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.

Oral milrinone for management of refractory right ventricular failure in patients with left ventricular assist devices.

AIMS: We present a single-centre retrospective experience using oral milrinone in patients with a left ventricular assist device (LVAD) and concurrent refractory right ventricular failure. METHODS AND RESULTS: All patients implanted with LVAD between January 2013 and July 2021 from a high-volume advanced heart failure service were reviewed. Eight patients were initiated on oral milrinone during this period. Oral milrinone was started 1.5 [inter-quartile range (IQR) 1-2.3] years after LVAD implantation and continued for 1.2 (IQR 0.5-2.8) years. Therapeutic milrinone levels were achieved (232.2 ± 153.4 ng/mL) with 62.4 ± 18% of time within the therapeutic range. Two patients had adverse events (non-sustained ventricular tachycardia and ventricular fibrillation effectively treated by internal cardioverter defibrillator) but did not require milrinone discontinuation. Four deaths occurred, one after transplant and three from disease progression determined to be unrelated to oral milrinone use. Three patients continue oral milrinone therapy in the community. There was no significant difference found after the initiation of oral milrinone on any of the physiological measures; however, there were trends in reduction of New York Heart Association class from 3.4 ± 0.5 to 3.0 ± 0.8 (P = 0.08), reduction of right atrial/wedge pressure from 0.9 ± 0.3 to 0.5 ± 0.2 (P = 0.08), and improvement of right ventricular stroke work index from 3.8 ± 2 to 5.8 ± 2.7 (P = 0.16). CONCLUSIONS: Oral milrinone appears safe for long-term use in the outpatient setting when combined with therapeutic monitoring in this complex medical cohort with limited management options. Further study is needed to ascertain whether this treatment is effective in reducing heart failure symptoms and admissions.

Comparative Effectiveness and Safety of Milrinone and Levosimendan as Initial Inotrope Therapy in Patients With Acute Heart Failure With Renal Dysfunction.

ABSTRACT: Levosimendan and milrinone are 2 effective inotropic drugs used to maintain cardiac output in acute heart failure (AHF). Using data from patients with AHF with and without abnormal renal function, we performed this single-center, retrospective cohort study to compare the effectiveness and safety of milrinone and levosimendan for the initial management of AHF. Patients admitted for heart failure between December 2016 and September 2019 who received levosimendan or milrinone as initial inotrope therapy in the cardiology department were identified. A total of 436 levosimendan and 417 milrinone patients with creatinine clearance (CrCl) ≥30 mL/min and 50 levosimendan and 71 milrinone patients with CrCl <30 mL/min or on dialysis were included. The primary outcome was a composite of changes in clinical status at 15 and 30 days after initial inotrope therapy discontinuation. Between subgroups of patients with CrCl ≥30 mL/min, there were no significant differences in primary outcomes; milrinone was associated with more frequent hypotension and cardiac arrhythmias during the infusion period (P < 0.01), while levosimendan was associated with more frequent cardiac arrhythmias within 48 hours after discontinuation (P < 0.05). Of the patients with CrCl <30 mL/min or on dialysis, more initial levosimendan than milrinone patients and those who switched to alternative inotropes experienced clinical worsening at 15 days and 30 days (P < 0.05). According to our results, patients with AHF with severe renal dysfunction should avoid initial inotrope therapy with levosimendan.

Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock.

BACKGROUND: Cardiogenic shock is associated with substantial morbidity and mortality. Although inotropic support is a mainstay of medical therapy for cardiogenic shock, little evidence exists to guide the selection of inotropic agents in clinical practice. METHODS: We randomly assigned patients with cardiogenic shock to receive milrinone or dobutamine in a double-blind fashion. The primary outcome was a composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite outcome. RESULTS: A total of 192 participants (96 in each group) were enrolled. The treatment groups did not differ significantly with respect to the primary outcome; a primary outcome event occurred in 47 participants (49%) in the milrinone group and in 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95% confidence interval [CI], 0.69 to 1.19; P = 0.47). There were also no significant differences between the groups with respect to secondary outcomes, including in-hospital death (37% and 43% of the participants, respectively; relative risk, 0.85; 95% CI, 0.60 to 1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio, 0.78; 95% CI, 0.29 to 2.07), receipt of mechanical circulatory support (12% and 15%; hazard ratio, 0.78; 95% CI, 0.36 to 1.71), or initiation of renal replacement therapy (22% and 17%; hazard ratio, 1.39; 95% CI, 0.73 to 2.67). CONCLUSIONS: In patients with cardiogenic shock, no significant difference between milrinone and dobutamine was found with respect to the primary composite outcome or important secondary outcomes. (Funded by the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; ClinicalTrials.gov number, NCT03207165.).

