Comparison of Different Treatments of Persistent Pulmonary Hypertension of the Newborn: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening disease. Despite being considered the gold standard treatment scheme, inhaled nitric oxide (iNO) is not readily available in settings with limited resources. Therefore, in recent years, research on related drugs is being actively pursued. Herein, we aimed to use random-effects network meta-analysis to evaluate the efficacy and associated mortality of different PPHN therapies. DATA SOURCES: We electronically searched the PubMed, Embase, and Cochrane Library for data up to January 27, 2023. STUDY SELECTION: Randomized controlled trials involving neonates with PPHN assessing efficacy and mortality of various treatments. DATA EXTRACTION: Details of study population, treatments, and outcomes were extracted. DATA SYNTHESIS: Direct pairwise comparisons and a network meta-analysis was performed under random effects. The ranking probability was further assessed based on the surface under the cumulative ranking curve (SUCRA). We analyzed 23 randomized clinical trials involving 902 newborns with PPHN. Sixteen different treatment strategies were compared with each other and conventional therapy (CON). A median concentration of 10-20 parts per million (ppm) iNO (MNO) coupled with sildenafil orally administered at a dose of 1-3 mg/kg/dose every 6-8 hours (OSID) demonstrated the best efficacy (MNO + OSID vs. CON: odds ratio [OR] = 27.53, 95% CI, 2.36-321.75; SUCRA = 0.818, ranking first; moderate quality). OSID combined with milrinone administered IV also performed well in terms of efficacy (OSID + milrinone vs. CON: OR = 25.13, 95% CI = 1.67-377.78; SUCRA = 0.811, ranking second; low quality) and mortality reduction (CON vs. OSID + milrinone: OR = 25.13, 95% CI = 1.67-377.78; SUCRA = 0.786, ranking last; low quality). CONCLUSIONS: MNO + OSID is the most effective PPHN treatment. If iNO is not available, OSID + milrinone is preferred.

Comparative Effectiveness and Safety of Intermittent, Repeated, or Continuous Use of Levosimendan, Milrinone, or Dobutamine in Patients With Advanced Heart Failure: A Network and Single-Arm Meta-analysis.

ABSTRACT: The aim of this study was to synthesize the available evidence regarding differences in the long-term safety and efficacy of intermittent, repeated, or continuous palliative inotropic therapy among patients with advanced heart failure. We systematically searched the PubMed, Embase, and Cochrane Library electronic databases, with a cutoff date of November 23, 2023, for studies reporting outcomes in adult patients with advanced heart failure treated with intermittent, repeated, or continuous levosimendan, milrinone, or dobutamine. Forty-one studies (18 randomized controlled trials and 23 cohort studies) comprising 5137 patients met the inclusion criteria. The results of the network meta-analysis of randomized controlled trials showed that levosimendan had significant advantages over milrinone or dobutamine in reducing mortality and improving left ventricular ejection fraction. A single-arm meta-analysis also indicated that levosimendan had the lowest mortality and significantly improved B-type brain natriuretic peptide and left ventricular ejection fraction. Regarding safety, hypotension events were observed more frequently in the levosimendan and milrinone groups. However, the current evidence is limited by the heterogeneity and relatively small sample size of the studies.

Which Inotropic Drug, Dobutamine or Milrinone, Is Clinically More Effective in the Treatment of Postligation Cardiac Syndrome in Preterm Infants?

OBJECTIVE: This study aimed to detect which of the two main medicines suggested in the treatment of postligation cardiac syndrome (PLCS)-dobutamine or mirinone-possesses a more therapeutic effect. While doing this, clinicians are provided with a broader perspective on the treatment and follow-up of cases. The desire was to increase the treatability and monitor ability of the cases in question and hence their survivability. STUDY DESIGN: A retrospective review of a cohort of infants with PLCS was conducted between March 2012 and December 2018. In the treatment of infants with PLCS, dobutamine (dobutamine study group-DSG) or milrinone (milrinone study group-MSG) was used. The respiration, cardiac, echocardiography, and perfusion parameters of the cases were assessed both before and after ligation. Based on the data obtained, both the effects of the medicines on PLCS and the difference between their therapeutic effects were studied. The accuracy of prognostication was assessed with receiver operating characteristic analyses. RESULTS: PLCS was detected in 29 (34.1%) of 85 patent ductus arteriosus ligation cases in total. Of all the PLCS cases, 13 (44.8%) were treated with dobutamine and 16 (55.2%) with milrinone. It was observed that the effects of the medicines on the respiratory system and cardiovascular system manifested in the third and 6th hour, respectively. It was detected that both medicines had more effect on the systolic blood pressure (SBP) (area under the curve [AUC]: 0.997/0.996, p = 0.001/0.002) than on the diastolic blood pressure (AUC: 0.911/0.843, p = 0.032/0.046). CONCLUSION: Dobutamine and milrinone, two primary medicines that can be used in the treatment of cases with PLCS, possess similar therapeutic effects on this pathology. In addition, their postoperative therapeutic effects on the SBP are more in the foreground.

