p = 0.003 and p = 0.001, respectively). Levosimendan appears safe for CA patients needing inotropic support. The diuretic response and weight decrease during hospitalization were comparable between CA patients and matched HF patients, despite the greater mortality of CA patients after discharge. [Display omitted] • CA patient on levosimendan were studied. • They were matched with HF patients without CA. • Urinary output, weight, NT-proBNP were monitored. • CA showed higher mortality at 6 and 12 months. • Levosimendan was deemed safe in CA. [ABSTRACT FROM AUTHOR]

The global prevalence of heart failure (HF) is increasing. Advancements in guideline-directed medical and device therapy have resulted in improved survival. Thus, there are more patients living – and living longer – with advanced HF. Only a small proportion of these patients are deemed appropriate for advanced surgical intervention (mechanical circulatory support or heart transplantation), and even if offered, some may decline such interventions if not aligned with their overall goals and values. Therefore, a growing number of patients with advanced HF receive chronic intravenous inotropic support (CIIS) for palliation of symptoms. Despite increased use, clinical evidence supporting use of palliative inotropes remains limited. However, available data suggest improvements in functional class, health-related quality of life (HRQoL) indicators, symptom burden, hemodynamic parameters, and possibly rehospitalization. While initial concerns regarding increased mortality have been assuaged in the modern era of guideline-directed medical therapy, palliative inotropes are certainly not without burden. Risks of infection and medication-related adverse effects, need for routine laboratory monitoring, frequent dressing changes, and presence of a reliable caregiver must be carefully considered prior to initiation. This review addresses pharmacology, guideline recommendations, benefits and burdens, considerations related to hospice and end-of-life care, and future directions of CIIS in advanced HF care. [ABSTRACT FROM AUTHOR]

Abstract Background Prior studies have suggested that pimobendan is associated with several positive effects in cats, including improved survival in cats with congestive heart failure and improved left atrial function in research colony cats with hypertrophic cardiomyopathy (HCM) and normal cats. However, there is still a paucity of pharmacodynamic data refuting or supporting the use of pimobendan in a clinical cat population. This clinical trial aimed to evaluate the pharmacodynamic effects and tolerability of a single dose of pimobendan in cats with HCM. Echocardiograms and Doppler-derived systolic blood pressures were performed in 21 client-owned cats with subclinical HCM at baseline and 90-min after oral administration of 1.25 mg of pimobendan (Vetmedin). Seven additional cats were evaluated post-placebo administration to account for intra-day variability. Results Heart rate, systolic blood pressure, and murmur grade were not significantly different between baseline and post-pimobendan evaluations. Left auricular blood flow velocity, left atrial size, and left ventricular fractional shortening were not significantly different between baseline and post-pimobendan evaluations. Mean (± standard deviation) tissue Doppler peak systolic velocity of the mitral annulus was significantly higher following pimobendan (7.4 cm/s ± 1.5 vs 8.5 ± 1.6; p = 0.02). Median (min, max) left-ventricular outflow tract maximum velocity was significantly higher following pimobendan [1.9 m/sec (1.5, 3.4) vs 2.6 m/sec (2.0, 4.0); p = 0.01]. Mean right-ventricular outflow tract maximum velocity was also significantly higher following pimobendan (1.5 m/s ± 0.51 vs 2.0 ± 0.53; p = 0.004). Mean left atrial fractional shortening was significantly higher following pimobendan (28% ± 6 vs 32% ± 7; p = 0.02). No adverse events were observed following pimobendan administration. Right ventricular outflow tract velocity was significantly higher following placebo in control cats (1.02 ± 0.21 versus 1.31 ± 0.31; p = 0.01). No other significant differences were detected. Conclusions In client-owned cats with HCM, pimobendan acutely increased left atrial function and mildly increased left ventricular systolic function. Left ventricular outflow tract velocity was increased after pimobendan. Pimobendan was well tolerated in the acute setting in cats with HCM. The findings of this prospective, acute-dosing study confirm previous findings in research animals and retrospective analyses and suggest that chronic dosing studies are safe and warranted.

