Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: a systematic review and meta-analysis.

To evaluate milrinone's impact on pediatric cardiac function, focusing on its specific role as an inotrope and lusitrope, while considering its systemic and pulmonary vasodilatory effects. Search of PubMed, EMBASE, and the Cochrane Library up to August 2023. We included all studies that evaluated milrinone in children under 18 years old in neonatal, pediatric, or cardiac intensive care units. We excluded case reports, studies that did not provide tabular information on milrinone's outcomes, and studies focused on non-intensive care populations. We extracted data on the research design, objectives, study sample, and results of each study, including the impact of milrinone and any associated factors. We screened a total of 9423 abstracts and 41 studies were ultimately included. Milrinone significantly improved left ventricular ejection fraction (WMD 3.41 [95% CI 0.61 - 6.21]), left ventricle shortening fraction (WMD 4.25 [95% CI 3.43 - 5.08]), cardiac index (WMD 0.50 [95% CI 0.32 to 0.68]), left ventricle output (WMD 55.81 [95% CI 4.91 to 106.72]), serum lactate (WMD -0.59 [95% CI -1.15 to -0.02]), and stroke volume index (WMD 2.95 [95% CI 0.09 - 5.82]). However, milrinone was not associated with improvements in ventricular myocardial performance index (WMD -0.01 [95% CI -0.06 to 0.04]) and ventricular longitudinal strain (WMD -2.14 [95% CI -4.56 to 0.28]). Furthermore, milrinone was not associated with isovolumetric relaxation time reduction (WMD -8.87 [95% CI -21.40 to 3.66]). CONCLUSION: Our meta-analysis suggests potential clinical benefits of milrinone by improving cardiac function, likely driven by its systemic vasodilatory effects. However, questions arise about its inotropic influence and the presence of a lusitropic effect. Moreover, milrinone's pulmonary vasodilatory effect appears relatively weaker compared to its systemic actions. Further research is needed to elucidate milrinone's precise mechanisms and refine its clinical applications in pediatric practice. WHAT IS KNOWN: • Milrinone is a phosphodiesterase III inhibitor that has been used to treat a variety of pediatric and neonatal conditions. • Milrinone is believed to exert its therapeutic effects by enhancing cardiac contractility and promoting vascular relaxation. WHAT IS NEW: • Milrinone may not have a significant inotropic effect. • Milrinone's pulmonary vasodilatory effect is less robust than its systemic vasodilatory effect.

Crisis adrenal neonatal secundaria a hipoplasia hipofisaria / Neonatal Adrenal Crisis Secondary to Pituitary Hypoplasia

Introducción: La insuficiencia adrenal hipotálamo hipofisaria usualmente se manifiesta secundaria a tumores y, cuando resulta congénita se asocia, con frecuencia, con otras deficiencias hormonales. La crisis adrenal suele presentarse en su debut y puede resultar potencialmente mortal. Objetivo: Examinar el caso de una paciente con insuficiencia adrenal central que debutó con una crisis adrenal congénita. Presentación del caso: Recién nacida a término, padres no consanguíneos, hospitalizada a los 9 días de vida por clínica de una semana con múltiples episodios eméticos y apnea. Ingresó con deshidratación severa, hipotensa y estuporosa. Además, se encontró acidosis metabólica severa, hipoglucemia persistente, hiponatremia e insuficiencia prerrenal. Ante la no mejoría de su estado hemodinámico, a pesar del uso de cristaloides y vasopresores, finalmente mejoró con la administración de dosis altas de hidrocortisona. El diagnóstico de deficiencia de cortisol de origen central se realizó con un test dinámico de insulina y la resonancia magnética nuclear hipofisaria. Conclusiones: La crisis adrenal se debe tener presente como diagnóstico diferencial en episodios agudos con inestabilidad hemodinámica persistente e hipoglucemia de difícil manejo. Adicionalmente, hay que considerar que existen otras causas menos comunes de insuficiencia adrenal en neonatos como la hipoplasia hipofisaria(AU)

Introduction: Hypothalamic-pituitary adrenal insufficiency usually manifests secondary to tumors and, when congenital, is often associated with other hormonal deficiencies. Adrenal crisis usually occurs at its onset and can be life threatening. Objective: To review the case of a patient with central adrenal insufficiency who had an onset with a congenital adrenal crisis. Case presentation: Term newborn, non-consanguineous parents, hospitalized at 9 days of life for a week-long clinical presentation with multiple emetic episodes and apnea. She was admitted with severe dehydration, hypotensive and stuporous. In addition, severe metabolic acidosis, persistent hypoglycemia, hyponatremia and prerenal failure were found. Given the lack of improvement of her hemodynamic status, despite the use of crystalloids and vasopressors, she finally improved with the administration of high doses of hydrocortisone. The diagnosis of cortisol deficiency of central origin was made with a dynamic insulin test and pituitary nuclear magnetic resonance imaging. Conclusions: Adrenal crisis should be kept in mind as a differential diagnosis in acute episodes with persistent hemodynamic instability and difficult-to-manage hypoglycemia. Additionally, other less common causes of adrenal insufficiency in neonates, such as pituitary hypoplasia, should be considered(AU)

[Levosimendan for preventing low output syndrome in pediatric patients with correction of tetralogy of Fallot]. / Levosimendán para prevenir el síndrome de bajo gasto en pacientes pediátricos con corrección de tetralogía de Fallot.