Cardiopulmonary effects of phosphine poisoning: A preliminary evaluation of milrinone.

Exposure to phosphine (PH3) presents with a host of diverse, non-specific symptoms that span multiple organ systems and is characterized by a high mortality rate. While a comprehensive mechanism for PH3 poisoning remains inconclusive, prior studies have implicated cardiac failure and circulatory compromise as potential pathways central to PH3-induced mortality. In this study, milrinone (MLR), a phosphodiesterase-3 inhibitor used to treat cardiac failure, was investigated as a potential countermeasure for PH3 poisoning. Lethality, physiological responses, and behavioral changes were evaluated in telemetrized female rats pretreated with water (sham) or one of three doses of MLR (40, 200, or 600 µg/kg) and exposed to PH3 (660 ppm for 25-40 min; 16,500-26,400 ppm × min). Animals receiving prophylactic administration of 600 µg/kg of MLR had nominally improved survivability compared to sham animals, although median lethal concentration-time and time of death did not differ substantially between treatment groups. Changes in respiration and behavior induced by PH3 appeared largely unaffected by MLR pretreatment, regardless of dose. Conversely, MLR pretreatment alleviated some aspects of PH3-induced cardiac function impairment, with slight dose-dependent effects observed for cardiac contractility, mean arterial pressure, and QRS duration. Together, these results illustrate the importance of circulatory compromise in PH3 poisoning and highlight the potential viability of MLR as a potential countermeasure option or part of a countermeasure regimen when administered prophylactically at 600 µg/kg.

Milrinone Acts as a Vasodilator But Not an Inotrope in Children After Cardiac Surgery-Insights From Wave Intensity Analysis.

OBJECTIVES: Milrinone is an inodilator widely used in the postoperative management of children undergoing cardiac surgery. The literature supporting its inotropic effect is sparse. We sought to study the effect of milrinone on the vasculature and its effects on the ventricular function using wave intensity analysis. We also intended to evaluate the feasibility of using wave intensity analysis by the bedside. DESIGN: prospective single-center observational study. SETTING: PICU of a tertiary children's hospital. PATIENTS: Children (< 18 yr) admitted to PICU following cardiac surgery who required to be commenced on a milrinone infusion. INTERVENTIONS: Echocardiography and Doppler ultrasound assessments for wave intensity analysis were performed prior to commencing milrinone and 4-6 hours after milrinone infusion. MEASUREMENTS AND MAIN RESULTS: Wave intensity analysis was successfully performed and analyzed in 15 of 16 patients (94%). We identified three waves-a forward compression wave, backward compression wave, and forward decompression wave. The waves were described with their cumulative intensity and wave-related pressure change. There was a 26% reduction in backward compression wave cumulative intensity following the introduction of milrinone. Other variables (backward compression wave cumulative intensity/forward compression wave cumulative intensity ratio, backward compression wave wave-related pressure change, backward compression wave wave-related pressure change/forward compression wave wave-related pressure change ratio) consistent with vasodilation also decreased after milrinone. It also decreased the vascular wavespeed by 7.1% and increased the distensibility of the vessels by 14.6%. However, it did not increase forward compression wave cumulative intensity, a variable indicating the systolic force generated by the ventricle. Forward decompression wave cumulative intensity indicating ventricular early diastolic relaxation also did not change. CONCLUSIONS: In a cohort of children recovering in PICU after having undergone cardiac surgery, we found that milrinone acted as a vasodilator but did not demonstrate an improvement in the contractility or an improved relaxation of the left ventricle as assessed by wave intensity analysis. We were able to demonstrate the feasibility and utility of wave intensity analysis to further understand ventriculo-vascular interactions in an intensive care setting.

Routine Intraoperative Inhaled Milrinone and Iloprost Reduces Inotrope Use in Patients Undergoing Cardiac Surgery: A Retrospective Cohort Pilot Study.

