Reversible severe pulmonary hypertension related to scurvy in children.

BACKGROUND: Severe pulmonary hypertension (PH) in childhood is rare and can manifest as a life-threatening episode. We present 2 children with restrictive dietary habits with severe pulmonary hypertension secondary to scurvy and iron deficiency anemia with treatment and outcome. CASE PRESENTATION: The first case is a 2-year-old boy who presented with vomiting, diarrhea, and fever. After rehydration, he had recurrent episodes of hypotension with intermittent abdominal pain. Fluid resuscitation and inotropic medication were given. Then he suddenly collapsed. After 4-min cardiopulmonary resuscitation, his hemodynamic was stabilized. Most of the medical workup was unremarkable except for PH from the echocardiogram with estimated systolic pulmonary artery pressure (PAP) at 67 mmHg. Transient PH was diagnosed, and milrinone was prescribed. Since he had restrictive dietary habits and sclerotic rim at epiphysis in chest films, his vitamin C level was tested and reported low-level result. The second case is a 6-year-old boy with acute dyspnea, a month of low-grade fever, mild cyanosis, and a swollen left knee. Echocardiogram indicated moderate TR with estimated systolic PAP at 56 mmHg (systolic blood pressure 90 mmHg). Milrinone was given. Right cardiac catheterization showed PAP 66/38 (mean 50) mmHg and PVRi 5.7 WU.m2. Other medical conditions causing PH were excluded. With a history of improper dietary intake and clinical suspicion of scurvy, vitamin C was tested and reported undetectable level. Administration of vitamin C in both cases rapidly reversed pulmonary hypertension. CONCLUSION: Pediatric PH related to vitamin C deficiency can manifest with a wide range of symptoms, varying from mild and nonspecific to severe life-threatening episodes characterized by pulmonary hypertensive crises. PH associated with scurvy is entirely reversible with appropriate investigation, diagnosis, and treatment. Our report highlights the importance of considering nutritional deficiencies as potential confounding factors in pediatric PH, emphasizing the need for comprehensive evaluation and management of these patients.

Neurogenic myocardial dysfunction post craniopharyngioma resection: A diagnostic dilemma.

Endoscopic transsphenoidal resection of craniopharyngioma is a commonly used technique. Cerebral vasospasm may occur in nearly 10% of cases leading to adverse neurological outcomes. Cardiopulmonary dysfunction may be seen in patients with severe vasospasm. The literature describing the occurrence of neurogenic stunned myocardium following craniopharyngioma resection in pediatric patients is very sparse. Here, we describe such a case managed with a combination of milrinone (to relieve vasospasm and improve cardiac pump function), noradrenaline (to obtain target blood pressure), and vasopressin (to control urine output). This case report proposes the treatment plan of neurogenic stunned myocardium following vasospasm in pediatric patients.

Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: a systematic review and meta-analysis.

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.

Anesthetic management of children with medically refractory pulmonary hypertension undergoing surgical Potts shunt.

