Milrinone Treatment Research Articles

Toxicology of milrinone by zebrafish embryotoxicity test.

Milrinone, a phosphodiesterase III inhibitor with contractile and vasodilatory effects, is widely used in acute decompensated heart failure and medically refractory end-stage heart failure (HF). The adverse reactions of milrinone have been extensively explored clinically, but its possible toxicities and underlying molecular mechanisms in embryo development need further understanding as its clinical applications increase. Herein, we assessed the milrinone toxicity using the zebrafish embryotoxicity test (ZET), with a view of providing evidence and guidancefor gravidas medicine. We carried out ZET by exposing embryos to a milrinone culture with a series concentration gradients since 1.5 hours post fertilization (hpf) and observed and assessed mortality and hatching rates of drug-treated zebrafishes at 24, 48, 72, and 96 hpf. No significant lethal effect was found in milrinone-treated zebrafish, but hatching rate of eggs at 48 hpf was up-regulated with the increase of milrinone concentration. The impact of milrinone on embryogenesis was assessed through body length, eye area, yolk sac area, swim bladder inflation area, pericardial area and venous congestion area at 96hpf. 150 μg/mL or higher milrinone treatment showed significant effects in the indicators. Organ disorders including enlarged pericardium, liver atrophy and decreased blood vessels were observed in dysplasia individuals versus controls. TUNEL assay suggested the ability of milrinone to induce apoptosis in malformation embryos. Quantitative real-time PCR showed aberrant expressions of transcription factors associated with heartdevelopment and genes related to liver development and apoptosis regulation. Therefore, ZET is feasible for the milrinone toxicity test, and high-dose milrinone causes harm to the embryonic development of zebrafish, especially in embryonic carcinogenesis, vasculogenesis, and hepatogenesis.

Neuroprotective Effects of Milrinone on Acute Traumatic Brain Injury

Traumatic brain injury is still an important health problem worldwide. Traumatic brain injury not only causes direct mechanical damage to the brain but also induces biochemical changes that lead to secondary nerve cell loss. In this study, we investigated the neuroprotective effect of milrinone after traumatic brain injury (TBI) in a rat model. Forty male Wistar albino rats, were used. Rats were divided into 4 groups: 1) sham, 2) TBI, 3) TBI+Ringers, and 4) TBI+Milrinone. In group 1 (sham), only craniotomy was performed. In group 2 (TBI), TBI was performed after craniotomy. In group 3 (TBI+Ringer), TBI was performed after craniotomy and intraperitoneal Ringers solution was given immediately afterward. Group 4 (TBI+Milrinone), TBI was performed after craniotomy, and milrinone was given 1.0mg/kg milrinone intraperitoneally directly (0.5mg/kg milrinone intraperitoneally again 24hours, 48hours, and 72hours after trauma). Tests were performed for neurological and neurobehavioral functions. Immunohistochemistry and histopathology studies were performed. In group 4 compared with group 2 and group 3 groups, tests for neurological functions and neurobehavioral functions were significantly better. In the milrinone treatment used in group 4, plasma and brain tissue tumor necrosis factor, 8-OH 2-deoxyguanosine , and interleukin 6 levels were significantly decreased, and increased plasma and tissue IL-10 levels were detected. Histopathological spinal cord injury and apoptotic index increased in groups 2 and 3, while significantly decreasing in group4. This study shows for the first time that the anti-inflammatory, antioxidant and antiapoptotic properties of milrinone may be neuroprotective after TBI.

Exploring the role of cAMP in gabapentin- mediated pain attenuating effects in chronic constriction injury model in rats

It has been shown that an increase in cAMP leads to pain sensitization and gabapentin is shown to decrease cAMP levels. However, the impact of drugs modulating cAMP levels on analgesic actions of gabapentin is not studied. The present study investigates the effect of milrinone on pain attenuating effects of gabapentin in chronic constriction injury (CCI). Neuropathic pain was induced by putting four loose ligatures around the sciatic nerve. The pain assessment was done by noting the paw withdrawal threshold in the pinprick test, paw withdrawal latency in hot plate test and paw withdrawal duration in acetone drop test before surgery and on 14th- day post-surgery. There was a significant development of cold allodynia, mechanical and heat hyperalgesia on 14th day in CCI rats. Gabapentin (100 mg/kg) treatment for 14 days significantly attenuated pain, while milrinone (50 mg/kg) treatment for 14 days significantly exacerbated neuropathic pain in CCI-subjected rats. Milrinone (30 and 50 mg/kg) also attenuated analgesic actions of gabapentin in CCI-subjected rats, suggests that gabapentin may abolish neuropathic pain by increasing the intracellular levels of cAMP in CCI-subjected rats.