Background: Tetralogy of Fallot is one of the most frequent cyanotic heart diseases in our country, occupying the second place reported by the national health program 2007- 2012 and its prevalence is around 11%. Patients undergoing correction for tetralogy of Fallot are considered patients with a prolonged ischemic time and a high risk of presenting low cardiac output syndrome. Objective: To compare levosimendan with milrinone to prevent low cardiac output syndrome in patients undergoing tetralogy of Fallot correction. Material and methods: Randomized controlled open, prospective, longitudinal and comparative clinical trial. The sample size consisted of 19 patients, with a 95% confidence level. Group 1: levosimendan 0.1 mcg/kg/min from anesthetic induction. Group 2: conventional management with milrinone 0.5 mcg/kg/min. Results: When comparing the final measurements, it can be observed that the mean arterial pressure of the intervention group (levosimendan) was statistically significant (p = 0.04), both in the intraoperative measurement and in the final measurement. When comparing uresis, we found that the intervention group had a greater amount of uresis (p = 0.03). Regarding lactate, both in the intraoperative measurement (p = 0.002) and in the final measurement (p = 0.02), a lower amount was found in the intervention group. Conclusions: The results in favor of the use of levosimendan were reported, demonstrating the prevention of low cardiac output syndrome.

Introducción: la tetralogía de Fallot es una de las cardiopatías cianóticas más frecuentes de nuestro país, pues ocupa el segundo lugar reportado por el Programa Nacional de Salud 2007-2012 y su prevalencia se sitúa aproximadamente en 11%. Los pacientes sometidos a corrección de tetralogía de Fallot se consideran pacientes con un tiempo de isquemia prolongado y con riesgo alto de presentar síndrome de bajo gasto cardiaco. Objetivo: comparar levosimendán con milrinona para prevenir el síndrome de bajo gasto cardiaco en pacientes operados de corrección de tetralogía de Fallot. Material y métodos: ensayo clínico aleatorizado, controlado, abierto, prospectivo, longitudinal y comparativo. El tamaño de la muestra se estimó en 19 pacientes, con un nivel de confianza del 95%. En el grupo 1 se empleó 0.1 mcg/kg/min de levosimendán desde la inducción anestésica; en el grupo 2 se usó el manejo convencional con milrinona de 0.5 mcg/kg/min. Resultados: al comparar las mediciones finales se pudo observar que la presión arterial media del grupo de intervención (levosimendán) fue estadísticamente significativa (p = 0.04), tanto en la medición transoperatoria como en la medición final. Al comparar la uresis encontramos que el grupo con intervención tuvo mayor cantidad de uresis (p = 0.03). En cuanto al lactato, tanto en la medición transoperatoria (p = 0.002) como en la medición final (p = 0.02) se encontró una menor cantidad en el grupo de intervención. Conclusiones: se reportaron los resultados a favor del uso del levosimendán, pues se demostró que previene el síndrome de bajo gasto cardiaco.

Eficacia y seguridad de milrinona en pacientes pediátricos con síndrome de bajo gasto cardíaco postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco) / Efficacy and safety of milrinone in pediatric patients with postoperative low cardiac output syndrome of congenital heart disease (including heart transplantation)

