Milrinone Versus Sildenafil in Treatment of Neonatal Persistent Pulmonary Hypertension: A Randomized Control Trial.

ABSTRACT: Persistent pulmonary hypertension of the newborn (PPHN) is a condition caused by failure of pulmonary vascular adaptation at birth, resulting in severe hypoxia. Several therapeutic modalities are being tried in developing countries where established therapies (inhaled nitric oxide and extracorporeal membrane oxygenation) are widely unavailable. This study aimed to assess the efficacy of milrinone versus sildenafil as available alternative therapeutics in treating PPHN. Forty neonates (>34 weeks) admitted to neonatal intensive care units with evidence of PPHN were randomly allocated to receive either oral sildenafil (0.5-2 mg/kg/6 hours) or intravenous milrinone (0.25-0.75 mic/kg/min). Primary outcomes included improvements in systolic pulmonary artery pressure and oxygen saturation index (OSI) at 24 and 48 hours after treatment. Secondary outcomes included the duration of hospitalization and mechanical ventilation. The ClinicalTrials identifier is NCT04391478. Both groups showed significant improvement in the post-treatment hemodynamic variables compared with pretreatment levels ( P < 0.05 for all parameters). Systolic pulmonary artery pressure and OSI values significantly improved in both study groups compared with baseline ( P < 0.001). The 24-hour and 48-hour post-treatment OSI values were much lower in the milrinone group than those in the sildenafil group ( P < 0.05). The length of hospital stay was significantly shorter in the milrinone group than that in the sildenafil group ( P < 0.05). There were no significant differences in the duration of mechanical ventilation, incidence of intracranial hemorrhage and pulmonary hemorrhage, or mortality between the 2 groups ( P > 0.05). In conclusion, milrinone and sildenafil are effective and well-tolerated in neonates with PPHN, particularly when inhaled nitric oxide and extracorporeal membrane oxygenation are not available. Milrinone is superior to sildenafil in improving oxygenation without lowering blood pressure parameters.

Levosimendan Versus Milrinone and Release of Myocardial Biomarkers After Pediatric Cardiac Surgery: Post Hoc Analysis of Clinical Trial Data.

OBJECTIVES: We compared the effect of two inodilators, levosimendan and milrinone, on the plasma levels of myocardial injury biomarkers, that is, high-sensitivity troponin T and heart-type fatty acid binding protein, and on N-terminal prohormone of brain natriuretic peptide as a biomarker of ventricular function. We hypothesized that levosimendan could attenuate the degree of myocardial injury when compared with milrinone. DESIGN: A post hoc, nonprespecified exploratory secondary analysis of the Milrinone versus Levosimendan-1 trial (ClinicalTrials.gov Identifier: NCT02232399). SETTING: Two pediatric tertiary university hospitals. PATIENTS: Infants 1-12 months old, diagnosed with ventricular septal defect, complete atrioventricular septal defect, or Tetralogy of Fallot undergoing corrective surgery with cardiopulmonary bypass. INTERVENTIONS: Seventy patients received a loading dose of either levosimendan or milrinone at the start of cardiopulmonary bypass followed by an infusion of the respective drug, which continued for 26 hours. MEASUREMENTS AND MAIN RESULTS: Plasma levels of the three cardiac biomarkers were measured prior to the initiation of cardiopulmonary bypass and 2, 6, and 24 hours after weaning from cardiopulmonary bypass. In both groups, the levels of high-sensitivity troponin T and heart-type fatty acid binding protein were highest at 2 hours post cardiopulmonary bypass, whereas the highest level of N-terminal prohormone of brain natriuretic peptide occurred at 24 hours post cardiopulmonary bypass. There was no significant difference in the biomarkers' plasma levels between the study groups over time. Neither was there a significant difference in the postoperative peak plasma levels of the cardiac biomarkers. CONCLUSIONS: In this post hoc analysis of the MiLe-1 trial, there was no demonstrable difference in the postoperative cardiac biomarker profile of myocardial injury and ventricular function when comparing infants managed in the perioperative period with levosimendan versus milrinone.

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.