INTRODUCTION: Pulmonary hypertension in children is associated with high rates of adverse events under anesthesia. In children who have failed medical therapy, a posttricuspid shunt such as a Potts shunt can offload the right ventricle and possibly delay or replace the need for lung transplantation. Intraoperative management of this procedure, during which an anastomosis between the pulmonary artery and the descending aorta is created, is complex and requires a deep understanding of the pathophysiology of acute and chronic right ventricular failure. This retrospective case review describes the intraoperative management of children undergoing surgical creation of a Potts shunt at a single center. METHODS: A retrospective case review of all patients under the age of 18 who underwent Potts shunt between April 2013 and June 2022. Medical records were examined, and clinical data of demographics, intraoperative vital signs, anesthetic management, and postoperative outcomes were extracted. RESULTS: Twenty-nine children with medically refractory pulmonary hypertension underwent surgical Potts shunts with a median age of 12 years (range 4 months to 17.4 years). Nineteen Potts shunts (65%) were placed via thoracotomy and 10 (35%) were placed via median sternotomy with use of cardiopulmonary bypass. Ketamine was the most frequently utilized induction agent (17 out of 29, 59%), and the majority of patients were initiated on vasopressin prior to intubation (20 out of 29, 69%). Additional inotropic support with epinephrine (45%), milrinone (28%), norepinephrine (17%), and dobutamine (14%) was used prior to shunt placement. Following opening of the Potts shunt, hemodynamic support was continued with vasopressin (66%), epinephrine (62%), milrinone (59%), dobutamine (14%), and norepinephrine (10%). Major intraoperative complications included severe hypoxemia (21 out of 29, 72%) and hypotension requiring boluses of epinephrine (10 out of 29, 34.5%) but no patient suffered intraoperative cardiac arrest. There were four in-hospital mortalities. DISCUSSION: A Potts shunt offers another palliative option for children with medically refractory pulmonary hypertension. General anesthesia in these children carries high risk for pulmonary hypertensive crises. Anesthesiologists must understand underlying physiological mechanisms responsble for acute hemodynaic decompensation during acute pulmonary hypertneisve crises. Severe physiological perturbations imposed by thoracic surgery and use of cardiopulmonay bypass can be mitigated by aggresive heodynamic support of ventricle function and maintainence of systemic vascular resistance. Early use of vasopressin, before or immidiately after anesthesia induction, in combination with other inotropes is a useful agent during the perioperative care of thes. Early use of vasopressin during anesthesia induction, and aggressive inotropic support of right ventricular function can help mitigate effects of induction and intubation, single-lung ventilation, and cardiopulmonary bypass. CONCLUSIONS: Our single center expereince shows that the Potts shunt surgery, despite high short-term mortaility, may offer another option for palliation in children with medically refractory pulmonary hypertension.

Effect of intravenous levosimendan or milrinone on left atrial pressure in patients undergoing off-pump coronary artery bypass grafting-A prospective double-blind, randomized controlled trial.

Background: Maintaining a low left atrial pressure (LAP) in off-pump coronary artery bypass grafting (OPCAB) is desirable. This study was done to compare the effects of intravenous levosimendan or milrinone on LAP at different stages of OPCAB. Materials and Methods: After institutional ethics committee clearance, this two-arm double-blind randomized control trial was done in 44 adult patients with triple vessel coronary artery disease undergoing OPCAB at cardiac OT of IPGME&R, Kolkata. The patients were randomly allocated into two groups receiving intraoperative either levosimendan or milrinone. Pulmonary capillary wedge pressure (PCWP) was compared as the primary outcome parameter, whereas other echocardiographic and hemodynamic parameters were also assessed during six stages of OPCAB, that is, after sternotomy, proximal(s), left anterior descending artery (LAD), obtuse marginal (OM), posterior descending artery (PDA) grafting, and before sternal closure. Numerical parameters were compared using Student's unpaired two-tailed t-test. Results: PCWP was found to be significantly lower (P < 0.05) in the levosimendan group during proximal (P = 0.047), LAD (P = 0.018), OM (P < 0.0001), PDA grafting (P = 0.028), and before sternal closure (P = 0.015). Other parameters indicate LAP, that is, from mitral early diastolic inflow velocity to mitral annular early diastolic velocity ratio (E/e'), which indicated significantly lower LAP in levosimendan group during LAD, OM, and PDA grafting and before sternal closure. Conclusion: Levosimendan may be used as a primary inotrope in terms of better reduction in left atrial pressure during different stages of OPCAB, translating to a decrease in left ventricular end-diastolic pressure, therefore maintaining optimum coronary perfusion pressure, which is the primary goal of the surgery.

Milrinone for the treatment of heart failure caused by severe Pneumonia in children with congenital heart disease: a meta-analysis.

