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Objective: To gather information for a future confirmatory trial of dobutamine (DB) for circulatory impairment (ie, low superior vena cava [SVC] flow)., Study Design: A total of 127 infants born at < 31 weeks gestational age were serially scanned from birth to 96 hours after birth. The infants were randomly assigned to 2 groups and were treated with DB (stepwise dose increase, 5-10-15-20 μg/kg/min) or placebo if they had an SVC flow < 41 mL/kg/min within the first 24 hours after birth. The primary outcome measures were the achievement and maintenance of an SVC flow ≥ 41 mL/kg/min. Secondary outcome measures were the short-term evolution of clinical and biochemical variables, near-infrared spectroscopy, cranial Doppler ultrasound, and clinical outcomes., Results: SVC flow increased throughout the first 96 hours for the entire cohort. All of the randomized infants (n = 28) except 2 achieved and maintained an SVC flow ≥ 41 mL/kg/min after intervention; however, the infants treated with DB (n = 16) showed a higher heart rate and improved base excess compared with those treated with placebo (n = 12). Low SVC flow was associated with low gestational age (P = .02) and poor condition at birth (P = .02). Low SVC flow significantly increased the risk of severe ischemic events (OR, 13; 95% CI, 2.4-69.2; P < .01)., Conclusion: This exploratory trial demonstrates a tendency toward improved short-term clinical and biochemical perfusion variable outcomes in infants with low SVC flow treated with DB., Trial Registration: ClinicalTrials.gov (NCT01605279) and the European Clinical Trials Database (EurodraCT 2009-010901-35)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Inodilators are routinely used in cardiovascular surgery with cardiopulmonary bypass (CPB). Information regarding safety and tolerability of the novel molecule, levosimendan (LEVO), in newborns is anecdotal; no pharmacokinetic data in this population are available., Methods: This was a phase I, randomized, and blinded study. Neonates undergoing surgical repair for congenital heart defects received stepwise dose increases of milrinone (MR; 0.5-1 μg/kg/min, n = 9) or LEVO (0.1-0.2 μg/kg/min, n = 11) as an i.v. continuous infusion, starting before CPB. Infants had continuous, time-locked, physiological, and near-infrared spectroscopy (NIRS) (cerebral and peripheral) recordings during the first 24 h, and at 48 and 96 h postsurgery. Serial biochemistry and pharmacokinetic studies were performed., Results: During the first 24 h postsurgery, patients showed time-related, group-independent increased cerebral tissue oxygenation and decreased diastolic blood pressure; in addition, group-dependent differences in heart rate and peripheral perfusion were found. Early postsurgery, MR-treated infants showed lower pH, higher glycemia, and higher inotrope score. The groups differed in cerebral NIRS-derived variables from 24 to 96 h. Study drug withdrawal at 96 h was more frequent with LEVO. LEVO intermediate metabolites were detected in plasma at day 14 after surgery., Conclusion: LEVO is well tolerated in critically ill neonates. LEVO may have advantages over MR in terms of the dosing regimen.

Background: Cardiovascular drugs play a major role in the pre- and postoperative care in neonates with congenital heart disease. Management strategies aim to optimise contractility, improve diastolic function, maintain adequate preload, and reduce afterload. Levosimendan, a novel inodilator agent, enhances myocardial contractility and causes peripheral and coronary vasodilation., Objectives: A systematic approach was used to evaluate the acute haemodynamic effects of levosimendan in critically ill infants with low cardiac output syndrome (LCOS)., Methods: Infants received a continuous infusion of levosimendan, at a dose increased stepwise (range 0.1-0.2 μg/kg/min), during 48 h. Two near-infrared units were used to assess cerebral (frontal-parietal, c) and peripheral (thigh, p) perfusion and oxygenation. The changes in cerebral blood volume (ΔCBV), cerebral (cΔHbD) and peripheral (pΔHbD) intravascular oxygenation and the cerebral (cTOI) and peripheral (pTOI) tissue oxygenation index that followed levosimendan administration were continuously monitored. Blood pressure, heart rate, and temperature were continuously recorded. In addition, baseline and end-of-study pH, blood gases, lactate and haematocrit were determined., Results: Seven doses of levosimendan were investigated. The mean study time was 13.3 (7-19) h. Levosimendan produced an increase in cΔHbD (p < 0.05) and pΔHbD (NS) and a decrease in heart rate (p < 0.001) and lactate (p < 0.05). Trends showed an increase in mean blood pressure (NS). These results were independent of the effect of time. Mixed linear model analysis identified blood pressure changes and levosimendan as factors independently associated with cΔHbD., Conclusions: Levosimendan improves cerebral and systemic perfusion and oxygenation in critically ill infants suffering from LCOS., (Copyright © 2010 S. Karger AG, Basel.)