BACKGROUND: Catecholamine inotropes are frequently used after cardiopulmonary bypass (CPB) but may have undesirable effects. The aim was to identify whether the routine use of inhaled pulmonary vasodilators might reduce the requirement for inotrope drugs after cardiac surgery. METHODS: Retrospective cohort study of sequential patients undergoing cardiac surgery at the Royal Melbourne Hospital performed by a single surgeon and anesthesia care team, within 14 months before and after routine implementation of inhaled pulmonary vasodilators, August 2017. Milrinone 4 mg and iloprost 20 µg were inhaled using a vibrating mesh nebulizer (Aerogen) before initiation of CPB and at chest closure. Other aspects of clinical management were unaltered over the time period. Two investigators blinded to each other extracted data from electronic and written medical records. The primary outcome was any use of inotropes in the perioperative period; a Fisher exact test was used to analyze any differences between the 2 groups. Demographic data, hemodynamic data, and use of inotropes and vasopressors were collected from induction of anesthesia to 36 hours postoperative in the intensive care unit (ICU). Hospital and ICU length of stay, cost, and complications were collected. RESULTS: Any use of inotropes was significantly lower with inhaled pulmonary dilators (62.5% vs 86.8%, odds ratio [95% confidence interval {CI}], 0.253 (0.083-0.764); P = .011), including intraoperative inotrope use (37.5% vs 86.8%, odds ratio [95% CI], 0.091 (0.03-0.275); P < .001). ICU length of stay was significantly lower with inhaled pulmonary dilators (45 hours, interquartile range [IQR], 27-65 vs 50 hours, IQR, 45-74; P = .026). There were no significant differences among major postoperative complications or costs between groups. CONCLUSIONS: Routine use of inhaled milrinone 4 mg and iloprost 20 µg before and after CPB is associated with reduced postoperative inotrope use.

Population Pharmacokinetics and Dosing of Milrinone After Patent Ductus Arteriosus Ligation in Preterm Infants.

OBJECTIVES: The postoperative course of patent ductus arteriosus ligation is often complicated by postligation cardiac syndrome, occurring in 10-45% of operated infants. Milrinone might prevent profound hemodynamic instability and improve the recovery of cardiac function in this setting. The present study aimed to describe the population pharmacokinetics of milrinone in premature neonates at risk of postligation cardiac syndrome and give dosing recommendations. DESIGN: A prospective single group open-label pharmacokinetics study. SETTINGS: Two tertiary care neonatal ICUs: Tallinn Children's Hospital and Tartu University Hospital, Estonia. PATIENTS: Ten neonates with postmenstrual age of 24.6-30.1 weeks and postnatal age of 5-27 days undergoing patent ductus arteriosus ligation and at risk of postligation cardiac syndrome, based on echocardiographic assessment of left ventricular output of less than 200 mL/kg/min 1 hour after the surgery. INTERVENTIONS: Milrinone at a dose of 0.73 µg/kg/min for 3 hours followed by 0.16 µg/kg/min for 21 hours. Four blood samples from each patient for milrinone plasma concentration measurements were collected. MEASUREMENTS AND MAIN RESULTS: Concentration-time data of milrinone were analyzed with nonlinear mixed-effects modeling software (NONMEM Version 7.3 [ICON Development Solutions, Ellicott City, MD]). Probability of target attainment simulations gave a dosing schedule that maximally attains concentration targets of 150-250 µg/L. Milrinone pharmacokinetics was described by a one-compartmental linear model with allometric scaling to bodyweight and an age maturation function of glomerular filtration rate. Parameter estimates for a patient with the median weight were 0.350 (L/hr) for clearance and 0.329 (L) for volume of distribution. The best probability of target attainment was achieved with a loading dose of 0.50 µg/kg/min for 3 hours followed by 0.15 µg/kg/min (postmenstrual age < 27 wk) or 0.20 µg/kg/min (postmenstrual age ≥ 27 wk). CONCLUSIONS: Population pharmacokinetic modeling and simulations suggest a slow loading dose followed by maintenance infusion to reach therapeutic milrinone plasma concentrations within the timeframe of the postligation cardiac syndrome.

The Effect of Levosimendan Versus Milrinone on the Occurrence Rate of Acute Kidney Injury Following Congenital Heart Surgery in Infants: A Randomized Clinical Trial.