Impact of baseline beta-blocker use on inotrope response and clinical outcomes in cardiogenic shock: a subgroup analysis of the DOREMI trial.

BACKGROUND: Cardiogenic shock (CS) is associated with significant morbidity and mortality. The impact of beta-blocker (BB) use on patients who develop CS remains unknown. We sought to evaluate the clinical outcomes and hemodynamic response profiles in patients treated with BB in the 24 h prior to the development of CS. METHODS: Patients with CS enrolled in the DObutamine compaREd to MIlrinone trial were analyzed. The primary outcome was a composite of all-cause mortality, resuscitated cardiac arrest, need for cardiac transplant or mechanical circulatory support, non-fatal myocardial infarction, transient ischemic attack or stroke, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite and hemodynamic response profiles derived from pulmonary artery catheters. RESULTS: Among 192 participants, 93 patients (48%) had received BB therapy. The primary outcome occurred in 47 patients (51%) in the BB group and in 52 (53%) in the no BB group (RR 0.96; 95% CI 0.73-1.27; P = 0.78) throughout the in-hospital period. There were fewer early deaths in the BB group (RR 0.41; 95% CI 0.18-0.95; P = 0.03). There were no differences in other individual components of the primary outcome or in hemodynamic response between the two groups throughout the remainder of the hospitalization. CONCLUSIONS: BB therapy in the 24 h preceding the development of CS did not negatively influence clinical outcomes or hemodynamic parameters. On the contrary, BB use was associated with fewer deaths in the early resuscitation period, suggesting a paradoxically protective effect in patients with CS. Trial registration ClinicalTrials.gov Identifier: NCT03207165.

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.

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.

Long-term milrinone therapy as a bridge to heart transplantation: Safety, efficacy, and predictors of failure.

BACKGROUND: Studies of long-term inotrope use in advanced HF have previously provided limited and conflicting results. This study aimed to evaluate the safety and efficacy of long-term milrinone use and identify predictors of failure to bridge to orthotropic heart transplant (OHT) in a cohort of end-stage heart failure (HF) patients listed for heart transplantation and receiving inotrope therapy. METHODS: The study included 150 adults listed for OHT at a single center from 2001 to 2017 who received milrinone therapy for ≥30 days. Multivariate Cox proportional hazards models were used to identify factors associated with "failure" (left ventricular assist device, intra-aortic balloon pump, status downgrade due to instability, death) vs. "success" (OHT, recovery) during bridging to OHT. RESULTS: "Failure" occurred in 33 (22%) patients. Factors independently associated with failure included male sex (HR = 7.6; p = 0.004), no implantable cardioverter-defibrillator (HR = 3.8; p = 0.009), and lack of guideline-directed medical therapy (GDMT) with a beta-blocker (HR = 7.8; p = 0.002) or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (HR = 6.3; p < 0.001). Patients who received fewer guideline-directed medications had a higher cumulative probability of failure. Adverse events included central line-associated bloodstream infection (2.55 per 1000 line-days) and arrhythmia (1.59 per 1000 treatment-days). CONCLUSIONS: Our findings suggest that long-term milrinone therapy in selected patients is associated with a high rate of successful bridging to OHT and a low rate of adverse events. Patients intolerant of GDMT are more likely to fail to bridge to OHT without mechanical support. Sex differences in outcomes associated with milrinone therapy should be explored.

Comparison of Positive Inotropic Agents in the Management of Acute Decompensated Heart Failure.