The effect of milrinone on mortality in adult patients who underwent CABG surgery: a systematic review of randomized clinical trials with a meta-analysis and trial sequential analysis.

BACKGROUND: As an inodilator, milrinone is commonly used for patients who undergo coronary artery bypass graft (CABG) surgery because of its effectiveness in decreasing the cardiac index and mitral regurgitation. The aim of this study was to perform a systematic review and meta-analysis of existing studies from the past 20 years to evaluate the impact of milrinone on mortality in patients who undergo CABG surgery. METHODS: We performed a systematic literature search on the application of milrinone in patients who underwent CABG surgery in studies published between 1997 and 2017 in BioMed Central, PubMed, EMBASE, and the Cochrane Central Register. The included studies evaluated milrinone groups compared to groups receiving either placebo or standard treatment and further compared the systemic administration. RESULTS: The network meta-analysis included 723 patients from 16 randomized clinical trials. Overall, there was no significant difference in mortality between the milrinone group and the placebo/standard care group when patients underwent CABG surgery. In addition, 9 trials (with 440 randomized patients), 4 trials (with 212 randomized patients), and 10 trials (with 470 randomized patients) reported that the occurrence of myocardial infarction (MI), myocardial ischemia, and arrhythmia was lower in the milrinone group than in the placebo/standard care group. Between the milrinone treatment and placebo/standard care groups, the occurrence of myocardial infarction, myocardial ischemia, and arrhythmia was significantly different. However, the occurrence of stroke and renal failure, the duration of inotropic support (h), the need for an intra-aortic balloon pump (IABP), and mechanical ventilation (h) between these two groups showed no differences. CONCLUSIONS: Based on the current results, compared with placebo, milrinone might be unable to decrease mortality in adult CABG surgical patients but can significantly ameliorate the occurrence of MI, myocardial ischemia, and arrhythmia. These results provide evidence for the further clinical application of milrinone and of therapeutic strategies for CABG surgery. However, along with milrinone application in clinical use, sufficient data from randomized clinical trials need to be collected, and the potential benefits and adverse effects should be analyzed and reevaluated.

Impact of Milrinone Administration in Adult Cardiac Surgery Patients: Updated Meta-Analysis.

OBJECTIVE: To determine the effects of milrinone on short-term mortality in cardiac surgery patients with focus on the presence or absence of heterogeneity of the effect. DESIGN: A systematic review and meta-analysis. SETTING AND PARTICIPANTS: Five hundred thirty-seven adult cardiac surgery patients from 12 RCTs. INTERVENTIONS: Milrinone administration. MEASUREMENTS AND MAIN RESULTS: The authors conducted a systematic Medline and Pubmed search to assess the effect of milrinone on short-term mortality in adult cardiac surgery patients. Subanalysis was performed according to the timing for commencement of milrinone administration and the type of comparators. The primary outcome was any short-term mortality. Overall analysis showed no difference in mortality rates in patients who received milrinone and patients who received comparators (odds ratio = 1.25, 95% CI 0.45-3.51, p = 0.67). In subanalysis for the timing to commence milrinone administration and the type of comparators, odds ratio for mortality varied from 0.19 (placebo as control drug, start of administration after cardiopulmonary bypass) to 2.58 (levosimendan as control drug, start of administration after cardiopulmonary bypass). CONCLUSIONS: Among RCTs to assess the effect of milrinone administration in adult cardiac surgery patients, there are wide variations of the odds ratios of administration of milrinone for short-term mortality according to the comparators and the timing of administration. This fact may suggest that a simple pooling meta-analysis is not applicable for assessing the risk and benefit of milrinone administration in an adult cardiac surgery cohort.

Predictors of respiratory instability in neonates undergoing patient ductus arteriosus ligation after the introduction of targeted milrinone treatment.