OBJECTIVES: It has been shown that, in contrast to other inotropic agents, levosimendan improves glomerular filtration rate after adult cardiac surgery. The aim of this study was to investigate the efficacy of levosimendan, compared with milrinone, in preventing acute kidney dysfunction in infants after open-heart surgery with cardiopulmonary bypass. DESIGN: Two-center, double-blinded, prospective, randomized clinical trial. SETTING: The study was performed in two tertiary pediatric centers, one in Sweden (Gothenburg) and one in Finland (Helsinki). PATIENTS: Infants between 1 and 12 months old, diagnosed with Tetralogy of Fallot, complete atrioventricular septal defect or nonrestrictive ventricular septal defect, undergoing total corrective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Seventy-two infants were randomized to receive a perioperative infusion of levosimendan (0.1 µg/kg/min) or milrinone (0.4 µg/kg/min). The infusion was initiated at the start of cardiopulmonary bypass and continued for 26 hours. MEASUREMENTS AND MAIN RESULTS: The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. Secondary outcomes included the following: 1) acute kidney injury according to the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes; 2) acute kidney injury with serum creatinine corrected for fluid balance; 3) plasma neutrophil gelatinase-associated lipocalin; 4) cystatin C; 5) urea; 6) lactate; 7) hemodynamic variables; 8) use of diuretics in the PICU; 9) need of dialysis; 10) length of ventilator therapy; and 11) length of PICU stays. There was no significant difference in postoperative serum creatinine between the treatment groups over time (p = 0.65). The occurrence rate of acute kidney injury within 48 hours was 46.9% in the levosimendan group and 39.5% in the milrinone group (p = 0.70). There were no significant differences in other secondary outcome variables between the groups. CONCLUSIONS: Levosimendan compared with milrinone did not reduce the occurrence rate of acute kidney injury in infants after total corrective heart surgery for atrioventricular septal defect, ventricular septal defect, or Tetralogy of Fallot.

Intravenous and Inhaled Milrinone in Adult Cardiac Surgery Patients: A Pairwise and Network Meta-Analysis.

OBJECTIVE: To summarize the evidence on the hemodynamic, echocardiographic, and clinical effects of inhaled and intravenous milrinone (iMil and IvMil) in adult cardiac surgery patients. DESIGN: Systematic review, pairwise and network meta-analysis. SETTING: Multi-institutional. PARTICIPANTS: Adult cardiac surgery patients. INTERVENTIONS: Comparison between iMil and IvMil versus other agents or placebo. MEASUREMENTS AND MAIN RESULTS: The primary endpoints were mean pulmonary artery pressure (MPAP) and peripheral vascular resistance (PVR). Secondary endpoints included the following: (1) mean arterial pressure, heart rate, and cardiac index (CI); (2) echocardiographic data; and (3) clinical outcomes. Random model, leave-one-out-analysis, and meta-regression were used. Thirty studies (6 iMil and 24 IvMil) were included for a total of 1,438 patients (194 iMil and 521 IvMil). IvMil was associated with a lower MPAP, lower PVR, and higher CI compared to placebo (standardized mean difference [SMD] = -0.22 [95% CI = -0.48 to 0.05], SMD = -0.49 [95% CI = -0.71 to -0.27], and SMD = 0.94 [95% CI = 0.51 to 1.37]). No difference in any outcome was found between iMil and placebo. At network meta-analysis, significantly lower PVR and shorter hospital length of stay were found for IvMil compared to iMil (SMD = -0.82 [95% CI = -1.53 to -0.10] and SMD = -0.50 [95% CI = -0.95 to -0.05], respectively). CONCLUSION: These results support the clinical use of IvMil in cardiac surgery patients. No evidence at present supports the adoption of iMil.

Acute Right Ventricular Failure in Cardiac Surgery During Cardiopulmonary Bypass Separation: A Retrospective Case Series of 12 Years' Experience With Intratracheal Milrinone Administration.