Background: Continuous outpatient inotrope infusion therapy (COIIT) can be used as palliative or interim treatment in patients with advanced heart failure (AHF). Despite widespread use, there is a relative lack of data informing best practices. This study aimed to examine whether patterns of COIIT use differed by region and to explore whether observed differences influenced clinical outcomes. Methods: Retrospective study of AHF patients receiving COIIT from May 2009 through June 2016. The primary outcome was regional difference, the secondary outcome was persistence (duration) on therapy. Cox proportional hazards model was used to calculate hazard ratios for treatment regimens. Results: There were 3,286 patients, mean (SD) age 61.9 (14.4) years and 74.0% (2,433) male. Inotrope selection and beta blocker use varied by region by chi square (χ2 (21) = 166.9, p

Background: An increasing number of patients undergo surgical procedures worldwide each year, and despite advances in quality and care, morbidity and mortality rates remain high. Perioperative hypotension is a well‐described condition, and is associated with adverse outcomes. Both fluids and vasoactive agents are commonly used to treat hypotension, however, whether one vasoactive agent is preferable over another has yet to be explored. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) statement, we plan to conduct a scoping review of studies assessing the use of vasoactive agents in patients undergoing non‐cardiac surgery. We will provide an overview of indications, agents used and outcomes assessed. We will assess and report the certainty of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: We will provide descriptive analyses of the included studies accompanied by tabulated results. Conclusion: The outlined scoping review will provide a summary of the body of evidence on the use of vasoactive agents in the non‐cardiac surgical population. [ABSTRACT FROM AUTHOR]

The inodilator levosimendan, in clinical use for over two decades, has been the subject of extensive clinical and experimental evaluation in various clinical settings beyond its principal indication in the management of acutely decompensated chronic heart failure. Critical care and emergency medicine applications for levosimendan have included postoperative settings, septic shock, and cardiogenic shock. As the experience in these areas continues to expand, an international task force of experts from 15 countries (Austria, Belgium, China, Croatia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Spain, Sweden, Switzerland, and the USA) reviewed and appraised the latest additions to the database of levosimendan use in critical care, considering all the clinical studies, meta-analyses, and guidelines published from September 2019 to November 2021. Overall, the authors of this opinion paper give levosimendan a "should be considered" recommendation in critical care and emergency medicine settings, with different levels of evidence in postoperative settings, septic shock, weaning from mechanical ventilation, weaning from veno-arterial extracorporeal membrane oxygenation, cardiogenic shock, and Takotsubo syndrome, in all cases when an inodilator is needed to restore acute severely reduced left or right ventricular ejection fraction and overall haemodynamic balance, and also in the presence of renal dysfunction/failure. [ABSTRACT FROM AUTHOR]

Cardiogenic shock (CS) is an acute complex condition leading to morbidity and mortality. Vasoactive medications, such as vasopressors and inotropes are considered the cornerstone of pharmacological treatment of CS to improve end-organ perfusion by increasing cardiac output (CO) and blood pressure (BP), thus preventing multiorgan failure. A critical review was conducted to analyze the currently available randomized studies of vasoactive agents in CS to determine the indications of each agent and to critically appraise the methodological quality of the studies. PubMed database search was conducted to identify randomized controlled trials (RCTs) on vasoactive therapy in CS. After study selection, the internal validity of the selected studies was critically appraised using the three-item Jadad scale. Nine studies randomized 2388 patients with a mean age ranged between 62 and 69 years, were identified. Seven of studies investigated CS in the setting of acute myocardial infarction (AMI). The studies evaluated the comparisons of norepinephrine (NE) vs. dopamine, epinephrine vs. NE, levosimendan vs. dobutamine, enoximone or placebo, and nitric oxide synthase inhibitors (NOSi) vs. placebo. The mean Jadad score of the nine studies was 3.33, with only three studies of a score of 5. The evidence from the studies of vasoactive agents in CS carries uncertainties. The methodological quality between the studies is variable due to the inherent difficulties to conduct a study in CS. Vasopressors and inotropes continue to have a fundamental role given the lack of pharmacological alternatives. [ABSTRACT FROM AUTHOR]