INTRODUCTION: The postoperative course of preterm babies undergoing surgical closure of a patent ductus arteriosus (PDA) is often complicated by postligation cardiac syndrome (PLCS). Despite targeted milrinone prophylaxis, some infants continue to experience postoperative respiratory deterioration. Our objective is to describe the immediate postoperative course and identify risk factors for respiratory instability when preterm infants undergoing PDA ligation are managed with targeted milrinone treatment. METHODS: A retrospective review of a cohort of infants undergoing PDA ligation between January, 2010 and August, 2013 was conducted. All infants had a targeted neonatal echocardiogram performed 1 hour after surgery. Infants received prophylactic milrinone treatment if the left ventricular output was <200 mL/kg/min. The primary outcome measure was the development of respiratory instability within 24 hours of surgery. Multivariable logistic regression was performed to identify predictors of respiratory instability. RESULTS: Eighty-six infants with a median gestational age of 25 weeks (interquartile range [IQR], 24-26) and a birth weight of 740 g (IQR, 640-853) were included in this study. Forty-nine (57.0%) received milrinone prophylaxis. There were 44 (51.2%) infants who developed oxygenation or ventilation failure, and 7 (8.1%) neonates developed PLCS. Infants with longer isovolumic relaxation time (IVRT ≥30 milliseconds) were more likely to develop either oxygenation or ventilation failure. CONCLUSIONS: Although the incidence of PLCS has declined after the introduction of targeted milrinone prophylaxis, many preterm infants continue to develop respiratory instability after surgical ligation. In this population, diastolic dysfunction manifested by prolonged IVRT could be associated with an adverse postoperative respiratory course.

Effect of milrinone on cardiac functions in patients undergoing coronary artery bypass graft: a meta-analysis of randomized clinical trials.

BACKGROUND AND AIM: Inotropes are commonly used to treat myocardial dysfunction, which is the major complication after coronary artery bypass graft (CABG). Milrinone, a phosphodiesterase 3 inhibitor, is one of these inotropes. Recently, a number of clinical studies have been carried out to evaluate the effects of milrinone on cardiac function in patients with low ventricular ejection fraction undergoing CABG. However, it has been inconclusive because of the inconsistent results. In addition, some studies found that milrinone increased the incidence of postoperative atrial arrhythmias and did not show any long-term beneficial effects on survival. Therefore, it is very important to perform a meta-analysis to summarize the results so as to determine the clinical efficacy and safety of milrinone. METHOD: Several databases and websites for clinical trials were searched until October 2015 for prospective clinical studies comparing milrinone versus placebo on cardiac functions in patients undergoing CAGB. RESULTS: Four articles were identified by our search strategy. 1) Milrinone decreased incidence of myocardial ischemia and myocardial infarction (15.6% versus 44.4%; 4.7% versus 18% in milrinone and control group, respectively). 2) Milrinone decreased duration of inotropic support (95% confidence interval [CI]: -6.52 to -1.68; P=0.0009) and mechanical ventilation (h) support (95% CI -5.00 to -0.69; P=0.010), but did not decrease the requirement for intra-aortic balloon pump or inotropic support (P>0.05). 3) Milrinone did not decrease the overall mortality or morbidity, intensive care unit stay (P>0.05). CONCLUSION: Perioperative continuous infusion of milrinone is effective to lower incidence of myocardial ischemia and myocardial infarction in patients post-CABG, but it was unable to improve the overall morbidity and mortality or decreased duration of intensive care unit stay. The available sample size is small; therefore, future studies should be directed toward a better understanding of the benefit of milrinone to CABG patients.

Prophylactic milrinone for the prevention of low cardiac output syndrome and mortality in children undergoing surgery for congenital heart disease.