OBJECTIVE: To report the authors' 12 years of experience with intratracheal milrinone administration and to assess the efficacy and limitations of intratracheal milrinone bolus administration for the treatment of unexpected acute right ventricular (RV) failure in patients undergoing cardiac surgery. DESIGN: Retrospective analysis. SETTING: Single-center university hospital. PARTICIPANTS: One hundred seventy-six patients (4.6%) undergoing on-pump cardiac surgery. INTERVENTIONS: Endotracheal tube administration of milrinone (5-mg bolus) after unexpected acute RV failure during separation from cardiopulmonary bypass (CPB) weaning. RV failure was defined as the simultaneous presence of all of the following criteria: (1) hemodynamic instability or difficult separation from CPB with associated elevated central venous pressure or abnormal RV pressure waveform, (2) >20% reduction of RV fractional area change from baseline evaluated by transesophageal echocardiography, and (3) anatomical visualization of impaired or absent RV wall motion by direct intraoperative visual inspection. MEASUREMENTS AND MAIN RESULTS: Intratracheal milrinone administration was found to improve RV failure in 109 patients (61.9%) whereas RV failure persisted in 67 patients (38.1%). Using a multiple logistic regression model, severely decreased left ventricular ejection fraction (<35% v >50%) (adjusted odds ratio [OR] 3.72; 95% confidence interval [CI] 1.2-11.3; p = 0.012), longer CPB time (adjusted OR 1.014; CI 1.01-1.02; p = 0.001) and elevated postoperative fluid balance (adjusted OR 1.39; CI 1.1-1.8; p = 0.02) were found to be significant predictors of persistent RV failure. CONCLUSION: Intratracheal instillation of milrinone was associated with clinical improvement of RV failure occurring during separation from CPB in almost two-thirds of patients. Factors limiting its therapeutic efficacy include severe left ventricular dysfunction, increased fluid balance, and long CPB time.

Management of purpura fulminans skin lesions in a premature neonate with sepsis: a case study.

Purpura fulminans is a severe and rapidly progressive septic process characterised by the development of haemorrhagic and ecchymotic lesions and skin necrosis. It can appear on any part of the body but predominantly affects the limbs. Purpura fulminans is a rare but possible complication in paediatric patients, especially neonates. It can increase their risk of morbidity and mortality if not treated early and cause a severe long-term condition in survivors of the infectious episode, including amputation. For professionals involved in wound healing, purpura fulminans poses a major challenge. This report describes the case of a premature neonate with extensive purpura fulminans of the legs and arms. Topical treatment of the limbs and purpuric areas with hyperoxygenated fatty acids (HOFAs) every two hours produced an improvement in the lesions. Complete healing was achieved using moist wound healing products. Early topical application of HOFAs appears to be a safe treatment that improves tissue microcirculation in paediatric patients with Purpura fulminans, minimising sepsis-related skin damage.

Novel Milrinone Nanoformulation for Use in Cardiovascular Diseases: Preparation and in Vitro Characterization.

Cardiovascular diseases are the leading causes of mortality across the globe. Over the years, various drug formulations and delivery methods have been tested for cardiac repair. Milrinone (MRN) is a widely known cardiac inotrope drug used for the treatment of congestive heart failure in patients, however, its efficacy is limited. This study is the first to report the design of a novel MRN-nanoformulation using human serum albumin nanoparticles (HSA-NPs). The HSA-NPs exhibit promising drug delivery characteristics, such as target specificity, nonimmunogenicity, biocompatibility, and enhanced bioavailability. This article describes a MRN-nanoformulation design for in vitro drug release, cellular uptake, biocompatibility, and other features. The MRN-nanoformulation was prepared by the ethanol desolvation technique and key parameters were optimized to obtain a desired particle size of 154.2 ± 5.8 nm, zeta potential of -29.5 ± 2.9 mV, and a drug encapsulation efficiency of 41.1 ± 1.7%. Molecular docking studies have revealed that MRN binds in the hydrophobic cavity of HSA, which has also been indicated by circular dichroism and enzyme-mediated drug release studies in the presence of trypsin, pepsin, proteinase K, protease, and cathepsin D. The intracellular uptake of fluorescently tagged MRN-HSA-NPs using HUVEC and H9c2 cells was evaluated by flow cytometry. The nanoparticle toxicity results indicated that MRN-HSA-NPs show significantly lower cytotoxicity and higher cell viability ( P < 0.0001) as compared to the MRN-lactate drug in HUVEC (61.6 ± 3.7% vs 36.2 ± 2.9%) and H9c2 (58.8 ± 5.7% vs 18.8 ± 4.9%) cells. These studies indicate that the novel MRN-nanoformulation offers better drug delivery procedures than currently used methods and has potential in treatment of congestive heart failure and other cardiovascular diseases.

Prevention of Low Cardiac Output Syndrome After Pediatric Cardiac Surgery: A Double-Blind Randomized Clinical Pilot Study Comparing Dobutamine and Milrinone.