Background: In a low-income setting like ours, chronic constrictive pericarditis is not uncommon. Affected patients present late for surgical management owing to poverty and ignorance. These two factors adversely affect the outcome of surgery. Objective: To review 45 cases of chronic constrictive pericarditis done in our center with a view to determining the challenges and outcome of surgery. Patients and Methods: This is a retrospective study spanning 10 years, 2011 to 2020. Data comprising of biodata, morphologic and histologic types including challenges and outcome of surgery were obtained from our hospital Record Department. Data were analyzed using SPSS version 22(Chicago) and results presented using bar chart, tables and pie chart. Results: There were 45 patients. Of this number, there were 33 males (73.3%) and 12 females (27.7%). Age ranges affected were from 11-20 to 61-70 years. Morphologic types were totally calcific chronic constrictive pericarditis (4.4%), effusive chronic constrictive pericarditis (40%) and isolated chronic constrictive pericarditis (55.6%). Histologically, tuberculosis (60.0%) was most common, followed by idiopathic (33.3%). 2 patients were treated using cardiopulmonary bypass while the remainder had off-pump pericardiectomy, ranging from partial, total and radical. The outcome was poor in 30%, because they were not able to progress beyond NYHA class III despite ionotropic support and repeated paracentesis abdominis. Conclusion: Chronic constrictive pericarditis especially when it presents late is a major cause of morbidity and mortality in the young population. Poorly equipped ICU and lack of highly trained personnels also affect adversely those who present for treatment.

Background : The potential harm and clinical benefits of inotropic therapy in patients with decompensated heart failure with reduced ejection fraction or advanced heart failure were debated for three decades. Nonetheless, confronted with a dismal quality of life in the last months to years of life, continuous home inotropic therapy has recently gained traction for palliative therapy in patients who are not candidates for left ventricular mechanical circulatory support or heart transplantation. Methods : As continuous inotropic therapy is only considered for patients who experience symptomatic relief and display objective evidence of improvement, clinical equipoise is no longer present, and randomized controlled trials are hard to conduct. Results : We first outline the transient use of inotropic therapy in patients with decompensated heart failure with reduced ejection fraction and emphasize the hemodynamic requisite for inotropic therapy, which is a demonstration of a low cardiac output through a low mixed venous oxygen saturation. Lastly, we review the current experience with the use of home inotropic therapy in patients who are not candidates or are awaiting mechanical circulatory support or heart transplantation. Conclusions : Evidence-based clinical data are needed to guide inotropic therapy for refractory decompensated heart failure with reduced ejection fraction in patients who are ineligible or awaiting mechanical circulatory support or heart transplantation.

Excessive myocardial oxygen consumption (MVO2) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective β3 adrenergic receptor (β3AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO2 to left ventricular work (PVA; pressure-volume area). Three groups received dobutamine (5 μg/kg/min), dobutamine + L-748,337 (bolus 50 μg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO2 from ½ hour and 47% increase in the slope of the PVA-MVO2 relation after 6 hours. Contractility increased immediately with dobutamine infusion (dP/dtmax; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and β3AR blockade may attenuate this effect. [ABSTRACT FROM AUTHOR]

BACKGROUND: PDE1 (phosphodiesterase type 1) hydrolyzes cyclic adenosine and guanosine monophosphate. ITI-214 is a highly selective PDE1 inhibitor that induces arterial vasodilation and positive inotropy in larger mammals. Here, we assessed pharmacokinetics, hemodynamics, and tolerability of single-dose ITI-214 in humans with stable heart failure with reduced ejection fraction. METHODS: Patients with heart failure with reduced ejection fraction were randomized 3:1 to 10, 30, or 90 mg ITI-214 single oral dose or placebo (n=9/group). Vital signs and electrocardiography were monitored predose to 5 hours postdose and transthoracic echoDoppler cardiography predose and 2-hours postdose. RESULTS: Patient age averaged 54 years; 42% female, and 60% Black. Mean systolic blood pressure decreased 3 to 8 mm Hg (P<0.001) and heart rate increased 5 to 9 bpm (P=0.001 for 10, 30 mg doses, RM-ANCOVA). After 4 hours, neither blood pressure or heart rate significantly differed among cohorts (supine or standing). ITI-214 increased mean left ventricular power index, a relatively load-insensitive inotropic index, by 0.143 Watts/mL2·104 (P=0.03, a +41% rise; 5-71 CI) and cardiac output by 0.83 L/min (P=0.002, +31%, 13-49 CI) both at the 30 mg dose. Systemic vascular resistance declined with 30 mg (-564 dynes·s/cm-5, P<0.001) and 90 mg (-370, P=0.016). Diastolic changes were minimal, and no parameters were significantly altered with placebo. ITI-214 was well-tolerated. Five patients had mild-moderate hypotension or orthostatic hypotension recorded adverse events. There were no significant changes in arrhythmia outcome and no serious adverse events. CONCLUSIONS: Single-dose ITI-214 is well-tolerated and confers inodilator effects in humans with heart failure with reduced ejection fraction. Further investigations of its therapeutic utility are warranted. [ABSTRACT FROM AUTHOR]