BACKGROUND: Children with congenital heart disease often undergo heart surgery at a young age. They are at risk for postoperative low cardiac output syndrome (LCOS) or death. Milrinone may be used to provide inotropic and vasodilatory support during the immediate postoperative period. OBJECTIVES: This review examines the effectiveness of prophylactic postoperative use of milrinone to prevent LCOS or death in children having undergone surgery for congenital heart disease. SEARCH METHODS: Electronic and manual literature searches were performed to identify randomised controlled trials. We searched CENTRAL, MEDLINE, EMBASE and Web of Science in February 2014 and conducted a top-up search in September 2014 as well as clinical trial registries and reference lists of published studies. We did not apply any language restrictions. SELECTION CRITERIA: Only randomised controlled trials were selected for analysis. We considered studies with newborn infants, infants, toddlers, and children up to 12 years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data according to a pre-defined protocol. We obtained additional information from all study authors. MAIN RESULTS: Three of the five included studies compared milrinone versus levosimendan, one study compared milrinone with placebo, and one compared milrinone verus dobutamine, with 101, 242, and 50 participants, respectively. Three trials were at low risk of bias while two were at higher risk of bias. The number and definitions of outcomes were non-uniform as well. In one study comparing two doses of milrinone and placebo, there was some evidence in an overall comparison of milrinone versus placebo that milrinone lowered risk for LCOS (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.28 to 0.96; 227 participants). The results from two small studies do not provide enough information to determine whether milrinone increases the risk of LCOS when compared to levosimendan (RR 1.22, 95% CI 0.32 to 4.65; 59 participants). Mortality rates in the studies were low, and there was insufficient evidence to draw conclusions on the effect of milrinone compared to placebo or levosimendan or dobutamine regarding mortality, the duration of intensive care stay, hospital stay, mechanical ventilation, or maximum inotrope score (where available). Numbers of patients requiring mechanical cardiac support were also low and did not allow a comparison between studies, and none of the participants of any study received a heart transplantation up to the end of the respective follow-up period. Time to death within three months was not reported in any of the included studies. A number of adverse events was examined, but differences between the treatment groups could not be proven for hypotension, intraventricular haemorrhage, hypokalaemia, bronchospasm, elevated serum levels of liver enzymes, or a reduced left ventricular ejection fraction < 50% or reduced left ventricular fraction of shortening < 28%. Our analysis did not prove an increased risk of arrhythmias in patients treated prophylactically with milrinone compared with placebo (RR 3.59, 95% CI 0.83 to 15.42; 238 participants), a decreased risk of pleural effusions (RR 1.78, 95% CI 0.92 to 3.42; 231 participants), or a difference in risk of thrombocytopenia on milrinone compared with placebo (RR 0.86, 95% CI 0.39 to 1.88; 238 participants). Comparisons of milrinone with levosimendan or with dobutamine, respectively, did not clarify the risk of arrhythmia and were not possible for pleural effusions or thrombocytopenia. AUTHORS' CONCLUSIONS: There is insufficient evidence of the effectiveness of prophylactic milrinone in preventing death or low cardiac output syndrome in children undergoing surgery for congenital heart disease, compared to placebo. So far, no differences have been shown between milrinone and other inodilators, such as levosimendan or dobutamine, in the immediate postoperative period, in reducing the risk of LCOS or death. The existing data on the prophylactic use of milrinone has to be viewed cautiously due to the small number of small trials and their risk of bias.

Outcomes of patients with right ventricular failure on milrinone after left ventricular assist device implantation.

Previous studies have grouped together both patients requiring right ventricular assist devices (RVADs) with patients requiring prolonged milrinone therapy after left ventricular assist device (LVAD) implantation. We retrospectively identified 149 patients receiving LVADs and 18 (12.1%) of which developed right ventricular (RV) failure. We then separated these patients into those requiring RVADs versus prolonged milrinone therapy. This included 10 patients who were treated with prolonged milrinone and eight patients who underwent RVAD placement. Overall, the RV failure group had worse survival compared with the non-RV failure cohort (p = 0.038). However, this was only for the subgroup of patients who required RVADs, who had a 1, 6, 12, and 24 month survival of 62.5%, 37.5%, 37.5%, and 37.5%, respectively, versus 96.8%, 92.1%, 86.7%, and 84.4% for patients without RV failure (p < 0.001). Patients treated with prolonged milrinone therapy for RV failure had similar survivals compared with patients without RV failure. In the RV failure group, age, preoperative renal failure, and previous cardiac surgery were predictors of the need for prolonged postoperative milrinone. As LVADs become a more widely used therapy for patients with refractory, end-stage heart failure, it will be important to reduce the incidence of RV failure, as it yields significant morbidity and increases cost.

Characteristics of patients with advanced heart failure having eosinophilic infiltration of the myocardium in the recent era.