OBJECTIVES: Dobutamine and milrinone are commonly used after open-heart surgery to prevent or treat low cardiac output syndrome. We sought to compare efficacy and safety of these drugs in pediatric patients. DESIGN: Prospective, single-center, double-blinded, randomized clinical pilot study. SETTING: Tertiary-care university children's hospital postoperative pediatric cardiac ICU. PATIENTS: After written consent, 50 consecutive patients (age, 0.2-14.2 yr; median, 1.2 yr) undergoing open-heart surgery for congenital malformations were included. INTERVENTIONS: After cardiopulmonary bypass, a continuous infusion of either dobutamine or milrinone was administered for the first 36 postoperative hours. Maximum dose: dobutamine 6 µg/kg/min, milrinone 0.75 µg/kg/min. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in demographic data, complexity of surgery, and intraoperative characteristics between the two study groups (dobutamine vs milrinone). Efficacy was defined as need for additional vasoactive support, which did not differ between groups (dobutamine 61% vs milrinone 67%; p = 0.71). Sodium nitroprusside was used more often in the dobutamine group (42% vs 13%; p = 0.019). Systolic blood pressure showed a trend toward higher values in the dobutamine group, whereas both drugs increased heart rate early postoperatively. Echocardiography demonstrated a consistently good cardiac function in both groups. Central venous oxygen saturation, serum lactate levels, urine output, time to chest tube removal, length of mechanical ventilation, ICU, and hospital stay were similar in both groups. Both drugs were well tolerated, no serious adverse events occurred. CONCLUSIONS: Dobutamine and milrinone are safe, well tolerated, and equally effective in prevention of low cardiac output syndrome after pediatric cardiac surgery. The hemodynamic response of the two drugs is comparable. In uncomplicated cases, a trend toward the more cost-saving dobutamine might be anticipated; however, milrinone demonstrated a trend toward higher efficacy in afterload reduction.

Pharmacokinetics and Pharmacodynamics of Nebulized and Intratracheal Milrinone in a Swine Model of Hypercapnia Pulmonary Hypertension.

OBJECTIVES: Milrinone pulmonary administration is used currently for the treatment of pulmonary hypertension. Several methods are available: simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. The aim of this study was to explore the concentration-effect relationship of milrinone for each of these methods. DESIGN: Observational open-label pharmacokinetic/pharmacodynamics cohort study. SETTING: Single-center, hospital animal laboratory. PARTICIPANTS: Twelve swine. INTERVENTIONS: After hypercapnia pulmonary hypertension, swine were administered equivalent inhaled milrinone doses of 15 or 50 µg/kg through simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization. MEASUREMENTS AND MAIN RESULTS: Blood and urine samples were taken up to 360 minutes postadministration. The ratio of mean systemic arterial pressure to mean pulmonary arterial pressure was monitored continuously. Right heart echographies were taken before and after hypercapnia and after drug administration. Mean elimination half-lives were similar for the 4 administrations. Mean percent changes in the ratio were of 37 (60%), 18 (31%), 17 (36%), and 20 (20%), for simple jet nebulization, vibrating mesh nebulization, intratracheal instillation, and intratracheal atomization, respectively. Mean maximum plasma concentrations for intratracheal administrations were reached at 8 and 45 min for atomization and instillation, respectively. Significant increases in right atrial diameter and right ventricular end-diastolic area were witnessed during pulmonary hypertension as well as a return to baseline values after milrinone administration. CONCLUSIONS: The intratracheal methods, particularly intratracheal atomization, showed less hemodynamic effect than nebulizations and, in the case of intratracheal instillation, unpredictable drug exposure. Nebulization methods on the other hand, especially simple jet nebulization, suggest better efficacy and sensitivity but are less fit for emergency situations.

Comparison of Levosimendan and Milrinone for ECLS Weaning in Patients After Cardiac Surgery-A Retrospective Before-and-After Study.