BACKGROUND: Children with congenital heart disease (CHD) are easily complicated by severe pneumonia and heart failure. We aimed to conduct a meta-analysis to evaluate the effects and safety of milrinone for the treatment of heart failure caused by severe pneumonia in children with CHD to provide evidence for the clinical CHD treatment. METHODS: Two authors searched MEDLINE, PubMed, Embase, Science Direct, Cochrane Central Register of Controlled Trials, the Cochrane Library, Wanfang database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI) for randomized controlled trials (RCTs) about the application of milrinone in the treatment of heart failure caused by severe pneumonia in children with CHD in children up to December 10, 2022. Two evaluators independently selected the literature, extracted data and evaluated the methodological quality, meta-analysis was carried out with RevMan 5.3 software. RESULTS: Eight RCTs involving 680 CHD children complicated by severe pneumonia and heart failure were included in this meta-analysis. Meta-analysis indicated that total effective rate of the milrinone group was higher than that of control group (RR = 1.25, 95%CI: 1.17 ~ 1.34, P < 0.001), the time to stable heart rate of the milrinone group was less than that of control group (RR=-0.88, 95%CI: -1.09~ -0.67, P < 0.001). The time to stable respiration of the milrinone group was less than that of control group (RR=-0.98, 95%CI: -1.17~ -0.78, P < 0.001). The LVEF of the milrinone group was higher than that of control group (RR = 6.46, 95%CI: 5.30 ~ 7.62, P < 0.001). There was no significant difference in the incidence of adverse reactions between the milrinone group and control group (RR = 0.85, 95%CI: 0.47 ~ 1.56, P = 0.061). Funnel plots and Egger regression test results indicated that there were no statistical publication bias amongst the synthesized outcomes (all P > 0.05). CONCLUSIONS: Milrinone is beneficial to improve clinical symptoms and cardiac function and increase the therapeutic effect and safety in children with CHD complicated by severe pneumonia and heart failure. However, more RCTs with large samples and rigorous design are needed to verify this finding.

Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study.

BACKGROUND: Accidental hypothermia, recognized by core temperature below 35 °C, is a lethal condition with a mortality rate up to 25%. Hypothermia-induced cardiac dysfunction causing increased total peripheral resistance and reduced cardiac output contributes to the high mortality rate in this patient group. Recent studies, in vivo and in vitro, have suggested levosimendan, milrinone and isoprenaline as inotropic treatment strategies in this patient group. However, these drugs may pose increased risk of ventricular arrhythmias during hypothermia. Our aim was therefore to describe the effects of levosimendan, milrinone and isoprenaline on the action potential in human cardiomyocytes during hypothermia. METHODS: Using an experimental in vitro-design, levosimendan, milrinone and isoprenaline were incubated with iCell2 hiPSC-derived cardiomyocytes and cellular action potential waveforms and contraction were recorded from monolayers of cultured cells. Experiments were conducted at temperatures from 37 °C down to 26 °C. One-way repeated measures ANOVA was performed to evaluate differences from baseline recordings and one-way ANOVA was performed to evaluate differences between drugs, untreated control and between drug concentrations at the specific temperatures. RESULTS: Milrinone and isoprenaline both significantly increases action potential triangulation during hypothermia, and thereby the risk of ventricular arrhythmias. Levosimendan, however, does not increase triangulation and the contractile properties also remain preserved during hypothermia down to 26 °C. CONCLUSIONS: Levosimendan remains a promising candidate drug for inotropic treatment of hypothermic patients as it possesses ability to treat hypothermia-induced cardiac dysfunction and no increased risk of ventricular arrhythmias is detected. Milrinone and isoprenaline, on the other hand, appears more dangerous in the hypothermic setting.

Successful echocardiography-guided medical management of severe early post-implant right ventricular failure in a patient with left ventricular assist device support: a case report.

BACKGROUND: Post-implant right heart failure (RHF) has been recognized as a crucial prognostic factor in patients receiving left ventricular assist devices (LVADs), and its management has long attracted attention from cardiologists and surgeons. CASE PRESENTATION: This report described an 18-year-old female with acutely deteriorating heart failure due to dilated cardiomyopathy who underwent paracorporeal pulsatile-flow LVAD and developed early post-implant RHF. At postoperative day (POD) six, she was almost asymptomatic at rest on 2.5 mg/kg/min of dobutamine; however, the echocardiogram, performed as part of the daily postoperative care, revealed a severely enlarged right ventricle with a decompressed left ventricle, implying the development of post-implant RHF. Bolus infusion of saline and reduction of pump flow (6.0 L/min to 3.0 L/min) led to normalization of both ventricular shapes in 30 s, suggesting that RHF could be managed without surgical interventions. Milrinone was started on POD six, followed by sildenafil administration on POD seven. Fluid balance was strictly adjusted under the close observation of daily echocardiograms. Milrinone and dobutamine were discontinued on PODs 18 and 21, respectively. The patient was listed for a heart transplant on POD 40. Despite reduced right ventricular function (right ventricular stroke work index of 182.34 mmHg*ml/m- 2, body surface area 1.5 m2), she was successfully converted to implantable LVAD on POD 44 with no recurrence of post-implant RHF thereafter for four years. CONCLUSIONS: In post-implant RHF management, early detection, together with proper and prompt medical management, is crucial to avoiding any surgical intervention. Close observation of daily echocardiograms might be helpful in detecting subclinical RHF and is useful for post-implant medical management.