Significance of monitoring pulmonary arterial pressure and cardiac function in neonates with pulmonary or extra-pulmonary acute respiratory distress syndrome

To evaluate the dynamic changes of pulmonary arterial pressure (PAP) and cardiac function in neonates with pulmonary or extra-pulmonary acute respiratory distress syndrome (ARDSp/ARDSexp). An observational study was conducted. A total of 128 neonates with ARDS admitted to neonatology department of the Affiliated Yancheng Hospital of Southeast University Medical College from January 2016 to December 2020 were enrolled, with 67 neonates in ARDSp group and 61 neonates in ARDSexp group. After starting mechanical ventilation, oxygenation index [OI, OI = mean airway pressure (Pmean)×fraction of inspired oxygen (FiO2)/arterial partial pressure of oxygen (PaO2)×100], PAP, cardiac function parameters [cardiac index (CI), left ventricular ejection fraction (LVEF), right ventricular Tei (RV-Tei)], and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) were compared between the two groups; the incidence of pulmonary arterial hypertension [PAH, pulmonary artery systolic pressure (PASP) was more than 35 mmHg (1 mmHg = 0.133 kPa) or more than 2/3 of the systolic blood pressure of the body circulation] of neonates was recorded. The correlation between PAP and NT-proBNP was analyzed by Pearson correlation method. The dynamically changes in PAP and RV-Tei before and after using Milrinone in neonates with ARDSp and ARDSexp combined with moderate-severe PAH (PASP 50-69 mmHg was moderate, and PASP ≥ 70 mmHg was severe) were observed. The duration of mechanical ventilation, total length of hospital stay and prognosis were recorded; Kaplan-Meier survival curve was drawn to analyze the 28-day survival of the two groups. The occurrence rate of PAH in ARDSp group was significantly higher than that in ARDSexp group (97.01% vs. 70.49%, P < 0.01). OI, PAP, NT-proBNP and RV-Tei were also higher [OI: 17.61±6.12 vs. 11.04±5.35, PAP (mmHg): 64.27±9.54 vs. 53.61±6.47, NT-proBNP (ng/L): 23 126.32±1 485.14 vs. 18 624.24±1 647.15, RV-Tei: 0.61±0.22 vs. 0.52±0.19, all P < 0.05], but there was no significant difference in CI or LVEF between the two groups. Pearson correlation analysis showed that PAP was significantly positively correlated with NT-proBNP (r = 0.918, P < 0.01). There were 97 ARDS neonates with moderate-severe PAH with 63 in ARDSp group and 34 in ARDSexp group. Both PAP and RV-Tei in the two group showed a decreasing trend with the prolongation of Milrinone treatment, the decrease was more significant in the ARDSexp group compared with ARDSp group, the difference was statistically significant at 72 hours of treatment [PAP (mmHg): 38.42±8.95 vs. 45.67±13.32, RV-Tei: 0.58±0.19 vs. 0.61±0.13, both P < 0.05]; there was no significant difference in PAP or RV-Tei before extubation between the two groups. The duration of mechanical ventilation and the total length of hospital stay in ARDSp group were significantly longer than those in ARDSexp group [duration of mechanical ventilation (days): 10.12±1.36 vs. 6.31±1.31, total length of hospital stay (days): 16.52±3.25 vs. 13.12±3.57, both P < 0.01]. Kaplan-Meier survival curve showed that neonate in ARDSp group had a significantly lower 28-day cumulative survival rate as compared with ARDSexp group (82.09% vs. 95.01%; Log-Rank test: χ2 = 5.062, P = 0.025). Both PAP and RV-Tei were significantly increased in neonates with ARDS, PAP in neonates with ARDSp were significantly higher than that in neonates with ARDSexp. Dynamic monitoring of PAP and RV-Tei can reflect the severity of ARDS in neonates, and targeted intervention of pulmonary surfactant combined with Milinone for improving oxygenation and reducing PAP is one of the effective methods for the treatment of PAH.

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

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. 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. 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 group4. Milrinone could reduce apoptosis and increase anti-inflammatory and antioxidative mediators, thus playing a protective role in secondary nerve injury after SCI in rats.