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de milrinona en pacientes pediátricos con síndrome de bajo gasto cardíaco (SBGC) en el periodo postoperatorio de cardiopatía congénita. El síndrome de bajo gasto cardíaco (SBGC) ocurre cuando la función de eyección del corazón es insuficiente para mantener un flujo sanguíneo adecuado para satisfacer la demanda de oxígeno de los tejidos del cuerpo. El SBGC es la principal causa de morbilidad y mortalidad en el estado postoperatorio de pacientes pediátricos con cardiopatías. En Estados Unidos, en el 2004, se reportó que el 25% de niños con cardiopatías desarrolló SBGC luego de una cirugía cardíaca. No existe consenso sobre los parámetros para el diagnóstico del SBGC en la población pediátrica. Algunos de estos parámetros son: valores altos o incremento rápido del lactato en sangre, disminución en la producción de orina, incremento de la diferencia entre la temperatura periférica y la temperatura corporal central, bajo gasto cardíaco, alto requerimiento de inotrópicos y fracción de eyección menor a 40 %. En EsSalud, se cuenta con agentes simpaticomiméticos como: adrenalina, dopamina, y dobutamina para el tratamiento del SBGC postoperatorio en población pediátrica (incluidos los pacientes con trasplante cardíaco). Sin embargo, los especialistas consideran que milrinona, podría ofrecer mayor beneficio en el tratamiento de pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco). METODOLOGÍA: La búsqueda de la literatura científica se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de milrinona, en comparación con el tratamiento convencional (dopamina, adrenalina, dobutamina), en pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco). La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, Lilacs y The Cochrane Library. Adicionalmente, se revisó la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), Scottish Medicines Consortium (SMC), Haute Autorité de Santé (HAS), Institute for Clinical and Economic Review (ICER), y Comissão nacional de incorporação de tecnologías no sus (CONITEC). También se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y se colectó información sobre el medicamento de interés del presente dictamen en las páginas web de la European Medicines Agency (EMA), y Food and Drug Administration (FDA). Finalmente, se realizó una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. RESULTADOS: Se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible en relación con la eficacia y seguridad de milrinona en comparación con el tratamiento convencional (dopamina, adrenalina, dobutamina), en pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco). La búsqueda de la literatura científica identificó tres GPC, el estudio pivotal de milrinona y un ensayo clínico no aleatorizado. Las GPC elaboradas por Sarris et al. y de Kantor et al., coinciden en recomendar fuertemente el uso de medicamentos inotrópicos para mejorar el gasto. la guía de Alphonso et al. recomienda el uso de medicamentos inodilatadores o vasodilatadores para mejorar el gasto cardiaco, sin mencionar algún medicamento en particular. El ECA PRIMACORP de fase III, doble-ciego y pivotal de milrinona, evaluó la eficacia y seguridad del uso de milrinona en comparación con placebo, para prevenir el desarrollo del SBGC en pacientes pediátricos. En otras palabras, este estudio no analizó el uso de milrinona en pacientes con el SBGC instaurado (como tratamiento del SBGC), población objetivo del presente dictamen. El estudio elaborado por Duggal et al, evaluó el efecto de milrinona en pacientes pediátricos con SBGC postoperatorio. El estudio reportó una mejora de la función biventricular, pero no se encontraron diferencias en las tasas de eyección cardiacas. Sin embargo, las limitaciones de su diseño, como la falta de un grupo control, impiden que se pueda asegurar que estos resultados se deben al uso de milrinona. La evidencia sugerida por los especialistas de EsSalud, correspondiente a un artículo de revisión y tres estudios que analizaron los patrones de prescripciones de medicamentos para el tratamiento o prevención del SBGC en pacientes pediátricos, no permite conocer si milrinona es más eficaz o seguro que las alternativas disponibles en EsSalud (dopamina, adrenalina, dobutamina) y/o no brindan información sobre el uso de milrinona en niños con SBGC. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI no aprueba el uso de milrinona en pacientes pediátricos con SBGC postoperatorio de cardiopatía congénita (incluido el trasplante cardíaco).

Eficácia e segurança da milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea: uma revisão sistemática / Efficacy and safety of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage: a systematic review

RESUMO Objetivo: Revisar sistematicamente a evidência atual da eficácia de milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea. Métodos: Triaram-se as bases de dados Pubmed®, Cochrane e Embase quanto a artigos publicados entre abril de 2001 e fevereiro de 2019. Dois revisores independentes realizaram uma triagem metodológica da qualidade e a extração dos dados dos estudos. Resultados: Encontraram-se 22 estudos considerados relevantes, sendo que apenas um deles era um ensaio randomizado controlado. Os estudos demonstraram acentuada heterogeneidade e debilidade de seus critérios metodológicos. A maioria dos pacientes apresentava vasoespasmo moderado a grave. O principal método para diagnóstico do vasoespasmo foi a angiografia. Em três estudos, realizou-se administração de milrinona por via intra-arterial; em nove estudos, a administração foi endovenosa, e, em seis estudos, utilizaram-se ambas as vias de administração. A via intratecal foi utilizada em dois estudos, em um estudo, a administração foi realizada via cisterna e, em um estudo, a via de administração foi a endovascular. Os efeitos colaterais de milrinona foram descritos em seis estudos. Vinte e um estudos indicaram a resolução do vasoespasmo. Conclusão: A evidência atual indica que o uso de milrinona teve um papel no tratamento do vasoespasmo após hemorragia subaracnóidea aneurismática. Contudo, só foi realizado um ensaio randomizado controlado, com baixo nível de qualidade. Nossos achados indicam a necessidade de futuros estudos randomizados controlados com desfechos centrados no paciente, com o fim de proporcionar recomendações definitivas.

ABSTRACT Objective: To systematically review the current evidence on the efficacy of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage. Methods: The Pubmed®, Cochrane and Embase databases were screened for articles published from April 2001 to February 2019. Two independent reviewers performed the methodological quality screening and data extraction of the studies. Results: Twenty-two studies were found to be relevant, and only one of these was a randomized control trial. Studies showed marked heterogeneity and weaknesses in key methodological criteria. Most patients presented with moderate to severe vasospasm. Angiography was the main method of diagnosing vasospasm. Intra-arterial administration of milrinone was performed in three studies, intravenous administration was performed in nine studies, and both routes of administration in six studies; the intrathecal route was used in two studies, the cisternal route in one study and endovascular administration in one study. The side effects of milrinone were described in six studies. Twenty-one studies indicated resolution of vasospasm. Conclusion: The current evidence indicates that milrinone may have a role in treatment of vasospasm after aneurysmal subarachnoid hemorrhage. However, only one randomized control trial was performed, with a low quality level. Our findings indicate the need for future randomized control trials with patient-centered outcomes to provide definitive recommendations.

Bioactive Oxylipins in Infants and Children With Congenital Heart Disease Undergoing Pediatric Cardiopulmonary Bypass.