Background: The duration and severity of systemic hypotension have been related with altered neurodevelopment. Cerebral circulation is pressure-passive in low birth weight infants with early systemic hypotension who receive cardiovascular support. The treatment of early systemic hypotension is controversial, because it has been associated with short-term and long-term morbidity in retrospective studies. However, there has been no prospective information on cardiovascular support for hypotension and morbidity., Objective: Our goal for this prospective study was to evaluate the effect on neurodevelopment resulting from the use of vasopressors/inotropes for early systemic hypotension., Methods: Low birth weight infants with early systemic hypotension (<24 hours of life; study group) were assigned randomly to receive dopamine (2.5-10 microg/kg per minute) or epinephrine (0.125-0.5 microg/kg per minute) in progressively larger doses until target blood pressure was attained (treatment-success subgroup). Hemodynamically stable patients who did not receive cardiovascular support were the control group. Outcome measures were serial cranial ultrasound up to 40 weeks, structured neurologic evaluation (every 3 months), and neurodevelopmental test at 2 to 3 years of age., Results: One hundred thirty patients were included (study = 60; treatment success = 38; controls = 70). Study-group patients had lower birth weight, gestational age, and 5-minute Apgar score, higher rates of premature rupture of membranes, need for cardiorespiratory resuscitation at birth, and sickness shortly after birth than the control group. The patients in the study group also had significantly higher serum troponin I levels at birth. Initial cranial ultrasound findings did not differ between groups, but the final cranial ultrasounds revealed higher rates of severe periventricular hemorrhage in the study group and higher rates of normal cranial ultrasounds in the control group. Only the latter remained when the treatment-success subgroup and control group were compared. Multivariate analysis did not detect any association between final cranial ultrasounds and the use of vasopressors/inotropes. Sixteen infants died and 103 were followed up (90% survival rate). No differences between groups were found in the rates of abnormal neurologic status, developmental delay, or combined adverse outcome (death or cerebral palsy or severe neurodevelopmental delay)., Conclusions: Cautious use of cardiovascular support to treat early systemic hypotension in low birth weight infants seems to be safe. The question of whether raising systemic blood pressure to within a normal range will improve outcome should be examined by using appropriate study designs.

Background: Early postnatal adaptation to transitional circulation in low birth weight infants frequently is associated with low blood pressure and decreased blood flow to organs. Catecholamines have been used widely as treatment, despite remarkably little empirical evidence on the effects of vasopressor/inotropic support on circulation and on clinically important outcomes in sick newborn infants., Aims: To explore the effectiveness of low/moderate-dose dopamine and epinephrine in the treatment of early systemic hypotension in low birth weight infants, evaluate the frequency of adverse drug effects, and examine neonatal clinical outcomes of patients in relation to treatment., Design/methods: Newborns of <1501-g birth weight or <32 weeks of gestational age, with a mean blood pressure lower than gestational age in the first 24 hours of life, were assigned randomly to receive dopamine (2.5, 5, 7.5, and 10 microg/kg per minute; n = 28) or epinephrine (0.125, 0.250, 0.375, and 0.5 microg/kg per minute; n = 32) at doses that were increased stepwise every 20 minutes until optimal mean blood pressure was attained and maintained (responders). If this treatment was unsuccessful (nonresponders), sequential rescue therapy was started, consisting first of the addition of the second study drug and then hydrocortisone., Outcome Measures: These included: (1) short-term changes (first 96 hours, only responders) in heart rate, mean blood pressure, acid-base status, lactate, glycemia, urine output, and fluid-carbohydrate debit; and (2) medium-term morbidity, enteral nutrition tolerance, gastrointestinal complications, severity of lung disease, patent ductus arteriosus, cerebral ultrasound diagnoses, retinopathy of prematurity, and mortality., Results: Patients enrolled in this trial did not differ in birth weight or gestational age (1008 +/- 286 g and 28.3 +/- 2.3 weeks in the dopamine group; 944 +/- 281 g and 27.7 +/- 2.4 