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

BackgroundAs 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.MethodsWe 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.ResultsThe 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.ConclusionsBased 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.

Addition of a β1-Blocker to Milrinone Treatment Improves Cardiac Function in Patients with Acute Heart Failure and Rapid Atrial Fibrillation

Background: Tachycardia worsens cardiac performance in acute decompensated heart failure (ADHF). We investigated whether heart rate (HR) optimization by landiolol, an ultra-short-acting β1-selective blocker, in combination with milrinone improved cardiac function in patients with ADHF and rapid atrial fibrillation (AF). Methods and Results: We enrolled9 ADHF patients (New York Heart Association classification IV; HR, 138 ± 18 bpm; left ventricular [LV] ejection fraction, 28 ± 8%; cardiac index [CI], 2.1 ± 0.3 L/min^–1/m^–2; pulmonary capillary wedge pressure [PCWP], 24 ± 3 mm Hg), whose HRs could not be reduced using standard treatments, including diuretics, vasodilators, and milrinone. Landiolol (1.5–6.0 µg/kg^–1/min^–1, intravenous) was added to milrinone treatment to study its effect on hemodynamics. The addition of landiolol (1.5 µg/kg^–1/min^–1) significantly reduced HR by 11% without changing systolic blood pressure (BP) and resulted in a significant decrease in PCWP and a significant increase in stroke volume index (SVI), suggesting that HR reduction restores incomplete LV relaxation. Administration of more than 3.0 µg/kg^–1/min^–1 of landiolol decreased BP, CI, and SVI. Conclusion: The addition of landiolol at doses of <3.0 µg/kg/min to milrinone improved cardiac function in decompensated chronic heart failure with rapid atrial fibrillation by selectively reducing HR.

Protective and therapeutic effects of milrinone on acoustic trauma in rat cochlea.

The aim of this study was to investigate the potential protective and therapeutic effects of milrinone, a specific phosphodiesterase (PDE) III inhibitor, on acoustic trauma-induced cochlear injury and apoptosis. A total number of 30 healthy Wistar albino rats were evenly divided into five groups as follows: group 1 was assigned as control group; group 2 and 3 were assigned as low-dosage groups (0.25mg/kg) in which milrinone was administered 1h before acoustic trauma (AT) and 2h after AT, respectively; group 4 and 5 were assigned as high-dosage groups (0.50mg/kg) in which the drug was administered 1h before AT and 2h after AT, respectively. Except control group, all treatment groups received a single dosage of milrinone for 5days. Distortion product otoacoustic emissions (DPOAE) measurements were recorded before AT as well as at second and fifth post-traumatic days. At the end of fifth day, all rats were sacrificed and the cochlea of the rats was removed for histopathological evaluation. In addition, the groups were compared in terms of apoptotic index via caspase-3 staining. In terms of signal-to-noise ratio (SNR), there was no statistically significant difference among the groups following AT (p > 0.05). After 5days of milrinone treatment, the best SNR values were found in group 5, though all groups did not statistically differ (p > 0.05). In histopathological evaluation, vacuolization, inflammation, and edema scores in all treatment groups were statistically lower than those of the control group (p < 0.05). In group 2 and 4 where the drug was administered before AT, the inflammation and apoptosis index was lower than those of group 3 and 5 where the drug was administered after AT (p < 0.0001). We reveal that milrinone has a protective effect on cochlear damage in the experimental acoustic model of rats. This protective effect was more apparent following the pre-traumatic milrinone administration, and is associated with its effect on decreasing inflammation and apoptosis. Based on DPOAE measurements following AT, especially in the group 5 (high-dosage group), milrinone may also have a therapeutic effect.

Levosimendan treatment in a child with treatment-resistant left ventricular systolic dysfunction after scorpion sting

Background: Scorpion stings are common in countries dominated by rural and coastal settlements with temperate climate. Scorpion stings are usually harmless and can be seen in local findings, but in some cases, systemic, neurotoxic, and cardiotoxic findings can be seen. Case report: A 3 year 7 month old girl was referred to pediatric emergency care 2 h after yellow scorpion (species of Leiurus abdullahbayrami) sting. In our case, cardiac function insufficiently progressed in spite of the standard inotropic and milrinone treatment. On the third day of hospitalization, levosimendan was initiated with good clinical effect. Conclusion: In the literature, the use of levosimendan in pediatric patients has been limited to those with low cardiac output syndrome after cardiovascular surgery. The use of levosimendan in children with scorpion sting has been previously reported only in Banille et al.’s study. Scorpion antivenom should be administered intravenously as soon as possible in cases of systemic findings that develop after scorpion stings. This report suggests that levosimendan is temporally associated with improvement in patients who have severe cardiac dysfunction due to scorpion sting and refractory to current treatment.

