Hemodynamic response and clinical outcome following intravenous milrinone plus norepinephrine-based hyperdynamic hypertensive therapy in patients suffering secondary cerebral ischemia after aneurysmal subarachnoid hemorrhage.

PURPOSE: Intravenous and intra-arterial milrinone as a rescue measure for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been adopted by several groups, but so far, evidence for the clinical benefit is unclear and effect on brain perfusion is unknown. The aim of the actual analysis was to define cerebral hemodynamic effects and outcome of intravenous milrinone plus norepinephrine supplemented by intra-arterial nimodipine as a rescue strategy for DCI following aneurysmal SAH. METHODS: Of 176 patients with aneurysmal SAH treated at our neurosurgical department between April 2016 and March 2021, 98 suffered from DCI and were submitted to rescue therapy. For the current analysis, characteristics of these patients and clinical response to rescue therapy were correlated with hemodynamic parameters, as assessed by CT angiography (CTA) and perfusion CT. Time to peak (TTP) delay in the ischemic focus and the volume with a TTP delay of more than 4 s (T4 volume) were used as hemodynamic parameters. RESULTS: The median delay to neurological deterioration following SAH was 5 days. Perfusion CT at that time showed median T4 volumes of 40 cc and mean focal TTP delays of 2.5 ± 2.1 s in these patients. Following rescue therapy, median T4 volume decreased to 10 cc and mean focal TTP delay to 1.7 ± 1.9 s. Seventeen patients (17% of patients with DCI) underwent additional intra-arterial spasmolysis using nimodipine. Visible resolution of macroscopic vasospasm on CTA was observed in 43% patients with DCI and verified vasospasm on CTA, including those managed with additional intra-arterial spasmolysis. Initial WFNS grade, occurrence of secondary infarction, ischemic volumes and TTP delays at the time of decline, the time to clinical decline, and the necessity for additional intra-arterial spasmolysis were identified as the most important features determining neurological outcome at 6 months. CONCLUSION: The current analysis shows that cerebral perfusion in the setting of secondary cerebral ischemia following SAH is measurably improved by milrinone and norepinephrine-based hyperdynamic therapy. A long-term clinical benefit by the addition of milrinone appears likely. Separation of the direct effect of milrinone from the effect of induced hypertension is not possible based on the present dataset.

Management of Neonatal Hypotension.

Hypotension is a common problem in neonates with complex underlying pathophysiology. Although treatment of low blood pressure is common, clinicians must use all available information to target neonates with compromised perfusion. Pharmacotherapy should be tailored to the specific physiologic perturbations of the individual neonate. Dopamine is the most commonly utilized agent and may be the most appropriate agent for septic shock with low diastolic blood pressure. However, alternative therapies should be considered for other etiologies of hypotension, including milrinone and vasopressin for persistent pulmonary hypertension of the newborn and dobutamine for patent ductus arteriosus. Additional studies are required to refine the approach to neonatal hypotension and document the long-term outcomes of treated neonates.

Milrinone and levosimendan during porcine myocardial ischemia -- no effects on calcium overload and metabolism.

BACKGROUND: Although inotropic stimulation is considered harmful in the presence of myocardial ischaemia, both calcium sensitisers and phosphodiesterase inhibitors may offer cardioprotection. We hypothesise that these cardioprotective effects are related to an acute alteration of myocardial metabolism. We studied in vivo effects of milrinone and levosimendan on calcium overload and ischaemic markers using left ventricular microdialysis in pigs with acute myocardial ischaemia. METHODS: Anaesthetised juvenile pigs, average weight 36 kg, were randomised to one of three intravenous treatment groups: milrinone 50 µg/kg bolus plus infusion 0.5 µg/kg/min (n = 7), levosimendan 24 µg/kg plus infusion 0.2 µg/kg/min (n = 7), or placebo (n = 6) for 60 min prior to and during a 45 min acute regional coronary occlusion. Systemic and myocardial haemodynamics were assessed, and microdialysis was performed with catheters positioned in the left ventricular wall. (45) Ca(2+) was included in the microperfusate in order to assess local calcium uptake into myocardial cells. The microdialysate was analysed for glucose, lactate, pyruvate, glycerol, and for (45) Ca(2+) recovery. RESULTS: During ischaemia, there were no differences in microdialysate-measured parameters between control animals and milrinone- or levosimendan-treated groups. In the pre-ischaemic period, arterial blood pressure decreased in all groups while myocardial oxygen consumption remained stable. CONCLUSIONS: These findings reject the hypothesis of an immediate energy-conserving effect of milrinone and levosimendan during acute myocardial ischaemia. On the other hand, the data show that inotropic support with milrinone and levosimendan does not worsen the metabolic parameters that were measured in the ischaemic myocardium.