Current guidelines recommend the consideration of positive inotropes in patients with acute decompensated heart failure (ADHF) who have low cardiac index and evidence of systemic hypoperfusion or congestion. However, there is no evidence detailing the first line agent for the management of ADHF. The purpose of this study was to compare the safety and efficacy of dobutamine to milrinone for the treatment of ADHF. This was a single-center, retrospective study at a tertiary academic medical center, approved by Partner's Health Care Institutional Review Board. Patients included in this study were those admitted with ADHF who received dobutamine or milrinone from June 2015 to July 2017. A total of 95 dobutamine and 40 milrinone patients were included in the analysis. Median hospital length of stay was 12 days in the dobutamine group versus 10 days in the milrinone group (P = 0.34). Rehospitalization within 30 days occurred in 29.5% of patients in the dobutamine group versus 17.5% of patients in the milrinone group (P = 0.15). Median intensive care unit length of stay was 4.5 days in the dobutamine group versus 10 days in the milrinone group (P < 0.01). All other minor end points including all-cause mortality, progression to renal failure within 72 hours, rehospitalization in 90 days, and urine output within 72 hours of therapy were not found to be statistically significant. In addition, a post hoc analysis compared major and minor outcomes between milrinone and dobutamine using linear and logistic regression with adjustment for baseline characteristics. There were not any statistically significant findings in the post hoc analysis. Overall, there were no statistically significant differences in outcomes between the 2 groups other than longer intensive care unit length of stay in the milrinone group.

Comparing the effects of milrinone and olprinone in patients with congestive heart failure.

Phosphodiesterase-3 (PDE3) inhibitors are widely used among patients with congestive heart failure (CHF). However, no studies have compared the cardiovascular outcomes between different PDE3 inhibitors in CHF management. In this report, we retrospectively compared the clinical benefits of two PDE3 inhibitors, milrinone and olprinone, to determine which better controls the progression of CHF. A total of 288 hospitalized patients who received PDE3 inhibitors [(milrinone; n = 77 and olprinone; n = 211, respectively)] for CHF were retrospectively enrolled. The primary endpoint was defined as having a major adverse cardiovascular and cerebrovascular event (MACCE) or cardiac death by day 60. Kaplan-Meier curves and multivariate Cox proportional models were used to compare the outcomes for patients treated with milrinone and olprinone. We found no significant differences in the baseline characteristics between the two groups. In patients treated with milrinone, a greater incidence of a MACCE or cardiac death was observed (log rank; P = 0.005 and P = 0.01, respectively). Milrinone-treated patients with ischemic heart disease and chronic kidney disease (CKD) at stage ≥ 4 presented with greater incidence of MACCE (log rank; P < 0.001 and P = 0.006, respectively). Similarly, these patients were significantly more likely to succumb to cardiac death (log rank; P < 0.001 and P = 0.02). Multivariate Cox proportional hazard models demonstrated that milrinone treatment was an independent predictor of MACCE [hazard ratio (HR) 3.17; 95% CI 1.64-6.10] and cardiac death (HR 2.64; 95% CI 1.42-4.91). Oral administration of a ß-blocker at discharge occurred more often in the olprinone-treated patients than in the milrinone-treated patients (63% vs. 29%, P = 0.004). We compared the outcomes of milrinone and olprinone treatment in patients with CHF. Those treated with milrinone were more likely to succumb to a MACCE or cardiac death within 60 days of treatment, which was especially true for patients with ischemic heart disease or CKD.

Which Protocol for Milrinone to Treat Cerebral Vasospasm Associated With Subarachnoid Hemorrhage?