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia?

Pulmonary hypertension with left ventricular dysfunction commonly occurs in congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-III inhibitor with lusitropic and vasodilator effects, is used in up to 30% of CDH infants across the United States. No randomized trials have tested the efficacy or safety of milrinone in CDH neonates. We performed a paired retrospective analysis of CDH infants to assess the efficacy of milrinone treatment (N = 24 pairs). Efficacy was assessed by change in oxygenation index (OI) and calculated pulmonary artery pressure (PAP). We evaluated safety on the basis of risks factors such as nonoperative bleeding, dysrhythmia, hypokalemia, and thrombocytopenia. The median age of milrinone initiation was 18 hours (interquartile range [IQR]: 9-38) and the median duration was 127 hours (IQR: 95-194). PAP did not change from the baseline of 49 ± 11 mm Hg (milrinone) and 53 ± 11 mm Hg (no milrinone; p = 0.327). Baseline OI was 9.6 ± 6.5. There was a similar decrease in OI (median [IQR]; milrinone: 58% [16-74]; vs. no milrinone: 65% [50-71]; p = 0.221 between groups; p < 0.005 within groups). Baseline left ventricle measurements were similar. Both groups showed significant improvement over time. No adverse events were noted. In OI-matched untreated neonates with mild-to-moderate CDH, milrinone use was associated with neither improved OI, PAP, or left ventricular measurements, nor adverse events. Study limitations warrant prospective randomized controlled trials.

The effects of specific and non-specific phosphodiesterase inhibitors and N-acetylcysteine on oxidative stress and remote organ injury in two-hit trauma model.

Sepsis is a systemic inflammatory response to infection and is one of the leading causes of morbidity and mortality. The second hit after trauma causes increased inflammatory response and multiple organ failure (MOF). The infection which develops after burn injury is a suitable model for a two-hit trauma study. Sepsis causes the release of biochemical mediators, such as Free Oxygen Radicals (FORs), which may lead to lipid peroxidation, which may play a key role in multiple organ failure. In this study, we aimed to investigate the effects of phosphodiesterase (PDE) inhibitors (sildenafil, milrinone, pentoxifylline) and N-acetylcysteine (NAS) on oxidative stress and organ damage in two-hit models. In this experimental study, peritonitis was created by cecal ligation and puncture (CLP) method in 40 rats, 72 hours after creating a 30% scalding injury. Rats were divided into five groups of eight rats each as follows: Group I: No treatment; Group II: 10/mg/kg/day dosage of intraperitoneal (i.p) sildenafil treatment was applied for 72 hours after CLP; Group III: 1/mg/kg/day dosage of i.p milrinone treatment was applied for 72 hours after CLP; Group IV: 150/mg/kg/day dosage of i.p NAS treatment was applied for 72 hours after CLP; Group V: 50/mg/kg/day dosage of i.p pentoxifylline treatment was applied for 72 hours after CLP. All rats were sacrificed on the seventh day of this study. Malondialdehyde (MDA), Glutathione Peroxidase (GPx), Superoxide Dismutase (SOD), catalase, Tumor Necrotic Factor-alpha (TNF-α) levels, and tissue (lung, kidney) and serum samples were taken for histopathological study. When compared to the control group, the tissue damage score was found to be lower in all treatment groups. Sildenafil, milrinone and NAS groups had higher kidney GPx levels compared to the control group. Milrinone and pentoxifylline were higher in the lung tissue compared to the SOD control group. TNFα levels were lower in pentoxifylline and milrinone groups compared to the control group. This experimental study has shown that PDE inhibitors and NAS have a decreasing effect on oxidative stress and distant organ damage in the two-hit model. Further clinical and experimental studies are needed on this subject.