Mechanisms of a reduced cardiac output and the effects of milrinone and levosimendan in a model of infant cardiopulmonary bypass.

OBJECTIVES: A low cardiac output state is an important cause of morbidity after pediatric cardiopulmonary bypass. The objectives of our study were to define the early precipitants of the reduced cardiac output and to investigate the effects on these of milrinone and levosimendan in a model of pediatric cardiopulmonary bypass. DESIGN: Experimental study. SETTING: : Research laboratory at a university-affiliated, tertiary pediatric center. SUBJECTS: Eighteen piglets. INTERVENTIONS: Piglets, instrumented with systemic, pulmonary arterial, and coronary sinus catheters, pulmonary and circumflex arterial flow probes, and a left ventricular conductance-micromanometer-tipped catheter, underwent cardiopulmonary bypass with aortic cross-clamp and cardioplegic arrest. At 120 mins, they were assigned to control, milrinone, or levosimendan groups and studied for a further 120 mins. MEASUREMENTS AND MAIN RESULTS: In controls, between 120 and 240 mins, cardiac output decreased by 15%. Systemic vascular resistance was unchanged, but pulmonary vascular resistance increased by 19%. Systemic arterial elastance increased by 17%, indicating increased afterload. End-systolic elastance was unchanged, and coronary sinus oxygen tension decreased by 4.0 +/- 1.7 mm Hg. In animals receiving milrinone cardiac output was preserved, and in animals receiving levosimendan cardiac output increased by 14%. Both drugs prevented an increase in arterial elastance and pulmonary vascular resistance after cardiopulmonary bypass. Systemic vascular resistance decreased by 31% after levosimendan, and end-systolic elastance increased by 48%, indicating improved contractility. Both agents prevented a decrease in coronary sinus oxygen tension. CONCLUSIONS: Increased afterload, which is not matched by an equivalent elevation in contractility, contributes to the reduced cardiac output early after pediatric cardiopulmonary bypass in this model. This increase is prevented by milrinone and levosimendan. Both agents exert additional beneficial effects on pulmonary vascular resistance and myocardial oxygen balance, although levosimendan has greater inotropic properties.

Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes.

The appropriate role of intravenous inodilator therapy (inotropic agents with vasodilator properties) in the management of acute heart failure syndromes (AHFS) has long been a subject of controversy, mainly because of the lack of prospective, placebo-controlled trials and a lack of alternative therapies. The use of intravenous inodilator infusions, however, remains common, but highly variable. As new options emerge for the treatment of AHFS, the available information should be reviewed to determine which approaches are supported by evidence, which are used empirically without evidence, and which should be considered inappropriate. For these purposes, we reviewed data available from randomized controlled trials on short-term, intermittent, and long-term use of intravenous inodilator agents (dobutamine, dopamine, and milrinone) in AHFS. Randomized controlled trials failed to show benefits with current medications and suggested that acute, intermittent, or continuous use of inodilator infusions may increase morbidity and mortality in patients with AHFS. Their use should be restricted to patients who are hypotensive as a result of low cardiac output despite a high left ventricular filling pressure.

Effects of a new phosphodiesterase enzyme type V inhibitor (UK 343-664) versus milrinone in a porcine model of acute pulmonary hypertension.

BACKGROUND: Perioperative pulmonary hypertension remains a clinical challenge. The phosphodiesterase enzyme type III inhibitor milrinone produces pulmonary vasodilation but lacks selectivity. Sildenafil, a phosphodiesterase enzyme type V inhibitor, can also induce relaxation of the pulmonary vasculature; however, only the oral formulation is presently available. This study evaluated the effects of a new intravenous sildenafil analogue--UK 343-664--compared with milrinone during acute pulmonary hypertension in a porcine model of thromboxane-induced pulmonary hypertension. METHODS: After acute pulmonary hypertension, 24 adult swine were randomized to 3 groups. Group 1 (n = 9) received an intravenous dose of 500 microg of UK 343-664, group 2 (n = 8) received milrinone 50 mg/kg, and group 3 (n = 7) received 10 mL of normal saline solution. All agents were administered for more than 5 minutes. Data were recorded continuously for 30 minutes. RESULTS: Both milrinone and UK 343-664 partially reversed thromboxane-induced pulmonary hypertension, with a notable decrease in mean pulmonary artery pressure and pulmonary vascular resistance and a concomitant increase in cardiac output. In addition, milrinone improved right ventricular contractility but produced marked systemic vasodilatation. In contrast, the administration of UK 343-664 was associated with pulmonary vasodilatation, without appreciable changes in systemic arterial pressure or vascular resistance. CONCLUSIONS: Milrinone and UK 343-664 were equally effective as pulmonary vasodilators; however, only UK 343-664 exhibited a high degree of pulmonary selectivity. Potential uses for this new phosphodiesterase enzyme type V inhibitor warrant further study.