Eosinophilic infiltration of the myocardium is occasionally observed as an incidental histological finding in endomyocardial biopsy specimens before heart transplantation (HTx) as well as in explanted heart obtained at the time of HTx. However, the indications for HTx in these patients have not yet been fully established. We investigated the pre-HTx characteristics of the recipients with myocardial eosinophilic infiltration in the explanted heart and diagnosed as hypersensitivity myocarditis (HSM) (21 among 761 recipients, 2.8%). Dobutamine, a common cause of HSM, was administered to 12 patients (57%). Ten patients (47.6%) were on milrinone and 4 (19.0%) were on ventricular assist devices. Post-transplant survival of HSM patients was comparable to that of patients transplanted for active myocarditis or other cause of heart failure. In conclusion, myocardial eosinophilic infiltration is associated with multiple medications in patients with advanced heart failure; however, it does not affect the post-transplant prognosis.

Milrinone and mortality in adult cardiac surgery: a meta-analysis.

OBJECTIVE: The authors conducted a review of randomized studies to show whether there are any increases or decreases in survival when using milrinone in patients undergoing cardiac surgery. DESIGN: A meta-analysis. SETTING: Hospitals. PARTICIPANTS: Five hundred eighteen patients from 13 randomized trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: BioMedCentral, PubMed EMBASE, the Cochrane central register of clinical trials, and conference proceedings were searched for randomized trials that compared milrinone versus placebo or any other control in the setting of cardiac surgery that reported data on mortality. Overall analysis showed that milrinone increased perioperative mortality (13/249 [5.2%] in the milrinone group v 6/269 [2.2%] in the control arm, odds ratio [OR] = 2.67 [1.05-6.79], p for effect = 0.04, p for heterogeneity = 0.23, I(2) = 25% with 518 patients and 13 studies included). Subanalyses confirmed increased mortality with milrinone (9/84 deaths [10.7%] v 3/105 deaths [2.9%] with other drugs as control, OR = 4.19 [1.27-13.84], p = 0.02) with 189 patients and 5 studies included) but did not confirm a difference in mortality (4/165 [2.4%] in the milrinone group v 3/164 [1.8%] with placebo or nothing as control, OR = 1.27 [0.28-5.84], p = 0.76 with 329 patients and 8 studies included). CONCLUSIONS: This analysis suggests that milrinone might increase mortality in adult patients undergoing cardiac surgery. The effect was seen only in patients having an active inotropic drug for comparison and not in the placebo subgroup. Therefore, the question remains whether milrinone increased mortality or if the control inotropic drugs were more protective.

The role of milrinone in children with cardiovascular compromise: review of the literature.

BACKGROUND: Cardiovascular instability is a common complication in children after cardiac surgery and in various forms of shock. METHODS: Systematic literature review. RESULTS: Four randomized controlled trials (RCTs) were included in this systematic literature review. In children after corrective surgery for congenital heart disease milrinone significantly reduced the risk of development of LCOS compared with placebo. In another study in children with high pulmonary vascular resistance and impaired oxygenation after Fontan operation, inhalation of NO with milrinone led to the most significant reduction of pulmonary vascular resistance and improvement of oxygenation. When only milrinone was given these changes were less pronounced. In non-hyperdynamic septic shock, CI, SVI, and DO2 significantly increased while SVRI significantly decreased after milrinone when compared to placebo. CONCLUSIONS: There are a limited number of RCTs in children that suggest a beneficial effect of milrinone in the optimization of cardiovascular function after cardiac surgery and in septic shock.

Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery.