ERYTHROPOIETIN HAS AN ADDITIVE CYTOPROTECTIVE AND BENEFICIAL EFFECT TO SILDENAFIL IN A MODEL OF DIASTOLIC HEART FAILURE IN RATS

Development of new forms of interventions for diastolic heart failure (HFpEF) remains a challenging task. The aim: Assessing the effect of combining erythropoietin and sildenafil on the left ventricle “LV” functions and morphometry in NG-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF model in rats. Method: Forty-eight female albino rats were randomly assigned to one of six treatment groups: “C” (Control), “L” (L-NAME-treated), “L+M” (L-NAME+milrinone-treated), “L+S” (L-NAME+sildenafil-treated), “L+E” (L-NAME+erythropoietin-treated), and “L+S+E” (L-NAME+sildenafil+erythropoietin-treated). Assessment was done by morphometric examination, LV ejection fraction (LVEF) and fraction of shortening (LVFS)], ECG changes, and mean time to peak tension (TPT) and to complete relaxation (TCR) of isometric contraction of LV muscle strip stimulated by single (TPT-S & TCR-S) and by repeated pulses (TPT-R & TCR-R), respectively. Results: L-NAME resulted in cardiac dysfunction with significant reduction in the mean “LVEF” and “LVFS”, and prolonged both the mean “TPT-R” and “TCR-R”. Milrinone and sildenafil treatment significantly corrected these parameters. In addition, erythropoietin significantly ameliorated “LVEF” and “LVFS” and shortened “TPT-S”. Similarly, “sildenafil+erythropoietin” treatment significantly corrected the measured parameters; however, they were insignificantly different from that of sildenafil only treatment. Morphometrically, sildenafil treatment resulted in significant but partial improvement in L-NAME-induced myocardial injury. Meanwhile, erythropoietin treatment showed more improvement. Moreover, combination treatment showed the best histologic picture in all of the treated groups. Conclusion: Sildenafil was able to improve cardiac functions mainly by accelerating diastolic relaxation. Addition of erythropoietin to sildenafil improved its cytoprotective effect.

Higher dose intra-arterial milrinone and intra-arterial combined milrinone-nimodipine infusion as a rescue therapy for refractory cerebral vasospasm.

Background Cerebral vasospasm (CV) is a major cause of delayed morbidity and mortality in patients with subarachnoid hemorrhage (SAH). Various cerebral protectants have been tested in patients with aneurysmal SAH. We aimed to research the success rate of treatment of CV via intra-arterial milrinone injection and aggressive pharmacological therapy for refractory CV. Methods A total of 25 consecutive patients who received intra-arterial milrinone and nimodipine treatment for CV following SAH between 2014 and 2017 were included in the study. Patients who underwent surgical clipping were excluded. Refractory vasospasm was defined as patients with CV refractory to therapies requiring ≥3 endovascular interventions. Overall, six patients had refractory CV. Long-term neurological outcome was assessed 6-18 months after SAH using a modified Rankin score and Barthel index. Results The median modified Rankin scores were 1 (min: 0, max: 3) and Barthel index scores were 85 (min: 70, max: 100) From each vasospastic territory maximal 10-16 mg milrinone was given to patients; a maximum of 24 mg milrinone was given to each patient in a session and a maximum of 42 mg milrinone was given to a patient in a day. Both milrinone and nimodipine were given to three patients. There was a large vessel diameter increase after milrinone and nimodipine injections. No patient died due to CV; only one patient had motor dysfunction on the right lower extremity. Conclusion Higher doses of milrinone can be used effectively to control refractory CV. For exceptional patients with refractory CV, high dose intra-arterial nimodipine and milrinone infusion can be used as a rescue therapy.

Effects of Combined Milrinone and Levosimendan Treatment on Systolic and Diastolic Function During Postischemic Myocardial Dysfunction in a Porcine Model.

It is not known whether there are positive or negative interactions on ventricular function when a calcium-sensitizing inotrope is added to a phosphodiesterase inhibitor in the clinical setting of acute left ventricular (LV) dysfunction. We hypothesized that when levosimendan is added to milrinone treatment, there will be synergetic inotropic and lusitropic effects. This was tested in an anesthetized porcine postischemic global LV injury model, where ventricular pressures and volumes (conductance volumetry) were measured. A global ischemic injury was induced by repetitive left main stem coronary artery occlusions. Load-independent indices of LV function were assessed before and after ventricular injury, after milrinone treatment, and finally after addition of levosimendan to the milrinone treatment. Nonparametric, within-group comparisons were made. The protocol was completed in 12 pigs, 7 of which received the inotrope treatment and 5 of which served as controls. Milrinone led to positive lusitropic effects seen by improvement in tau after myocardial stunning. The addition of levosimendan to milrinone further increased lusitropic state. The latter effect could however not be attributed solely to levosimendan, since lusitropic state also improved spontaneously in time-matched controls at the same rate during the corresponding period. When levosimendan was added to milrinone infusion, there was no increase in systolic function (preload recruitable stroke work) compared to milrinone treatment alone. We conclude that in this model of postischemic LV dysfunction, there appears to be no clear improvement in systolic or diastolic function after addition of levosimendan to established milrinone treatment but also no negative effects of levosimendan in this context.

