First-year outcomes of very low birth weight preterm singleton infants with hypoxemic respiratory failure treated with milrinone and inhaled nitric oxide (iNO) compared to iNO alone: A nationwide retrospective study.

BACKGROUND: Inhaled nitric oxide (iNO) has a beneficial effect on hypoxemic respiratory failure. The increased use of concurrent iNO and milrinone was observed. We aimed to report the trends of iNO use in the past 15 years in Taiwan and compare the first-year outcomes of combining iNO and milrinone to the iNO alone in very low birth weight preterm (VLBWP) infants under mechanical ventilation. METHODS: This nationwide cohort study enrolled preterm singleton infants with birth weight <1500g treated with iNO from 2004 to 2019. Infants were divided into two groups, with a combination of intravenous milrinone (Group 2, n = 166) and without milrinone (Group 1, n = 591). After propensity score matching (PSM), each group's sample size is 124. The primary outcomes were all-cause mortality and the respiratory condition, including ventilator use and duration. The secondary outcomes were preterm morbidities within one year after birth. RESULTS: After PSM, more infants in Group 2 needed inotropes. The mortality rate was significantly higher in Group 2 than in Group 1 from one month after birth till 1 year of age (55.1% vs. 13.5%) with the adjusted hazard ratio of 4.25 (95%CI = 2.42-7.47, p <0.001). For infants who died before 36 weeks of postmenstrual age (PMA), Group 2 had longer hospital stays compared to Group 1. For infants who survived after 36 weeks PMA, the incidence of moderate and severe bronchopulmonary dysplasia (BPD) was significantly higher in Group 2 than in Group 1. For infants who survived until one year of age, the incidence of pneumonia was significantly higher in Group 2 (28.30%) compared to Group 1 (12.62%) (p = 0.0153). CONCLUSION: Combined treatment of iNO and milrinone is increasingly applied in VLBWP infants in Taiwan. This retrospective study did not support the benefits of combining iNO and milrinone on one-year survival and BPD prevention. A future prospective study is warranted.

Time-Varying Clearance in Milrinone Pharmacokinetics from Premature Neonates to Adolescents.

BACKGROUND AND OBJECTIVES: Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable therapeutic range of 100-300 µg/L, but weight-based dosing alone is associated with poor target attainment. We aimed to develop a population pharmacokinetic model for milrinone from premature neonates to adolescents, and to evaluate how age, renal function and recovery from CPB may impact dose selection. METHODS: Fifty paediatric patients (aged 4 days to 16 years) were studied after undergoing cardiac surgery supported by CPB. Data from 29 premature neonates (23-28 weeks' postmenstrual age) treated for prophylaxis of low systemic blood flow were available for a pooled pharmacokinetic analysis. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1). RESULTS: There were 369 milrinone measurements available for analysis. A one-compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were clearance 17.8 L/70 kg [95% CI 15.8-19.9] and volume 20.4 L/h/70 kg [95% CI 17.8-22.1]. Covariates included size, postmenstrual age and renal function for clearance, and size and postnatal age for volume. Milrinone clearance is reduced by 39.5% [95% CI 24.0-53.7] immediately after bypass, and recovers to baseline clearance with a half-time of 12.0 h [95% CI 9.7-15.2]. Milrinone volume was 2.07 [95% CI 1.87-2.27] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.977 days [95% CI 0.833-1.12]. CONCLUSION: Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in clearance. Increasing clearance over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to baseline following CPB.

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.

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.

Neuroprotective Effects of Milrinone on Experimental Acute Spinal Cord Injury: Rat Model.

OBJECTIVE: Spinal cord injury (SCI) disrupts nerve axons with devastating neurological consequences, but there is no effective clinical treatment. The secondary damage mechanism is a mainstay process, and it starts within a few minutes after trauma. We aim to investigate the neuroprotective effects of milrinone on the SCI model. MATERIALS AND METHODS: A total of 36 Wistar albino rats, each weighing 300-400 g, were randomly split into 4 groups that received different treatments: in group 1 (sham) (n = 9) control, only a laminectomy was performed; in group 2 (SCI) (n = 9), SCI was imitated after laminectomy; in group 3 (SCI + saline) (n = 9), physiological saline solution was injected intraperitoneally immediately after the SCI; and in group 4 (SCI + milrinone), milrinone was administered intraperitoneally on lateral decubitus position immediately after the SCI. Spinal cord contusion was established by the weight-drop technique after laminectomy. Neurological examination scores were recorded, and rats were killed 72 hours later. Serum and spinal cord tissue glutathione peroxidase, total antioxidant status, total oxidant status, 8-hydroxiguanosine, interleukin-6 and interleukin-10 levels, histopathological spinal cord damage score, and apoptotic index were examined and compared between groups. RESULTS: Neurological examination scores were significantly better in the milrinone-treated group compared with groups 2 and 3. SCI significantly increased serum and spinal cord tissue glutathione peroxidase, total oxidant status, 8-hydroxiguanosine, and interleukin-6 levels that were successfully reduced with milrinone treatment. Interleukin-10 and total antioxidant status levels decreased as a result of SCI increased with milrinone treatment. Increased histopathological spinal cord damage score and apoptotic index in groups 2 and 3 significantly decreased in group 4. CONCLUSIONS: Milrinone could reduce apoptosis and increase anti-inflammatory and antioxidative mediators, thus playing a protective role in secondary nerve injury after SCI in rats.