OBJECTIVES: To determine the production of 9-hydroxyoctadecadienoic acid and 13-hydroxyoctadecadienoic acid during cardiopulmonary bypass in infants and children undergoing cardiac surgery, evaluate their relationship with increase in cell-free plasma hemoglobin, provide evidence of bioactivity through markers of inflammation and vasoactivity (WBC count, milrinone use, vasoactive-inotropic score), and examine their association with overall clinical burden (ICU/hospital length of stay and mechanical ventilation duration). DESIGN: Prospective observational study. SETTING: Twelve-bed cardiac ICU in a university-affiliated children's hospital. PATIENTS: Children were prospectively enrolled during their preoperative clinic appointments with the following criteria: greater than 1 month to less than 18 years old, procedures requiring cardiopulmonary bypass INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected at the start and end of cardiopulmonary bypass in 34 patients. 9-hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, plasma hemoglobin, and WBC increased. 9:13-hydroxyoctadecadienoic acid at the start of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours postcardiopulmonary bypass (R = 0.25; p < 0.01), milrinone use (R = 0.17; p < 0.05), and WBC (R = 0.12; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the end of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours (R = 0.17; p < 0.05), 24-48 hours postcardiopulmonary bypass (R = 0.12; p < 0.05), and milrinone use (R = 0.19; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the start and end of cardiopulmonary bypass were associated with the changes in plasma hemoglobin (R = 0.21 and R = 0.23; p < 0.01). The changes in plasma hemoglobin was associated with milrinone use (R = 0.36; p < 0.001) and vasoactive-inotropic score less than 2 hours (R = 0.22; p < 0.01), 2-24 hours (R = 0.24; p < 0.01), and 24-48 hours (R = 0.48; p < 0.001) postcardiopulmonary bypass. Cardiopulmonary bypass duration, 9:13-hydroxyoctadecadienoic acid at start of cardiopulmonary bypass, and plasma hemoglobin may be risk factors for high vasoactive-inotropic score. Cardiopulmonary bypass duration, changes in plasma hemoglobin, 9:13-hydroxyoctadecadienoic acid, and vasoactive-inotropic score correlate with ICU and hospital length of stay and/mechanical ventilation days. CONCLUSIONS: In low-risk pediatric patients undergoing cardiopulmonary bypass, 9:13-hydroxyoctadecadienoic acid was associated with changes in plasma hemoglobin, vasoactive-inotropic score, and WBC count, and may be a risk factor for high vasoactive-inotropic score, indicating possible inflammatory and vasoactive effects. Further studies are warranted to delineate the role of hydroxyoctadecadienoic acids and plasma hemoglobin in cardiopulmonary bypass-related dysfunction and to explore hydroxyoctadecadienoic acid production as a potential therapeutic target.

Efficacy and safety of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage: a systematic review. / Eficácia e segurança da milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea: uma revisão sistemática.

OBJECTIVE: To systematically review the current evidence on the efficacy of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage. METHODS: The Pubmed®, Cochrane and Embase databases were screened for articles published from April 2001 to February 2019. Two independent reviewers performed the methodological quality screening and data extraction of the studies. RESULTS: Twenty-two studies were found to be relevant, and only one of these was a randomized control trial. Studies showed marked heterogeneity and weaknesses in key methodological criteria. Most patients presented with moderate to severe vasospasm. Angiography was the main method of diagnosing vasospasm. Intra-arterial administration of milrinone was performed in three studies, intravenous administration was performed in nine studies, and both routes of administration in six studies; the intrathecal route was used in two studies, the cisternal route in one study and endovascular administration in one study. The side effects of milrinone were described in six studies. Twenty-one studies indicated resolution of vasospasm. CONCLUSION: The current evidence indicates that milrinone may have a role in treatment of vasospasm after aneurysmal subarachnoid hemorrhage. However, only one randomized control trial was performed, with a low quality level. Our findings indicate the need for future randomized control trials with patient-centered outcomes to provide definitive recommendations.

OBJETIVO: Revisar sistematicamente a evidência atual da eficácia de milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea. MÉTODOS: Triaram-se as bases de dados Pubmed®, Cochrane e Embase quanto a artigos publicados entre abril de 2001 e fevereiro de 2019. Dois revisores independentes realizaram uma triagem metodológica da qualidade e a extração dos dados dos estudos. RESULTADOS: Encontraram-se 22 estudos considerados relevantes, sendo que apenas um deles era um ensaio randomizado controlado. Os estudos demonstraram acentuada heterogeneidade e debilidade de seus critérios metodológicos. A maioria dos pacientes apresentava vasoespasmo moderado a grave. O principal método para diagnóstico do vasoespasmo foi a angiografia. Em três estudos, realizou-se administração de milrinona por via intra-arterial; em nove estudos, a administração foi endovenosa, e, em seis estudos, utilizaram-se ambas as vias de administração. A via intratecal foi utilizada em dois estudos, em um estudo, a administração foi realizada via cisterna e, em um estudo, a via de administração foi a endovascular. Os efeitos colaterais de milrinona foram descritos em seis estudos. Vinte e um estudos indicaram a resolução do vasoespasmo. CONCLUSÃO: A evidência atual indica que o uso de milrinona teve um papel no tratamento do vasoespasmo após hemorragia subaracnóidea aneurismática. Contudo, só foi realizado um ensaio randomizado controlado, com baixo nível de qualidade. Nossos achados indicam a necessidade de futuros estudos randomizados controlados com desfechos centrados no paciente, com o fim de proporcionar recomendações definitivas.