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

IntroductionThe 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. MethodsA 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. ResultsEighty-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. ConclusionsAlthough 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.

Abstract 17697: Myocardial Response to Milrinone in Single Ventricle Heart Disease

Background: Single ventricle heart disease (SV) is a subset of congenital heart defects characterized by a univentricular circulation. Despite surgical intervention, progressive heart failure (HF) is a common cause of death and indication for heart transplantation in children with SV. The exact mechanisms underlying SV HF are poorly understood, limiting the ability to identify effective therapies. Empiric treatment with milrinone, a phosphodiesterase 3 inhibitor (PDE3i), has become increasingly common in SV HF; however the response to milrinone has yet to be characterized in the pediatric SV population. The purpose of this study was to determine the myocardial response to PDE3i in children with SV. Methods and Results: Cyclic adenosine monophosphate (cAMP) levels, phosphodeisterase (PDE) activity, and phospholamban phosphorylation (pPLB) were determined in explanted human ventricular myocardium from non-failing pediatric donors (n=10) and pediatric patients transplanted secondary to SV HF (of right ventricular [RV] morphology). SV HF subjects were divided into those who received milrinone therapy (n=13) and those who did not (n=12). In comparison to non-failing RV myocardium, cAMP levels are lower in SV HF patients treated with milrinone (ANOVA, p=0.046). Chronic milrinone treatment does not alter total PDE or PDE3 activity in SV myocardium. Additionally, when compared with non-failing RV myocardium, SV myocardium (both with and without milrinone) demonstrates equivalent pPLB at the protein kinase A site (serine 16 residue). Conclusions: As evidenced by preserved pPLB, the molecular adaptation associated with SV HF differs significantly from that demonstrated in pediatric HF due to dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of HF in pediatric SV patients, which has direct implications regarding the putative response to PDE3i treatment in this population.

Milrinone for the Treatment of Acute Heart Failure After Acute Myocardial Infarction: A Systematic Review and Meta‐Analysis

Despite advancements in modern medicine, the treatment of acute heart failure (AHF) after acute myocardial infarction (AMI) remains challenging. Milrinone is effective in the treatment of chronic congestive heart failure, but its safety and efficacy in patients with AHF after AMI have not been systematically evaluated. This meta-analysis was performed to assess the safety and efficacy of milrinone in patients with AHF after AMI. We used a pre-designed protocol to search electronic databases for randomized trials assessing milrinone for the treatment of AHF after AMI. Data were abstracted from relevant studies. Heterogeneity was assessed qualitatively using a Q test and quantified using the I(2) statistic. Pooled risk estimates with 95% confidence intervals (CIs) were obtained using fixed-effects models unless substantial heterogeneity was observed (I(2) ≥ 50% and heterogeneity p ≤ 0.1). Four randomized trials met the inclusion criteria. However, there were no significant differences in deaths, blood pressure, premature ventricular contractions, gastrointestinal reactions, or ventricular tachycardia or fibrillation (all p > 0.05) between control group and milrinone treatment group. Pooled estimates showed that milrinone significantly increased the left ventricular ejection fraction (MD 5.69; 95% CI 4.27 to 7.10; p < 0.00001) and cardiac output (MD 0.35, 95% CI: 0.13 to 0.56; p = 0.002, I(2) = 24%). While studies to date are few and limited by small sample sizes and poor quality, they suggest that treatment with milrinone may be safe and effective for patients with AHF after AMI. However, this meta-analysis did not show that milrinone could improve prognosis or the survival rate.

The effect of milrinone on right and left ventricular function when used as a rescue therapy for term infants with pulmonary hypertension.