OBJECTIVES: Pharmacodynamics suggests that levosimendan might be a valuable inotrope for weaning from extracorporeal life support (ECLS). As there is a paucity of evidence regarding the effectiveness and safety of such an approach, the aim was to report the authors' experiences in ECLS weaning before and after the implementation of levosimendan in clinical practice. DESIGN: Retrospective before-and-after study. SETTING: Cardiac intensive care unit of a university hospital. PARTICIPANTS: A total of 64 patients under ECLS for postcardiotomy cardiac failure, who underwent an ECLS weaning trial. INTERVENTION: Group comparisons between patients treated with levosimendan and patients treated with milrinone were made with the Mann-Whitney U test or the Pearson chi-squared test. Results are given as median (interquartile range) or numbers (percentages). MEASUREMENTS AND MAIN RESULTS: Of 64 patients, 26 (41%) received levosimendan. Successful ECLS weaning was achieved in 24 (92%) and 30 patients (79%) in the levosimendan and milrinone group, respectively (p = 0.18). In the levosimendan group, fewer patients had an intra-aortic balloon pump for weaning (2 [7.7%] v 15 [40%], p = 0.008). The support with norepinephrine was similar in the levosimendan and milrinone groups at the time of ECLS removal (0.06 [0.01-0.11] v 0.07 [0.01-0.16] µg/kg/min, p = 0.64) and 24 hours later (0.06 [0.04-0.09] v 0.04 [0.00-0.09] µg/kg/min, p = 0.15). Twenty-eight days (9/26 (35%) v 14/35 (40%), p = 0.28) and 180 days (13/26 [50%] v 15/34 [44%], p = 0.80) mortalities after ECLS removal were similar in the levosimendan and the milrinone groups. CONCLUSION: Levosimendan enabled ECLS weaning without increasing norepinephrine requirements when compared to a control group receiving milrinone.

The Effect of Inhaled Milrinone Versus Inhaled Levosimendan in Pulmonary Hypertension Patients Undergoing Mitral Valve Surgery - A Pilot Randomized Double-Blind Study.

OBJECTIVE: To compare the effects of inhaled milrinone and levosimendan on pulmonary and systemic hemodynamics in patients with pulmonary hypertension. DESIGN: Prospective, double-blind, randomized controlled study. SETTING: Tertiary care cardiac institute with 650 beds. PARTICIPANTS: The study comprised 150 adult patients with pulmonary hypertension undergoing mitral valve surgery. INTERVENTIONS: Patients were assigned randomly into 1 of the following 3 groups: milrinone (M), levosimendan (L), or control (C); n = 50 per group. In group M, inhaled milrinone (50 µg/kg); in group L, inhaled levosimendan (24 µg/kg); and in group C, normal saline was administered when the patient arrived in the recovery room. Pre-inhalation and post-inhalation hemodynamics (mean arterial pressure [MAP], pulse rate, and systemic vascular resistance [SVR]) were noted until 24 hours of inhalation of the drug. The change in pulmonary artery pressures (pulmonary artery systolic pressure [PASP] and mean pulmonary artery pressure [MPAP]) and the duration for which they remained decreased compared with the control group, were noted. MEASUREMENTS AND MAIN RESULTS: MAP, pulse rate, and SVR were comparable in the 3 groups at various time intervals. PASP and MPAP decreased comparably after inhalation of levosimendan and milrinone. However, they reached levels near the control group values after 2.5 to 3 hours in group L and after 0.5 hours in group M. CONCLUSIONS: Because inhaled levosimendan causes a decrease in PASP and MPAP without causing a decrease in SVR and MAP, the authors conclude that inhaled levosimendan is a selective pulmonary vasodilator. It is as effective as milrinone in reducing pulmonary artery pressures. In addition, it has advantage over inhaled milrinone because it is has a longer duration of action.

Milrinone-Induced Postconditioning Requires Activation of Mitochondrial Ca2+-sensitive Potassium (mBKCa) Channels.

OBJECTIVES: Cardioprotection by postconditioning requires activation of mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels. The involvement of these channels in milrinone-induced postconditioning is unknown. The authors determined whether cardioprotection by milrinone-induced postconditioning involves activation of mBKCa channels in the rat heart in vitro. DESIGN: Randomized, prospective, blinded laboratory investigation. SETTING: Experimental laboratory. PARTICIPANTS: Male Wistar rats. INTERVENTIONS: Hearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. At the onset of reperfusion, hearts were perfused with different concentrations of milrinone (0.3-100 µM) for determination of a dose-effect curve. In a second set of experiments, 3 µM milrinone was administered in combination with the mBKCa channel inhibitor paxilline (1 µM). Infarct size was determined by triphenyltetrazoliumchloride staining. MEASUREMENTS AND MAIN RESULTS: In control animals, infarct size was 37 ± 7%. Milrinone at a concentration of 3 µM reduced infarct size to 22 ± 7% (p < 0.05 v control). Higher milrinone concentrations did not confer stronger protection. Paxilline completely blocked milrinone-induced cardioprotection whereas paxilline alone had no effect on infarct size. CONCLUSIONS: This study shows that activation of mBKCa channels plays a pivotal role in milrinone-induced postconditioning.

Dobutamine and Nitroglycerin Versus Milrinone for Perioperative Management of Pulmonary Hypertension in Mitral Valve Surgery. A Randomized Controlled Study.