Effect of magnesium sulphate and milrinone on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a randomized study / Efeitos do sulfato de magnésio e da milrinona sobre o vasoespasmo cerebral após hemorragia subaracnoidea por aneurisma: estudo randômico

Abstract Background: Aneurysmal subarachnoid hemorrhage is an important cause of premature death and disability worldwide. Magnesium sulphate is shown to have a neuroprotective effect and it reverses cerebral vasospasm. Milrinone is also used in the treatment of cerebral vasospasm. The aim of the present study was to compare the effect of prophylactic magnesium sulphate and milrinone on the incidence of cerebral vasospasm after subarachnoid hemorrhage. Methods: The study included 90 patients with aneurysmal subarachnoid hemorrhage classified randomly (by simple randomization) into two groups: magnesium sulphate was given as an infusion of 500 mg.day-1 without loading dose for 21 days. Group B: milrinone was given as an infusion of 0.5 µg.kg-1.min-1 without loading dose for 21 days. The cerebral vasospasm was diagnosed by mean cerebral blood flow velocity in the involved cerebral artery (mean flow velocity ≥ 120 cm.s-1), neurological deterioration by Glasgow coma scale, or angiography (the decrease in diameter of the involved cerebral artery >25%). Results: The mean cerebral blood flow velocity decreased significantly in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p < 0.001). The incidence of cerebral vasospasm decreased significantly with magnesium compared to milrinone (p = 0.007). The Glasgow coma scale significantly improved in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p = 0.036, p = 0.012, p = 0.016, respectively). The incidence of hypotension was higher with milrinone than magnesium (p = 0.012). Conclusions: The incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage was significantly lower and Glasgow coma scale significantly better with magnesium when compared to milrinone. Milrinone was associated with a higher incidence of hypotension and requirement for dopamine and norepinephrine when compared to magnesium.

Resumo Justificativa: A hemorragia subaracnoidea por aneurisma é uma importante causa de morte prematura e de incapacidade em todo o mundo. O sulfato de magnésio mostra um efeito neuroprotetor e reverte o vasoespasmo cerebral. A milrinona também é usada no tratamento de vasoespasmo cerebral. O objetivo do presente estudo foi comparar o efeito profilático do sulfato de magnésio e da milrinona sobre a incidência de vasoespasmo cerebral após hemorragia subaracnoidea. Métodos: O estudo incluiu 90 pacientes com hemorragia subaracnoidea por aneurisma randomicamente distribuídos (randomização simples) em dois grupos: sulfato de magnésio foi administrado em infusão de 500 mg.dia-1 sem dose de ataque durante 21 dias. O Grupo B recebeu milrinona em infusão de 0,5 µg.kg-1·min-1 sem dose de ataque durante 21 dias. O vasoespasmo cerebral foi diagnosticado pela velocidade média do fluxo sanguíneo cerebral na artéria cerebral envolvida (velocidade média do fluxo ≥ 120 cm.s-1), a deterioração neurológica por escala de coma de Glasgow ou angiografia (diminuição do diâmetro da artéria cerebral envolvida > 25%). Resultados: A velocidade média do fluxo sanguíneo cerebral diminuiu significativamente no grupo magnésio em comparação com o grupo milrinona nos dias 7, 14 e 21 (p < 0,001). A incidência de vasoespasmo cerebral diminuiu significativamente com o magnésio em comparação com milrinona (p = 0,007). A escala de coma de Glasgow melhorou significativamente no grupo magnésio em comparação com o grupo milrinona nos dias 7, 14 e 21 (p = 0,036, p = 0,012, p = 0,016, respectivamente). A incidência de hipotensão foi maior com milrinona do que com magnésio (p = 0,012). Conclusões: A incidência de vasoespasmo cerebral após hemorragia subaracnoidea por aneurisma foi significativamente menor e a escala de coma de Glasgow significativamente melhor com magnésio em comparação com milrinona. A milrinona foi associada a uma maior incidência de hipotensão e necessidade de dopamina e norepinefrina em comparação com o magnésio.

[Effect of magnesium sulphate and milrinone on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a randomized study]. / Efeitos do sulfato de magnésio e da milrinona sobre o vasoespasmo cerebral após hemorragia subaracnoidea por aneurisma: estudo randômico.