BACKGROUND: Postoperative atrial fibrillation (AF), a frequent complication after cardiac surgery, causes morbidity and prolongs hospitalization. Inotropic drugs are commonly used perioperatively to support ventricular function. This study tested the hypothesis that the use of inotropic drugs is associated with postoperative AF. METHODS AND RESULTS: We evaluated perioperative risk factors in 232 patients who underwent elective cardiac surgery. All patients were in sinus rhythm at surgery. Sixty-seven patients (28.9%) developed AF a mean of 2.9+/-2.1 days after surgery. Patients who developed AF stayed in the hospital longer (P<0.001) and were more likely to die (P=0.02). Milrinone use was associated with an increased risk of postoperative AF (58.2% versus 26.1% in nonusers; P<0.001). Older age (63.4+/-10.7 versus 56.7+/-12.3 years; P<0.001), hypertension (P=0.04), lower preoperative ejection fraction (P=0.03), mitral valve surgery (P=0.02), right ventricular dysfunction (P=0.03), and higher mean pulmonary artery pressure (27.1+/-9.3 versus 21.8+/-7.5 mm Hg; P=0.001) also were associated with postoperative AF. In multivariable logistic regression, age (P<0.001), ejection fraction (P=0.02), and milrinone use (odds ratio, 4.86; 95% confidence interval, 2.31 to 10.25; P<0.001) independently predicted postoperative AF. When only data from patients with pulmonary artery catheters were analyzed and pulmonary artery pressure was included in the model, age, milrinone use (odds ratio, 4.45; 95% confidence interval, 2.01 to 9.84; P<0.001), and higher pulmonary artery pressure (P=0.02) were associated with an increased risk of postoperative AF. Adding other potential confounders or stratifying analysis by mitral valve surgery did not change the association of milrinone use with postoperative AF. CONCLUSIONS: Milrinone use is an independent risk factor for postoperative AF after elective cardiac surgery.

Comparative hemodynamic effects of vasopressin and norepinephrine after milrinone-induced hypotension in off-pump coronary artery bypass surgical patients.

OBJECTIVE: Phosphodiesterase inhibitor is essential to the pharmacologic management of decompensated heart failure because it increases contractility and decreases afterload of right ventricle. It also improves hemodynamics and increases blood flow of the grafted internal mammary arteries and middle cerebral arteries during coronary artery bypass surgery. However, it induces vasodilation and necessitates the use of vasoconstrictors, such as norepinephrine. We hypothesized that vasopressin could recover hypotension induced by milrinone with less effect on pulmonary vascular resistance (PVR) compared to norepinephrine. METHODS: Fifty patients, undergoing coronary artery bypass graft (CABG) surgery, were assigned randomly in a double-blind manner to receive either vasopressin or norepinephrine. After baseline hemodynamic measurements, a loading dose of milrinone 50 microg/kg was infused slowly for 20 min followed by continuous infusion of 0.5 microg/(kg min). Immediately after the loading dose of milrinone, hemodynamic variables were measured, and vasopressin (VP group) or norepinephrine (NE groups) was infused. After being titrated until the mean arterial pressure was increased by 20%, hemodynamic variables were measured again. RESULTS: Milrinone infusion reduced both systemic vascular resistance (SVR, 1218+/-299 dynes/cm5 vs 838+/-209 dynes/cm5, 1345+/-299 dynes/cm5 vs 1011+/-195 dynes/cm5) and PVR (95+/-34 dynes/cm5 vs 72+/-30 dynes/cm5, 119+/-85 dynes/cm5 vs 87+/-33 dynes/cm5) in the VP and NE groups, respectively. Vasopressin and norepinephrine infusion increased both SVR (838+/-209 dynes/cm5 vs 1100+/-244 dynes/cm5, 1011+/-195 dynes/cm5 vs 1446+/-681 dynes/cm5, respectively) and PVR (72+/-30 dynes/cm5 vs 84+/-18 dynes/cm5, 87+/-33 dynes/cm5 vs 139+/-97 dynes/cm5, respectively). The PRV/SVR ratio was decreased after vasopressin infusion (0.10+/-0.03 vs 0.08+/-0.03), while no changes were found after norepinephrine infusion (0.09+/-0.02 vs 0.09+/-0.02). CONCLUSIONS: In the patients undergoing CABG surgery, both norepinephrine and low dose vasopressin were effective in restoring milrinone-induced decrease of SVR. However, only low-dose vasopressin decreased the PVR/SVR ratio that was increased by milrinone. Considering the importance of maintaining systemic perfusion pressure as well as reducing right heart afterload, milrinone-vasopressin may provide better hemodynamics than milrinone-norephinephrine during the management of right heart failure.

Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease.

BACKGROUND: Low cardiac output syndrome (LCOS), affecting up to 25% of neonates and young children after cardiac surgery, contributes to postoperative morbidity and mortality. This study evaluated the efficacy and safety of prophylactic milrinone in pediatric patients at high risk for developing LCOS. METHODS AND RESULTS: The study was a double-blind, placebo-controlled trial with 3 parallel groups (low dose, 25- microg/kg bolus over 60 minutes followed by a 0.25- microg/kg per min infusion for 35 hours; high dose, 75- microg/kg bolus followed by a 0.75- microg/kg per min infusion for 35 hours; or placebo). The composite end point of death or the development of LCOS was evaluated at 36 hours and up to 30 days after randomization. Among 238 treated patients, 25.9%, 17.5%, and 11.7% in the placebo, low-dose milrinone, and high-dose milrinone groups, respectively, developed LCOS in the first 36 hours after surgery. High-dose milrinone significantly reduced the risk the development of LCOS compared with placebo, with a relative risk reduction of 55% (P=0.023) in 238 treated patients and 64% (P=0.007) in 227 patients without major protocol violations. There were 2 deaths, both after infusion of study drug. The use of high-dose milrinone reduced the risk of the LCOS through the final visit by 48% (P=0.049). CONCLUSIONS: The use of high-dose milrinone after pediatric congenital heart surgery reduces the risk of LCOS.

Postoperative junctional ectopic tachycardia in children: incidence, risk factors, and treatment.

BACKGROUND: Junctional ectopic tachycardia (JET) occurs commonly after pediatric cardiac operation. The cause of JET is thought to be the result of an injury to the conduction system during the procedure and may be perpetuated by hemodynamic disturbances or postoperative electrolyte disturbances, namely hypomagnesemia. The purpose of this study was to determine perioperative risk factors for the development of JET. METHODS: Telemetry for each patient admitted to the cardiac intensive care unit from December 1997 through November 1998 for postoperative cardiac surgical care was examined daily for postoperative JET. A nested case-cohort analysis of 33 patients who experienced JET from 594 consecutively monitored patients who underwent cardiac operation was performed. Univariate and multivariate analyses were conducted to determine factors associated with the occurrence of JET. RESULTS: The age range of patients with JET was 1 day to 10.5 years (median, 1.8 months). Univariate analysis revealed that dopamine or milrinone use postoperatively, longer cardiopulmonary bypass times, and younger age were associated with JET. Multivariate modeling elicited that dopamine use postoperatively (odds ratio, 6.2; p = 0.01) and age less than 6 months (odds ratio, 4.0; p = 0.02) were associated with JET. Only 13 (39%) of the patients with JET received therapeutic interventions. CONCLUSIONS: Junctional ectopic tachycardia occurred in 33 (5.6%) of 594 patients who underwent cardiac operation during the study period. Postoperative dopamine use and younger age were associated with JET. It may be speculated that dopamine should be discontinued in the presence of postoperative JET.

Acute renal failure secondary to milrinone in a patient with cardiac amyloidosis.

Milrinone is a phosphodiesterase type III inhibitor with positive inotropic and vasodilatory effects. A common side effect of milrinone is hypotension from the peripheral vasodilation. Although mild elevations in serum creatinine have been described previously in the setting of milrinone-induced hypotension, acute oligoanuric renal failure requiring renal replacement therapy has not yet been described. This case report is the first to document such a result and to report the successful use of peritoneal dialysis in this setting. Previous case reports documented vasopressin as an effective alternative to catecholamines in the treatment of milrinone-induced hypotension. This report documents the use of four vasopressor agents (including vasopressin) in this patient, with only vasopressin resulting in improvement in systemic vascular resistance and blood pressure. Vasopressin may be the most effective vasopressor agent in the treatment of milrinone-induced hypotension.

Prophylactic intravenous use of milrinone after cardiac operation in pediatrics (PRIMACORP) study. Prophylactic Intravenous Use of Milrinone After Cardiac Operation in Pediatrics.