Milrinone may be an appropriate adjuvant therapy for infants with persistent pulmonary hypertension of the newborn. We aimed to describe the effect of milrinone administration on right and left ventricular function in infants with persistent pulmonary hypertension not responding to inhaled nitric oxide after 4 hours of administration. This is a retrospective review of infants born after or at 34 weeks of gestation with persistent pulmonary hypertension who received milrinone treatment. The primary endpoint was the effect of milrinone on myocardial performance and haemodynamics, including right and left ventricular outputs, tissue Doppler velocities, right ventricle and septal strain, and strain rate. Secondary endpoints examined included duration of inhaled nitric oxide and oxygen support. A total of 17 infants with a mean (standard deviation) gestation and birth weight of 39.8 (2.0) weeks and 3.45 (0.39) kilograms, respectively, were included in the study. The first echocardiogram was performed 15 hours after the commencement of nitric oxide inhalation. Milrinone treatment was started at a median time of 1 hour after the echocardiogram and was associated with an increase in left ventricular output (p=0.04), right ventricular output (p=0.004), right ventricle strain (p=0.01) and strain rate (p=0.002), and left ventricle s` (p<0.001) and a` (p=0.02) waves. There was a reduction in nitric oxide dose and oxygen requirement over the subsequent 72 hours (all p<0.05). The use of milrinone as an adjunct to nitric oxide is worth further exploration, with preliminary evidence suggesting an improvement in both oxygenation and myocardial performance in this group of infants.

The use of intravenous Milrinone to treat cerebral vasospasm following traumatic subarachnoid hemorrhage.

IntroductionTraumatic subarachnoid hemorrhage (SAH) is a common intracranial lesion after traumatic brain injury (TBI). As in aneurysmal SAH, cerebral vasospasm is a common cause of secondary brain injury and is associated with the thickness of traumatic SAH. Unfortunately, there is limited literature on an effective treatment of this entity. The vasodilatory and inotropic agent, Milrinone, has been shown to be effective in treating vasospasm following aneurysmal SAH. The authors hypothesized that this agent could be useful and safe in treating vasospasm following tSAH.Case descriptionsCase reports of 2 TBI cases from a level 1 trauma centre with tSAH and whom developed delayed ischemic neurological deficits (DINDs) are presented. Intravenous Milrinone treatment was provided to each patient following the “Montreal Neurological Hospital Protocol”.Discussion and evaluationBoth patients had an improvement in their DINDs following the treatment protocol. There were no complications of treatment and the Glasgow Outcome Scores of the patients ranged from 4 to 5.ConclusionThis is the first report of the use of intravenous Milrinone to treat cerebral vasospasm following traumatic SAH. This treatment option appeared to be safe and potentially useful at treating post-traumatic vasospasm. Prospective studies are necessary to establish Milrinone’s clinical effectiveness in treating this type of cerebral vasospasm.

195: Regulatory T cells and cyclic adenosine monophosphate in enterovirus 71 infection

Background Since 1998, Taiwan has experienced several hand, foot, and mouth disease (HFMD) epidemics caused by enterovirus 71 (EV71). Two notable features of severe EV71 infection in young children are brainstem encephalitis (BE) and fatal pulmonary edema (PE). This study investigated the specific immunoregulatory characterizations of EV71 neurological complications according to the disease severity. Methods Patients younger than 18 years with virologically confirmed EV71 infections were enrolled and divided into 2 groups: the HFMD or BE group, and the autonomic nervous system (ANS) dysregulation or PE group. Laboratory findings, cytokine and cyclic adenosine monophosphate (cAMP) levels, immunophenotypes, and the regulatory T cell (Tregs) profiles of the EV71-infected patients were determined. Results Patients with ANS dysregulation or PE exhibited a significantly low frequency of CD4+ CD25+ Foxp3+ and CD4+ Foxp3+ T cells compared with patients with HFMD or BE. The expression frequency of CD4−CD8− was also significantly decreased in patients with ANS dysregulation or PE. Among patients with ANS dysregulation or PE, the expression frequency of CD4+ Foxp3+ increased markedly after milrinone treatment, and was associated with a reduction of plasma levels IL-6, IL-8 and IL-10. Plasma concentrations of cAMP were significantly decreased in patients with ANS dysregulation or PE compared with patients with HFMD or BE, however, cAMP levels increased after milrinone treatment. Conclusions These findings provided new insight into the role of regulatory T cells. Furthermore, CD4+ CD25+ Foxp3+ and cAMP expression might be related to the progression of severe EV71 infection, and its responses to milrinone treatment.