BACKGROUND: Aneurysmal subarachnoid hemorrhage is an important cause of premature death and disability worldwide. Magnesium sulphate is shown to have a neuroprotective effect and it reverses cerebral vasospasm. Milrinone is also used in the treatment of cerebral vasospasm. The aim of the present study was to compare the effect of prophylactic magnesium sulphate and milrinone on the incidence of cerebral vasospasm after subarachnoid hemorrhage. METHODS: The study included 90 patients with aneurysmal subarachnoid hemorrhage classified randomly (by simple randomization) into two groups: magnesium sulphate was given as an infusion of 500mg.day-1 without loading dose for 21 days. Group B: milrinone was given as an infusion of 0.5µg.kg-1.min-1 without loading dose for 21 days. The cerebral vasospasm was diagnosed by mean cerebral blood flow velocity in the involved cerebral artery (mean flow velocity≥120cm.s-1), neurological deterioration by Glasgow coma scale, or angiography (the decrease in diameter of the involved cerebral artery >25%). RESULTS: The mean cerebral blood flow velocity decreased significantly in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p<0.001). The incidence of cerebral vasospasm decreased significantly with magnesium compared to milrinone (p=0.007). The Glasgow coma scale significantly improved in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p=0.036, p=0.012, p=0.016, respectively). The incidence of hypotension was higher with milrinone than magnesium (p=0.012). CONCLUSIONS: The incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage was significantly lower and Glasgow coma scale significantly better with magnesium when compared to milrinone. Milrinone was associated with a higher incidence of hypotension and requirement for dopamine and norepinephrine when compared to magnesium.

Myocardial Response to Milrinone in Single Right Ventricle Heart Disease.

OBJECTIVES: Empiric treatment with milrinone, a phosphodiesterase (PDE) 3 inhibitor, has become increasingly common in patients with single ventricle heart disease of right ventricular (RV) morphology (SRV); our objective was to characterize the myocardial response to PDE3 inhibition (PDE3i) in the pediatric population with SRV. STUDY DESIGN: Cyclic adenosine monophosphate levels, PDE activity, and phosphorylated phospholamban (PLN) were determined in explanted human ventricular myocardium from nonfailing pediatric donors (n = 10) and pediatric patients transplanted secondary to SRV. Subjects with SRV were further classified by PDE3i treatment (n = 13 with PDE3i and n = 12 without PDE3i). RESULTS: In comparison with nonfailing RV myocardium (n = 8), cyclic adenosine monophosphate levels are lower in patients with SRV treated with PDE3i (n = 12, P = .021). Chronic PDE3i does not alter total PDE or PDE3 activity in SRV myocardium. Compared with nonfailing RV myocardium, SRV myocardium (both with and without PDE3i) demonstrates equivalent phosphorylated PLN at the protein kinase A phosphorylation site. CONCLUSIONS: As evidenced by preserved phosphorylated PLN, the molecular adaptation associated with SRV differs significantly from that demonstrated in pediatric heart failure because of dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of heart failure in pediatric patients with SRV, which has direct implications regarding the presumed response to PDE3i treatment in this population.

The Effect of Milrinone on Splanchnic and Cerebral Perfusion in Infants With Congenital Heart Disease Prior to Surgery: An Observational Study.

Despite the advancement in the postoperative care of neonates with congenital heart disease (CHD), there is little information on preoperative management of systemic and regional hemodynamics, which may be related to outcomes. We aimed to determine the preoperative effect of milrinone, a phosphodiesterase III inhibitor, on cardiac output and splanchnic and cerebral perfusion in neonates with CHD. Neonates with CHD requiring cardiac surgery were enrolled in a prospective, single-blinded study once a clinical decision of starting milrinone (0.75 µg/kg per minute intravenously) using institutional criteria was made. Demographic and clinical variables and outcomes were recorded. Combined cardiac output and measures of splanchnic (superior mesenteric and celiac arteries) and cerebral (anterior and middle cerebral arteries) perfusion were determined by Doppler studies at 0, 6, 24, and 48 h after milrinone infusion. Investigators were unaware of intervention time points and patients in analyzing blood flow measurements. Seventeen term (39.2 ± 1.3 weeks) neonates were included with hypoplastic left-sided heart syndrome (78.5%) as the most common diagnosis. Combined cardiac output increased by 28% within 48 h (613 ± 154 vs. 479 ± 147 mL/kg per minute at baseline, P < 0.05). Superior mesenteric artery mean velocity increased at 6 h and throughout 48 h of milrinone infusion (P < 0.05). Peak and mean velocities at cerebral arteries increased with milrinone infusion (P < 0.05~0.08), and the corresponding changes at celiac artery were modest. There were no significant changes in splanchnic and cerebral resistive and pulsatility indices during milrinone infusion. Milrinone increases cardiac output with concurrent effects on splanchnic and cerebral blood flows during the short-term preoperative use in neonates with CHD.

Milrinone attenuates arteriolar vasoconstriction and capillary perfusion deficits on endotoxemic hamsters.

BACKGROUND AND OBJECTIVE: Apart from its inotropic property, milrinone has vasodilator, anti-inflammatory and antithrombotic effects that could assist in the reversal of septic microcirculatory changes. This paper investigates the effects of milrinone on endotoxemia-related microcirculatory changes and compares them to those observed with the use of norepinephrine. MATERIALS AND METHODS: After skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg-1), male golden Syrian hamsters were treated with two regimens of intravenous milrinone (0.25 or 0.5 µg.kg-1.min-1). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables. Macro-hemodynamic, biochemical, and hematological parameters and survival rate were also analyzed. Endotoxemic non-treated animals, endotoxemic animals treated with norepinephrine (0.2 µg.kg-1.min-1), and non-endotoxemic hamsters served as controls. RESULTS: Milrinone (0.5 µg.kg-1.min-1) was effective in reducing lipopolysaccharide-induced arteriolar vasoconstriction, capillary perfusion deficits, and inflammatory response, and in increasing survival. Norepinephrine treated animals showed the best mean arterial pressure levels but the worst functional capillary density values among all endotoxemic groups. CONCLUSION: Our data suggests that milrinone yielded protective effects on endotoxemic animals' microcirculation, showed anti-inflammatory properties, and improved survival. Norepinephrine did not recruit the microcirculation nor demonstrated anti-inflammatory effects.

Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit.

This paper summarizes the pharmacologic properties of vasoactive medications used in the treatment of shock, including the inotropes and vasopressors. The clinical application of these therapies is discussed and recent studies describing their use and associated outcomes are also reported. Comprehension of hemodynamic principles and adrenergic and non-adrenergic receptor mechanisms are salient to the appropriate therapeutic utility of vasoactive medications for shock. Vasoactive medications can be classified based on their direct effects on vascular tone (vasoconstriction or vasodilation) and on the heart (presence or absence of positive inotropic effects). This classification highlights key similarities and differences with respect to pharmacology and hemodynamic effects. Vasopressors include pure vasoconstrictors (phenylephrine and vasopressin) and inoconstrictors (dopamine, norepinephrine, and epinephrine). Each of these medications acts as vasopressors to increase mean arterial pressure by augmenting vascular tone. Inotropes include inodilators (dobutamine and milrinone) and the aforementioned inoconstrictors. These medications act as inotropes by enhancing cardiac output through enhanced contractility. The inodilators also reduce afterload from systemic vasodilation. The relative hemodynamic effect of each agent varies depending on the dose administered, but is particularly apparent with dopamine. Recent large-scale clinical trials have evaluated vasopressors and determined that norepinephrine may be preferred as a first-line therapy for a broad range of shock states, most notably septic shock. Consequently, careful selection of vasoactive medications based on desired pharmacologic effects that are matched to the patient's underlying pathophysiology of shock may optimize hemodynamics while reducing the potential for adverse effects.

Assessment and treatment of post patent ductus arteriosus ligation syndrome.

OBJECTIVE: To compare differences in tissue Doppler imaging, global longitudinal strain (GLS), and cardiac troponin T (cTnT) between infants with low (<200 mL/kg/min) and high (>200 mL/kg/min) left ventricular (LV) output 1 hour after duct ligation and assess the impact of milrinone treatment on cardiac output and myocardial performance. STUDY DESIGN: LV function was assessed preoperatively and 1 and 18 hours postoperatively. Infants were categorized into a low-output or a normal-output group based on the echocardiographic assessment of LV output at 1 hour. RESULTS: Thirty infants with a mean gestation of 25.3 weeks were enrolled. LV basal lateral S', basal septal S', and basal right ventricular S' were lower in the low-output group (n = 19) at 1 hour postoperatively, with no significant difference in GLS (low-output -10.3% vs high-output -14.4%, P >.05) or cTnT between the groups. Patients in the low-output group were treated with milrinone, and by 18 hours LV performance recovered to levels comparable with the high output group. cTnT values increased at 18 hours in the whole cohort with no significant difference between the groups. CONCLUSION: Tissue Doppler imaging and GLS provide novel insights and further characterization of myocardial performance immediately after patent ductus arteriosus ligation. A reduction in tissue Doppler-derived LV systolic velocity may further help in monitoring cardiac performance after patent ductus arteriosus ligation and for monitoring the effects of treatment.

Milrinone as a rescue therapy for symptomatic refractory cerebral vasospasm in aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Delayed ischemic neurological deficit associated to cerebral vasospasm is the most common cause of sequelae and death that follows the rupture of an aneurysm. The objective of this study was to evaluate the safety and efficacy of intra-arterial Milrinone in patients with symptomatic refractory cerebral vasospasm. PATIENTS AND METHOD: Eight patients diagnosed with aneurysmal subarachnoid hemorrhage who developed symptomatic cerebral vasospasm refractory to conventional medical therapy were enrolled. They received an intra-arterial infusion of Milrinone at a rate of 0.25 mg/min, with a total dose of 10-15 mg. Qualitative evaluation of angiographic response, neurological and systemic complications as well as functional outcome at 3 months were documented. RESULTS: All patients had a significant angiographic response. This was evidenced by a pre-treatment vessel stenosis greater than 70%, that improved to less than 50% after the intra-arterial Milrinone infusion. Three patients developed recurrent vasospasm that improved after a second intra-arterial Milrinone infusion. None of the patients developed neurologic or systemic complications attributed to the intervention. At 3 months follow-up all patients were alive and had a mean modified Rankin scale of 2 +/- 1 and a Barthel index of 83 +/- 10. CONCLUSION: Intra-arterial Milrinone infusion seems to be a safe and effective treatment for patients who develop refractory symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

Randomized trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants.