weeks in the epinephrine group). Other main antenatal variables were also comparable. However, responders and nonresponders differed significantly with respect to the need for cardiorespiratory resuscitation at birth (3% vs 23%), Critical Risk Index for Babies score (3.8 +/- 3 vs 7 +/- 5), and premature rupture of membranes >24 hours (39.5% vs 13.6%), respectively. No differences were found in the rate of treatment failure (dopamine: 36%; epinephrine: 37%) or need for rescue therapy according to treatment allocation. Groups did not differ in age at initiation of therapy (dopamine: 5.3 +/- 3.9 hours; epinephrine: 5.2 +/- 3.3 hours), but withdrawal was significantly later in the dopamine group. For short-term changes, mean blood pressure showed a significant increase from baseline throughout the first 96 hours with no differences between groups. However, epinephrine produced a greater increase in heart rate than dopamine. After treatment began, epinephrine patients showed higher plasma lactate (first 36 hours) and lower bicarbonate and base excess (first 6 hours) and received more bicarbonate. Patients in the epinephrine group also had higher glycemia (first 24 hours) and needed insulin therapy more often. Groups did not differ in urine output or fluid-carbohydrate supply during the first 96 hours. For medium-term morbidity, there were no differences in neonatal clinical outcomes in responders. However, significant differences were found in the incidence of patent ductus arteriosus, bronchopulmonary dysplasia, need for high-frequency ventilation, occurrence of necrotizing enterocolitis, and death between responders and nonresponders., Conclusions: Low/moderate-dose epinephrine is as effective as low/moderate-dose dopamine for the treatment of hypotension in low birth weight infants, although it is associated with more transitory adverse effects.

Background: Maintaining adequate organ blood flow is the target of vasopressor treatment, but the impact of these measures on cerebral perfusion has not yet been evaluated systematically in a randomized, blinded, clinical trial., Objectives: To explore the effects on brain hemodynamics of 2 different inotropic agents used to treat systemic hypotension among low birth weight (LBW) infants., Design and Methods: Newborns of <1501 g birth weight or <32 weeks' gestational age, with a mean blood pressure (MBP) lower than gestational age in the first 24 hours of life, were assigned randomly to receive dopamine (DP) (2.5, 5, 7.5, or 10 microg/kg per minute; n = 28) or epinephrine (EP) (0.125, 0.250, 0.375, or 0.5 microg/kg per minute; n = 32), at doses that were increased in a stepwise manner every 20 minutes until the optimal MBP (MBP-OP) was attained and maintained., Outcome Measures: Continuous monitoring of quantitative changes in cerebral concentrations of oxyhemoglobin and deoxyhemoglobin, cerebral intravascular oxygenation (HbD) (the difference between oxyhemoglobin and deoxyhemoglobin), and cerebral blood volume (CBV) were assessed with near-infrared spectroscopy. MBP, heart rate, transcutaneous Pco2 and Po2, and peripheral oxygen saturation were recorded continuously and analyzed at baseline, 20 minutes after each dose increase (T1, T2, T3, and T4) until MBP-OP was reached, and then every 20 minutes up to 1 hour of stable MBP-OP., Results: Fifty-nine infants were considered for analysis. Patients did not differ in birth weight or gestational age (1008 +/- 286 g and 28.3 +/- 2.3 weeks, respectively, in the DP group and 944 +/- 281 g and 27.7 +/- 2.4 weeks in the EP group). Studies were performed at a mean age of 5.3 +/- 3.7 hours of life (range: 2-16 hours). MBP-OP was attained for 96.3% of patients with DP and 93.7% with EP (responders). For those patients, MBP, heart rate, CBV, and HbD increased from baseline throughout the study period, with no differences between groups except for a higher heart rate with EP. Changes in MBP were correlated significantly with changes in HbD. Dose escalation of drugs produced no differences between groups in the behavior of the variables, except for a greater heart rate with EP from 20 minutes after dose 2 (T2) onward. Drug-induced changes in cerebral hemodynamics varied with gestational age; the EP-induced increase in CBV was greater among less mature patients (<28 weeks), whereas the DP-induced increase in CBV was greater among patients of > or =28 weeks., Conclusions: Among hypotensive LBW infants, cardiovascular support with low/moderate-dose DP or low-dose EP increased cerebral perfusion, as indicated by the increase in both CBV and HbD. Low-dose EP was as effective as low/moderate-dose DP in increasing MBP among LBW infants.