BACKGROUND: Milrinone has emerged as an option to treat delayed cerebral ischemia after subarachnoid hemorrhage. However, substantial variation exists in the administration of this drug. We retrospectively assessed the effectiveness of 2 protocols in patients with angiographically proven cerebral vasospasm. METHODS: During 2 successive periods, milrinone was administered using either a combination of intra-arterial milrinone infusion followed by intravenous administration until day 14 after initial bleeding (IA+IV protocol), or a continuous intravenous milrinone infusion for at least 7 days (IV protocol). The primary endpoint was the reversion rate of vasospastic arterial segments following the first IA infusion of milrinone (IA+IV protocol) compared with the reversion rate during the first week of IV infusion (IV protocol). RESULTS: There were 24 and 77 consecutive patients in IA+IV and IV protocols, respectively. The reversion rate was comparable between the 2 protocols: 71% (95% confidence interval [CI], 59%-83%) in the IA+IV protocol versus 64% (95% CI, 58%-71%) in the IV protocol (P=0.36). Rescue procedures for persistence or recurrence of vasospasm, that is, mechanical angioplasty and/or IA milrinone infusion, were similar between the 2 protocols. Patients with a good neurological outcome at 1 year, that is, modified Rankin Scale scores 0-2, were comparable between the 2 protocols. Side effects of milrinone were uncommon and equally distributed within the 2 protocols. CONCLUSIONS: These findings indicate that a continuous IV infusion of milrinone was as efficient as combined IA+IV infusion and suggest that this modality could be considered as a first easy-to-use option to treat patients with CVS.

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.

Milrinone-Associated Cardiomyopathy and Arrhythmia in Cerebral Vasospasm.

BACKGROUND: Milrinone is an inotropic and vasodilatory drug proven safe for use in treatment of cerebral vasospasm. Despite its reported safety profile, its use is not free of side effects. Milrinone-associated cardiomyopathy and arrhythmia can occur in patients with cerebral vasospasm. CASE DESCRIPTION: This is a retrospective chart review of a patient who presented with aneurysmal subarachnoid hemorrhage and developed clinical vasospasm twice over a period of 2 weeks. Sustained intravenous milrinone infusion was used in association with norepinephrine infusion during this period. The patient developed R-on-T triggered torsades de pointes and cardiogenic shock requiring resuscitation. Follow-up echocardiogram showed decreased ejection fraction from 64% to 43% consistent with cardiac remodeling. Systemic complications such as cardiotoxicity and arrhythmias with the use of intravenous milrinone can be seen particularly when used in combination with catecholamines. CONCLUSIONS: With increased combined milrinone and catecholamine use for the treatment of cerebral vasospasm, physicians should be aware of the potential cardiac complications of these agents. Close monitoring with daily electrocardiograms may be helpful to detect changes that suggest cardiotoxicity. If changes are noted, an echocardiogram and cardiology consultation may be warranted.

Effect of phosphodiesterase inhibitors on renal functions and oxidant/antioxidant parameters in streptozocin-induced diabetic rats.

The goal of this study was to investigate the effect of different phosphodiesterase inhibitors (PDEIs), on renal oxidant/antioxidant balance in diabetic rats. Our study was conducted on 125 rats, diabetes was induced in 100 rats by a single administration of streptozocin (STZ). Diabetic rats were divided into four equal groups. The first group was assigned as diabetic control, the remaining three groups were treated with pentoxifylline, sildenafil and milrinone via drinking water for 15 successive days, another group of 25 normal rats was assigned as non-diabetic control. Significant increase in plasma levels of glucose, urea, creatinine, malondialdehyde (MDA), and nitric oxide (NO) with a concomitant decrease in the levels of insulin, reduced glutathione (GSH), glutathione peroxidase (Gpx), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC) were observed in diabetic rats. These alterations were reverted back to near normal level after treatment with PDEIs. Our data seem to suggest a potential role of PDEIs in maintaining health in diabetes by reducing the progression of diabetic nephropathy.

Basilar artery vasospasm after pretuncal non-aneurysmal subarachnoid hemorrhage responding to milrinone.

Pretruncal (perimesencephalic) non-aneurysmal subarachnoid hemorrhage (PNSAH) is uniformly associated with an excellent outcome. Although cerebral vasospasm remains a common complication of SAH and constitutes an important predictor of outcome, in the setting of PNSAH, it is extremely rare. Preturnal non-aneurysmal subarac refers to a subset of SAH patients with a characteristic pattern of localized blood on CT of the head, normal cerebral angiography, and benign course when compared to the aneurysmal SAH population. The presence of radiological or even clinical vasospasm does not exclude the diagnosis of PNSAH. To our knowledge, this is the first case of symptomatic cerebral vasospasm due to PNSAH that responded to milrinone.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.