BACKGROUND: Many pediatric patients undergoing cardiac surgery involving cardiopulmonary bypass have a predictable fall in the cardiac index 6 to 18 hours after surgery, the so-called low cardiac output syndrome (LCOS). Because patients who have LCOS require more monitoring and support and have a prolonged stay in the intensive care unit, the syndrome is associated with a costly morbidity. Milrinone, a phosphodiesterase III inhibitor, improves cardiac muscle contractile force and vascular muscle relaxation through positive inotropic and vasodilatory effects. The purpose of the Prophylactic Intravenous Use of Milrinone After Cardiac Operation in Pediatrics (PRIMACORP) study is to evaluate the safety and efficacy of the prophylactic use of milrinone in pediatric patients at high risk for development of LCOS after undergoing cardiac surgery. METHODS: Patients in the multicenter, randomized, double-blind, placebo-controlled, parallel treatment study will be randomized to 1 of 3 treatment arms: (1) low-dose milrinone (25 microg/kg intravenous bolus over 60 minutes followed by a 0.25 microg/kg/min infusion for 35 hours), (2) high-dose milrinone (75 microg/kg intravenous bolus over 60 minutes followed by a 0.75 microg/kg/min infusion for 35 hours), or (3) placebo. RESULTS: The primary end point for efficacy evaluation will be based on a composite variable consisting of death or development of LCOS requiring additional mechanical or pharmacologic support, up to 36 hours after randomization. A 2-sided test with a 0.025 type I error will be used for the primary end point analysis. The PRIMACORP study will enroll a total of 240 patients. Six additional secondary end points will be analyzed. CONCLUSIONS: The PRIMACORP study will address several questions regarding the safety and efficacy of prophylactic milrinone use in pediatric patients at high risk for development of LCOS after cardiac surgery.

Comparison of the hemodynamic effects of milrinone with dobutamine in patients after cardiac surgery.

OBJECTIVE: To compare the hemodynamic effects, efficacy, and safety of intravenous milrinone (M), 50 microg/kg during 10 minutes followed by 0.5 microg/kg/min, with intravenous dobutamine (D), 10 to 20 microg/kg/min, in patients with low cardiac output after cardiac surgery. DESIGN: Randomized, open-label, multicenter study. SETTING: Cardiothoracic surgery departments, operating rooms, and intensive care units in 6 university hospitals. PARTICIPANTS: Patients (n = 120; 60 per group) after elective cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analysis compared the hemodynamics at baseline and the percentage change from baseline during 4 hours of the drug infusion. The incidence of adverse events was recorded. Both groups had low mean (+/- SEM) cardiac indices (M, 1.6 ([0.03] L/min/m(2); D, 1.7 [0.03] L/min/m(2)) in association with adequate mean pulmonary capillary wedge pressures (M, 13.7 [1.3] mmHg; D, 12.7 [1.9] mmHg) at baseline. Group M had significantly higher systemic arterial pressures and systemic vascular resistances compared with group D; otherwise, the hemodynamics in both groups were comparable. During the study, hemodynamic responses included the following: group D had greater increases in cardiac index (at 1 hour, D = 55%, M = 36%; p < 0.01), heart rate (at 1 hour, D = 35%, M = 10%; p < 0.001), arterial pressures (mean arterial pressure at 1 hour, D = 31%, M = 7%; p < 0.001), and left ventricular stroke work index (at 1 hour, D = 75%, M = 45%; p < 0.05). Group M had greater decreases in mean pulmonary capillary wedge pressure (at 1 hour, D = -3%, M = -14%; p < 0.05). Comparisons of adverse events showed that dobutamine was associated with a higher incidence of hypertension (D = 40%, M = 13%; p < 0.02) and change of rhythm from sinus to atrial fibrillation (D = 18%, M = 5%; p < 0.04). Milrinone was associated with a higher incidence of sinus bradycardia (D = 2%, M = 13%; p < 0.03). CONCLUSIONS: Milrinone and dobutamine are appropriate and comparable for the pharmacologic treatment of the low- output syndrome after cardiopulmonary bypass.