The choice of perioperative inotropic support impacts the outcome of small infants undergoing complex cardiac surgery: an observational study.

BACKGROUND: Vaso-inotropic agents are frequently used to prevent and/or treat low cardiac output syndrome in infants undergoing surgery for congenital heart disease. Due to the lack of comparative studies, their use is largely dependent on physician- and center preferences. The aim was to assess the impact of two different inotropic regimens, milrinone-epinephrine versus dobutamine on postoperative morbi-mortality in young children undergoing complex cardiac surgery. METHODS: All consecutive children younger than one year of age admitted for complex cardiac surgery (Risk Adjustment in Congenital Heart Surgery-1 [RACHS-1] score ≥3) with cardiopulmonary bypass (CPB) from January 2008 to December 2018 were included. Children received either milrinone in association with low dose epinephrine (milrinone-epinephrine group) or dobutamine (dobutamine group) groups were matched and compared using a propensity score. Our primary outcome was a composite measure including either hospital death and/or the presence of at least two of the following events: respiratory failure, prolonged inotropic support, or renal failure. RESULTS: Two hundred and fifty patients were included in the analysis. Children in the milrinone-epinephrine group (N.=184) suffered more frequently from a cyanotic heart disease and had longer surgery, CPB, and aortic cross clamp times than those in the dobutamine group (N.=66). After matching, children in the milrinone-epinephrine group had a higher incidence of severe postoperative morbidity or mortality compared to those in the dobutamine group (27.4 versus 13.9%; P=0.016). Respiratory failure (28% vs. 12%), prolonged inotropic support (71% vs. 35%) and in-hospital death (3 vs. 0%) were more frequent in the milrinone-epinephrine group. CONCLUSIONS: In young infants undergoing complex cardiac surgery, milrinone combined with epinephrine is associated with a higher incidence of postoperative morbidity or mortality compared to dobutamine for perioperative inotropic support. Further prospective randomized studies are required to confirm this finding.

Outcome of obstructed total anamalous pulmonary venous connection (TAPVC) repair patients with milrinone versus milrinone and inhaled nitric oxide (INO): A prospective randomized observational study.

Background: Obstructed total anomalous pulmonary venous connection (TAPVC) typically present with severe cardiovascular decompensation and requires urgent surgical management. Pulmonary arterial hypertension (PAH) is a major risk factor affecting mortality. Perioperative management focuses on providing inotropic support and managing potential pulmonary hypertensive episodes. Milrinone and inhaled nitric oxide (iNO) efficiently reduce pulmonary artery pressure (PAP) and help to improve the outcome. The aim was to determine the outcome of patients with high PAP with milrinone alone and a combination of iNO and milrinone. Material and Method: After ethical committee approval, the study was conducted over a period of 3 years in 80 patients with obstructed TAPVC repair. A total of 80 patients having severe PAH (supra systemic arterial pressure) randomly divided into two groups with 40 patients in each (M & MN). Group M (milrinone) patients received milrinone and Group MN (milrinone & iNO) patients received both milrinone (after opening aortic cross clamp) and iNO (post operative ICU). Ventilation time, hospital stay, ICU stay, complications, in hospital mortality were compared between both groups. Result: Ventilation time, Intensive Care Unit (ICU) stay, hospital stay for group M was 8.02 ± 5.74 days, 11.25 ± 7.33 day, 14.92 ± 8.55 days, respectively, and for group MN was 5.02 ± 1.78 days, 8.27 ± 3.24 days, 10.3 ± 3.18 days, respectively. In hospital mortality for group M and MN was 10% and 2.5%, respectively. P value for each variable was significant < 0.05 (except mortality). Conclusion: Most of the patients with obstructed TAPVC had severe PAH. Management of severe PAH with a combination of milrinone with iNO had a better outcome than milrinone alone.