OBJECTIVE: To assess the effectiveness of early prophylactic milrinone versus placebo for prevention of low systemic blood flow in high-risk preterm infants. STUDY DESIGN: Double-blind randomized placebo controlled trial of milrinone (loading dose 0.75 microg/kg/min for 3 hours then maintenance 0.2 microg/kg/min until 18 hours after birth) versus placebo. Infants born <30 weeks gestational age and <6 hours of age were eligible and were monitored with serial echocardiography, head ultrasound scanning, and continuous invasive blood pressure. Primary outcome was maintenance of superior vena cava (SVC) flow > or =45 mL/kg/min through the first 24 hours. The exit criterion was hypotension unresponsive to volume and inotropes. RESULTS: Ninety infants were enrolled, equal proportions maintained SVC flow > or =45 mL/kg/min after treatment commenced. No significant difference was observed in SVC flow, right ventricular output, and blood pressure during the first 24 hours; or grades 3 to 4 periventricular/intraventricular hemorrhage and death. Heart rate was higher and constriction of the ductus was slower in the infants randomized to milrinone. CONCLUSIONS: Milrinone did not prevent low systemic blood flow during the first 24 hours in very preterm infants, and no adverse effects were attributable to milrinone. Use of a preventative treatment with rescue model allowed comparison of an inotrope with placebo in this high-risk group of infants.

Uso de milrinona no tratamento da hipertensão pulmonar persistente do recém-nascido / Milrinone for persistent pulmonary hypertension of the newborn treatment

OBJETIVO: Descrever uma série de casos de recém-nascidos com hipertensão pulmonar persistente grave, que receberam milrinona para promover a vasodilatação pulmonar. MÉTODOS: Análise retrospectiva de prontuários de 28 pacientes com diagnóstico de hipertensão pulmonar persistente do recém-nascido (HPPRN). Após o diagnóstico, todos os pacientes receberam uma dose de ataque de 50mcg/kg de milrinona, seguida por 0,75mcg/kg/min. O índice de oxigenação (IO) foi calculado no início da infusão e 72 horas após o início da medicação. RESULTADOS: Todos os neonatos receberam milrinona e o sildenafil foi associado em 54 por cento. O uso de dopamina assegurou a manutenção da pressão arterial em nível adequado em todos os casos. Sedação contínua, alcalinização e surfactante foram medidas coadjuvantes no tratamento. Durante a internação, sete pacientes (25 por cento) evoluíram a óbito e todos eles apresentaram aumento do IO, com elevação da média de 25 para 38 com a milrinona. Os sobreviventes, com exceção de um neonato, apresentaram redução do IO em uso de milrinona, com queda da média de 19 para 7. CONCLUSÕES: O uso da milrinona parece ser uma alternativa para o tratamento da HPPRN, na ausência do óxido nítrico. A redução do IO com a medicação foi fator determinante da boa evolução dos pacientes. O índice de falha no tratamento com a milrinona nesta casuística foi semelhante ao encontrado na literatura para o uso de óxido nítrico.

OBJECTIVE: To describe a series of neonates with severe persistent pulmonary hypertension, who received milrinone as the main treatment for pulmonary vasodilatation. METHODS: Retrospective analysis by chart review of 28 neonates with persistent pulmonary hypertension. A dose of 0.75µg/kg/min of milrinone was given, after a loading dose of 50µg/kg. The oxygenation index (OI) was calculated before and 72 hours after the medication. RESULTS: All infants received milrinone and sildenafil was associated to milrinone in 54 percent. The use of dopamine assured normal blood pressure during milrinone treatment in all patients. Continuous sedation, alcalinization and surfactant were additional measures in the treatment. During the hospitalization period, seven (25 percent) patients died and all of them presented an OI increase after milrinone (the average OI rose from 25 to 38). All but one of the 21 surviving patients presented improvement of the OI with milrinone, with a reduction of the mean index from 19 to 7. CONCLUSIONS: Milrinone can be used to treat persistent pulmonary hypertension of the newborn, in the absence of nitric oxide. The reduction of the OI during treatment was associated with clinical improvement. The failure rate for milrinone treatment in this series of cases was similar to that found in the literature regarding nitric oxide.

Uso profiláctico de la milrinona en el postoperatorio inmediato de la cirugía correctiva de la transposición de grandes arterias / Prophylactic use of milrinone in immediate postoperatory of surgical correction for transposition of the great arteries

Objetivo: en las primeras horas del postoperatorio de la corrección quirúrgica de la transposición de grandes arterias, suele aparecer una caída del gasto cardíaco. Con el fin de disminuir su impacto en un grupo de neonatos con extrema labilidad hemodinámica, presentamos nuestra experiencia clínica preliminar con el empleo profiláctico de milrinona. Material y métodos: seis neonatos consecutivos portadores de transposición de grandes arterias y sometidos a corrección quirúrgica recibieron, antes de la separación de la circulación extracorpórea, una infusión intravenosa a dosis media (0,54 µg/kg/min) sin previa realización de dosis carga. Se analizaron la mortalidad intrahospitalaria, la presencia de signos clínicos y hemodinámicos de bajo gasto cardíaco y la aparición de efectos adversos ligados a la milrinona. Resultados: no hubo mortalidad, ni presencia de síndrome de bajo gasto cardíaco, así como tampoco detectamos efectos colaterales debido al fármaco en estudio. Conclusiones: la milrinona, utilizada de acuerdo a nuestro protocolo, se reveló eficaz y confiable para evitar la caída del gasto cardíaco en 6 neonatos consecutivos sometidos a la cirugía correctiva de la transposición de grandes arterias. (AU)