OBJECTIVE: To compare the effects of dobutamine and nitroglycerin to milrinone in young patients with severe pulmonary hypertension undergoing mitral valve replacement. DESIGN: A prospective randomized, double-blinded, controlled study. SETTING: Single university hospital. PARTICIPANTS: Forty patients had systolic pulmonary arterial pressure ≥60 mmHg and were scheduled for elective mitral valve replacement. The patients were divided randomly into 2 equal groups according to the drugs given during the study. INTERVENTIONS: The patients in group I received 5 to 20 µg/kg/min of dobutamine and 0.5 to 3 µg/kg/min of nitroglycerin, and patients in group II received a loading dose of milrinone, 50 µg/kg over 10 minutes, followed by a maintenance dose of 0.25 to 0.75 µg/kg/min. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the effects of interventional drugs on mean pulmonary artery pressure. The secondary outcomes were the effects of interventional drugs on systemic and pulmonary hemodynamic parameters measured from induction of anesthesia until the first 12 hours in the intensive care unit stay. There was a more significant decrease in mean pulmonary artery pressure, pulmonary capillary wedge pressure, and central venous pressure in group II than group I at all time points after cardiopulmonary bypass. There were more significant increases in heart rate, mean arterial pressure, cardiac output, and mixed venous oxygen tension in group I than group II, which became more obvious in time. In both groups, there was a significant decrease in systemic vascular resistance and pulmonary vascular resistance at all times. CONCLUSION: Milrinone provides adequate cardiac performance, causing a greater reduction in pulmonary artery pressure and pulmonary capillary wedge pressure.

Ambulatory Intravenous Inotropic Support and or Levosimendan in Pediatric and Congenital Heart Failure: Safety, Survival, Improvement, or Transplantation.

End-stage heart failure (HF) frequently needs continuous inotropic support in hospital and has high morbidity and mortality in absence of heart transplantation. This study reports outcome, efficacy, and safety of continuous ambulatory inotropes (AI) and/or periodic levosimendan (LS) infusions in pediatric HF patients. The study included 27 patients, median age 9.4 (0.1-26.1) years, with severe HF (6 myocarditis, 13 dilated cardiomyopathy, 2 restrictive cardiomyopathy, 6 repaired congenital heart disease). Dobutamine and milrinone AI were administered in 21 patients through a permanent central catheter for median duration 1.0 (0.3-3.7) years. Additionally, 14 AI patients and the remaining 6 study patients received periodic LS infusions for median duration 1.1 (0.2-4.2) years. During median follow-up 2.1 (0.3-21.3) years, 4 patients died of worsening HF after 0.8-2.1 years AI, 6 patients underwent heart transplantation with only 3 survivors, while the rest remained stable out of the hospital with complications 4 line infections treated with antibiotics and 4 catheter reinsertions due to dislodgement. Severe pulmonary hypertension was reversed with AI in 2 patients, allowing successful heart-only transplantation. Therapy with AI was discontinued after 1.4-0.4 years in 6 improved myocarditis and 3 cardiomyopathy patients without deterioration. In conclusion, prolonged AI and/or LS infusions in HF are safe and beneficial even in small infants, allowing stabilization and reasonable social and family life out of the hospital. It may provide precious time for heart transplantation or myocardial remodeling, improvement, and possible discontinuation even after long periods of support.

Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia, cardiac dysfunction and pulmonary hypertension. Inhaled nitric oxide (iNO) and milrinone are commonly used pulmonary vasodilators in CDH. We studied the hemodynamic effects of iNO and milrinone in infants with CDH. METHODS: A retrospective chart review was performed of all CDH infants admitted to two regional perinatal centers and infants classified into three groups: No-iNO group; iNO-responders and iNO-nonresponders. Oxygenation and hemodynamic effects of iNO and milrinone were assessed by blood gases and echocardiography. RESULTS: Fifty-four percent (39/72) of infants with CDH received iNO and 31% of these infants (12/39) had complete oxygenation response to iNO. Oxygenation response to iNO was not associated with a decrease in right ventricular pressures (RVP) or ECMO use. Four infants (33%) in the iNO-responder group and eight infants (30%) in the iNO-nonresponder group received milrinone. Milrinone lowered RVP and improved ejection fraction (EF). Response to iNO was associated with improved oxygenation to milrinone and increased survival following ECMO (67 vs. 20% among nonresponders). CONCLUSIONS: Response to inhaled nitric oxide in combination with milrinone may be associated with improved oxygenation and better survival after ECMO in infants with CDH.