Inhaled versus intravenous milrinone in mitral stenosis with pulmonary hypertension.

OBJECTIVE: To evaluate and compare the hemodynamic effects of intraoperative intravenous milrinone versus inhalational milrinone at two timepoints in patients with severe pulmonary hypertension undergoing mitral valve surgery. METHODS: A prospective observational study was performed in 100 patients with severe rheumatic mitral stenosis (with/without regurgitation) and right ventricular systolic pressure > 50 mm Hg. They were divided into two groups based on the strategy used to reduce pulmonary hypertension. Fifty patients had inhalational milrinone after sternotomy until initiation of cardiopulmonary bypass and after release of the aortic crossclamp until weaning off cardiopulmonary bypass. The other 50 patients received an intravenous loading dose of milrinone 50 µg·kg-1 over 10 min on release of the aortic crossclamp. Both groups received intravenous milrinone 0.5 µg·kg-1 during weaning from cardiopulmonary bypass. Hemodynamic data were evaluated at the 3 timepoints. RESULTS: Pulmonary artery pressures, central venous pressure, and pulmonary capillary wedge pressure decreased significantly in the inhalational milrinone group compared to the intravenous milrinone group. Systemic vascular resistance index and cardiac index were significantly higher and pulmonary vascular resistance index was significantly lower in the inhalational milrinone group. The mean arterial pressure-to-mean pulmonary artery pressure ratio was significantly lower in the intravenous milrinone group. Tricuspid annular plane systolic excursion and right ventricular fractional area change were increased significantly in the inhalational milrinone group. CONCLUSION: Intraoperative inhalational milrinone before and after cardiopulmonary bypass is safe, easy to administer, and results in significant improvements in right ventricular hemodynamics, right ventricular function, and systemic hemodynamics.

[COVID-19-associated hyperinflammatory state in a 15-year-old female patient]. / Covid-19-geassocieerde hyperinflammatie.

Paediatric Multisystem Inflammatory Syndrome Temporally Related to SARS-CoV-2 (PIMS-TS) is a rare novel clinical entity observed in children and adolescents with evidence of a recent COVID-19 infection, and is characterized by a marked hyperinflammatory state with involvement of multiple organ systems.We report a case of a previously healthy 15-year-old female patient, who was admitted to paediatric intensive care with cardiac failure and was subsequently shown to have positive COVID-19 serology. The presenting symptoms were fever, cough, chest pain and gastro-intestinal symptoms. She was supported with milrinone and a low dose of vasopressors. Her hyperinflammatory state was treated with intravenous immunoglobulins, high dose aspirin and high-dose methylprednisolone. PIMS-TS is a rare, potentially life threatening novel clinical entity in children and adolescents with evidence of a COVID-19 infection. Clinicians need to be aware of the possibility of this new disease, to ensure prompt recognition and treatment.

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.

Extended-Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction.

Background Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent form of heart failure, representing half of the total burden of heart failure. We hypothesised that modulation of the phosphodiesterase type 3/cyclic AMP using a novel oral formulation of milrinone might exert favorable effects HFpEF via pulmonary and systemic vasodilation and enhancement of ventricular relaxation. We assessed the safety and efficacy of oral milrinone on quality of life and functional outcomes in patients with HFpEF. Methods and Results The MilHFPEF (Extended Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction) study was a randomized, double-blind, placebo-controlled pilot study in 23 patients with symptomatic HFpEF. Efficacy end points included changes from baseline in Kansas City Cardiomyopathy Questionnaire summary score and 6-minute walk distance. The primary safety end point was the development of clinically significant arrhythmia. The Kansas City Cardiomyopathy Questionnaire score improved significantly in milrinone-treated patients compared with placebo (+10±13 versus -3±15; P=0.046). Six-minute walk distance also tended to improve in the treatment group compared with placebo (+22 [-8 to 49] versus -47 [-97 to 12]; P=0.092). Heart rate (-1±5 versus -2±9 bpm; P=0.9) and systolic blood pressure (-3±18 versus +1±12 mm Hg; P=0.57) were unchanged. Early filling velocity/early mitral annular velocity (-0.3±3.0 versus -1.9±4.8; P=0.38) was unchanged. One patient in the placebo arm was hospitalized for heart failure. Holter monitoring did not demonstrate evidence of a proarrhythmic effect of milrinone. Conclusions In this novel pilot study, extended release oral milrinone was well tolerated and associated with improved quality of life in patients with HFpEF. Further longer-term studies are warranted to establish the role of this therapeutic approach in HFpEF. Registration URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12616000619448.