Effects of Milrinone on Neonates after Patent Ductus Arteriosus Ligation: A Retrospective Nationwide Database Study.

INTRODUCTION: Milrinone is administered after patent ductus arteriosus (PDA) ligation to prevent and treat postoperative hemodynamic instability (i.e., postligation cardiac syndrome). We aimed to explore the effectiveness of milrinone on in-hospital outcomes in infants who underwent PDA ligation using a nationwide inpatient database in Japan. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified patients who received milrinone after PDA ligation (n = 428) in neonatal intensive care units between July 2010 and March 2021 and those who did not (n = 3,392). We conducted a 1:4 propensity score-matched analysis with adjustment for background characteristics (e.g., gestational age, birth weight, comorbidities, preoperative treatments, and hospital background) to compare morbidities (bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity), mortality, total hospitalization costs, and other outcomes. For sensitivity analysis, we performed an overlap propensity score-weighted analysis. RESULTS: In-hospital morbidity, bronchopulmonary dysplasia, intraventricular hemorrhage, and necrotizing enterocolitis occurred in 58%, 48%, 9.5%, and 7.1% of patients, respectively; the in-hospital mortality was 5.4%. After 1:4 propensity score matching, no significant difference was observed regarding mortality (7.1 vs. 5.7%), in-hospital morbidity (55 vs. 50%), bronchopulmonary dysplasia (44 vs. 41%), intraventricular hemorrhage (7.8 vs. 9.1%), necrotizing enterocolitis (8.5 vs. 8.9%), retinopathy of prematurity (21 vs. 22%), or total hospitalization costs (median: approximately 86,000 vs. 82,000 US dollars) between milrinone users (n = 425) and nonusers (n = 1,698). Sensitivity analyses yielded consistent results. CONCLUSIONS: Milrinone use after PDA ligation was not associated with improved in-hospital outcomes, such as mortality and morbidity.

Hematopoietic cell transplantation for Mucopolysaccharidosis I in the presence of decreased cardiac function.

BACKGROUND: Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT. METHODS: Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation. RESULTS: Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF. CONCLUSION: Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT.

Improved mortality and haemodynamics with milrinone in cardiogenic shock due to acute decompensated heart failure.

AIMS: Studies in cardiogenic shock (CS) often have a heterogeneous population of patients, including those with acute myocardial infarction and acute decompensated heart failure (ADHF-CS). The therapeutic profile of milrinone may benefit patients with ADHF-CS. We compared the outcomes and haemodynamic trends in ADHF-CS receiving either milrinone or dobutamine. METHODS AND RESULTS: Patients presenting with ADHF-CS (from 2014 to 2020) treated with a single inodilator (milrinone or dobutamine) were included in this study. Clinical characteristics, outcomes, and haemodynamic parameters were collected. The primary endpoint was 30 day mortality, with censoring at the time of transplant or left ventricular assist device implantation. A total of 573 patients were included, of which 366 (63.9%) received milrinone and 207 (36.1%) received dobutamine. Patients receiving milrinone were younger, had better kidney function, and lower lactate at admission. In addition, patients receiving milrinone received mechanical ventilation or vasopressors less frequently, whereas a pulmonary artery catheter was more frequently used. Milrinone use was associated with a lower adjusted risk of 30 day mortality (hazard ratio = 0.52, 95% confidence interval 0.35-0.77). After propensity-matching, the use of milrinone remained associated with a lower mortality (hazard ratio = 0.51, 95% confidence interval 0.27-0.96). These findings were associated with improved pulmonary artery compliance, stroke volume, and right ventricular stroke work index. CONCLUSIONS: The use of milrinone compared with dobutamine in patients with ADHF-CS is associated with lower 30 day mortality and improved haemodynamics. These findings warrant further study in future randomized controlled trials.

Cocrystallization-Driven Double-Optimized Stratagem toward Directional Self-Assembly for the First Ternary Salt Cocrystal of Cardiotonic Drug Milrinone with Different Phenolic Acids Exhibits Optimal In Vitro/Vivo Biopharmaceutical Peculiarities.

The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL's biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA-]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA-] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.