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.

Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization.

Inhaled milrinone administered before cardiopulmonary bypass (CPB) reduces the severity of pulmonary hypertension during cardiac surgery. However, milrinone pharmacokinetics has not been determined for this route of administration. The objective of this study was to investigate inhaled milrinone dosing in vitro and early plasma concentrations in vivo after jet and mesh nebulization. Twelve pulmonary hypertensive patients scheduled for cardiac surgery were randomized to receive milrinone (5 mg) by inhalation before CPB using a jet or mesh nebulizer. In vitro experiments were conducted to determine the inhaled dose delivered with either jet or mesh nebulization. In vivo experiments involved hemodynamic monitoring and blood samples drawn from patients for the first 15 min after the end of inhalation to determine early plasma concentrations. After mesh nebulization, the mean in vitro inhaled dose was almost 3-fold higher compared to jet nebulization (46.4% vs 16.6% for mesh and jet, respectively; mean difference, 29.8%; 95% CI, 14.1 to 45.5; P = 0.006). Consistent with this, the early plasma concentrations in vivo were also 2-3 fold higher after mesh nebulization (P = 0.002-0.005). After inhalation (jet or mesh nebulization), milrinone early plasma concentrations remained within the therapeutic range. No systemic hypotension was reported in our patients.

Safety of Outpatient Milrinone Infusion in End-Stage Heart Failure: ICD-Level Data on Atrial Fibrillation and Ventricular Tachyarrhythmias.

BACKGROUND: Milrinone infusion is one of a few select "non-device" therapies for patients with New York Heart Association (NYHA) class IV, stage D heart failure, which has been associated with an increase in ventricular tachyarrhythmia and atrial fibrillation. Milrinone improves hemodynamics and provides symptomatic relief. Many patients with end-stage heart failure die from cardiac pump failure, and the impact of ventricular tachyarrhythmia and atrial fibrillation on their mortality is unclear. METHODS: This is a retrospective study of 98 consecutive patients receiving outpatient milrinone in a single center from 2008 to 2016. The primary endpoint of the study was overall survival on milrinone. Secondary endpoints were incidence of post-milrinone implantable cardioverter defibrillator (ICD) shocks and development of ventricular tachyarrhythmia or atrial fibrillation. RESULTS: Median survival was 581 ± 96 days with no difference between those with prior ventricular tachyarrhythmia and those without at 1 month (92% vs 97%, P = 0.34), 6 months (67% vs 73%, P = 0.75), and 12 months (67% vs 61%, P = 0.88). Seven out of 12 (58%) patients with prior ventricular tachyarrhythmia had ICD shocks, as compared to 5 out of 78 (6.4%) (P <0.001). Thirty-five patients had atrial fibrillation prior to starting milrinone, which decreased to 72% (P <0.05) by the third follow-up time period (7-9 months). Amiodarone use was protective against new onset atrial fibrillation. CONCLUSIONS: Patients with stage D heart failure with a history of ventricular tachyarrhythmia have similar survival on outpatient milrinone compared to those without. However, those with prior ventricular tachyarrhythmia received more ICD shocks for more ventricular tachyarrhythmias. Milrinone remains a viable therapy for patients with stage D heart failure with limited therapeutic options.

A novel role for milrinone in neonatal acute limb ischaemia: successful conservative treatment of thrombotic arterial occlusion without thrombolysis.

Acute neonatal limb ischaemia (NLI) is most frequently an iatrogenic complication, however, may also occur in utero due to thromboembolism. There is no widely accepted protocol for treatment of NLI and limited evidence to guide management. Thrombolysis and surgical management have been attempted, though both are associated with significant morbidities. Milrinone is a phosphodiesterase-3 inhibitor used for its vasodilatory effects on the systemic and pulmonary vasculature. There is also emerging evidence for benefit of milrinone in ameliorating ischaemia-reperfusion injury. The authors present a case report of a term infant with spontaneous perinatal acute limb ischaemia secondary to near-completely occlusive thrombosis of the right subclavian artery. The infant was successfully managed conservatively with milrinone without requirement for thrombolysis or surgical intervention. Milrinone represents a novel treatment option for neonates with acute limb ischaemia and consideration of a trial of milrinone prior to higher risk treatment options is warranted in this patient group.