Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery.

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.

Predischarge morbidities in extremely and very low-birth-weight infants in Spanish neonatal units.

We sought to describe neonatal morbidities and therapeutic interventions in very low-birth-weight (VLBW) and extremely low-birth-weight (ELBW) infants cared for in Spanish hospitals. We preformed a prospective collection of data covering the perinatal period until discharge by the SEN1500 network. This network, set up by the Spanish Society of Neonatology, targets VLBW and ELBW infants (400 to 1500 g) admitted to neonatal units in Spanish hospitals. Data were recorded in electronic form and controlled for possible errors or inconsistencies before analysis. We report data for 8836 neonates admitted to 48 neonatal units from January 2002 to December 2005. Prenatal steroids were given to significantly more newborns in 2003 to 2005 (79.4%) than in 2002 (73.4%), although the remaining perinatal data examined failed to significantly vary. Delivery was by cesarean section in 69.8% of cases but significantly lower (35.9%) for infants under a postmenstrual age of 26 weeks. Hyaline membrane disease was diagnosed in 53.9% of the newborns and bronchopulmonary dysplasia (BPD) in 10.46%. Mechanical ventilation was employed in 69.1%, surfactant in 50.3%, and steroids for BPD in 5.3%. Intraventricular hemorrhage grades 3 to 4 (8.1%) and cystic leukomalacia (2.6%) were the most relevant brain ultrasonography findings. Rates of early- and late-onset septicemia were 5% and 29.4%, respectively. Further diagnoses were necrotizing enterocolitis (NEC; 6.9%) and persistent ductus arteriosus (PDA; 24.2%); 40.6% of the cases of NEC and 15.3% of those of PDA required surgery. In addition, 26.6% of the newborns required supplementary oxygen at 28 days of life. The number of newborns who had not recovered their birth weight at this age fell from 3.1% in 2002 to 1.5% in 2005. Rates of prenatal steroid use, cesarean delivery, and main morbidities were comparable to figures cited for other patient series, although our BPD rate was among the lowest reported and nosocomial sepsis rate among the highest.

Randomised controlled clinical trial of standard versus echocardiographically guided ibuprofen treatment for patent ductus arteriosus in preterm infants: a pilot study.

OBJECTIVE: The aim of this study was to explore the efficacy of echocardiographically guided (EchoG) pharmacological closure of the ductus arteriosus in reducing the number of required ibuprofen doses without increasing the reopening rate. METHODS: We performed a randomised controlled trial that included 49 infants with a duct ≥1.5 mm who were randomised to either EchoG or standard ibuprofen treatment. Echocardiography was serially performed on days 1, 2, 3, 4, 7, 10 and 17 after inclusion. The primary outcome was the ductus reopening rate, and an intention-to-treat analysis was performed. RESULTS: Twenty-eight (EchoG treatment) and 21(standard treatment) infants were enrolled (27.2 versus 27.3 weeks, p = 0.3). The patients received 2 (1-5.7) and 3 (3-4) doses of ibuprofen in the EchoG and standard treatment groups, respectively (p = 0.04) and experienced a similar ductus reopening rate (11% versus 5%, p = 0.6). CONCLUSION: Echocardiographically guided ibuprofen treatment of patent ductus arteriosus is feasible and reduces unnecessary doses of medication.

Acute effects of levosimendan on cerebral and systemic perfusion and oxygenation in newborns: an observational study.

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.

Low mortality in necrotizing enterocolitis associated with coagulase-negative Staphylococcus infection.

The aim of this study was to correlate the clinical course of necrotizing enterocolitis (NEC) with infection by coagulase-negative Staphylococcus at the onset of the illness. Records of all newborn infants developing NEC between January 1998 and December 2001 were reviewed. NEC was classified according to the criteria of Bell et al. Numeric variables were described by standard statistical methods. Comparisons between subgroups were performed by parametric statistical tests. Forty-four patients developed NEC stage II (n = 25) or III (n = 19). The incidence was 0.024% of live births in the hospital, and the mortality rate was 9%. The main risk factor was prematurity (84%). Only one-fourth of the patients had gastric residuals. A platelet count of <100,000 cells/mm3 occurred only in grade III NEC. Blood cultures were positive in 34% of the patients. The predominant organism (73%) was coagulase-negative Staphylococcus (CoNS). Neither Clostridium nor Bacteroides species were isolated. Stage II patients were maintained nothing per os (NPO) for 9 +/- 3 days and received antibiotics for 10 +/- 3 days. All of the stage III patients required an operation. In one-third of them, primary peritoneal drainage was initially performed but all required further operative procedures. We report a low incidence and mortality rate of necrotizing enterocolitis. Thrombocytopenia is confirmed as a marker of severity. Positive blood cultures for CoNS may explain, at least in part, the low mortality reported.

Mortality for newborns of birthweight less than 1500 g in Spanish neonatal units (2002-2005).

The purpose of this study was to analyze the mortality and its prognostic factors in a Spanish cohort of very low birthweight (VLBW) infants during the period 2002 to 2005. Using the Spanish Society of Neonatology database (SEN 1500), 8942 infants with a birthweight < 1500 g were recruited. The overall mortality was 17.3%. However, this incidence underwent a significant decrease over the study period, from 19.4% in 2002 to 15.2% in 2005 ( P = 0.003). Mortality ranged from 12.4% in 25% of the participating neonatal units to 19.4% in a further 25%. Mortality was higher in outborn infants (25.8%) than in inborn infants (16.6%) ( P < 0.001). The mortality rates of these neonates are also presented by 100-g intervals (401 to 1500) and for the different hospitalization times: in the delivery room, within 24 hours and 28 days of birth, at 36 weeks of postmenstrual age, and on discharge. Of note was that mortality was greatest within 24 hours and 28 days of birth in each of the weight groups ( P < 0.001). In conclusion, in the cohort of infants < 1500 g examined, mortality in the period from 2002 to 2005 was still high, especially among newborns weighing < 1000 g. We did, however, observe a decreasing trend in mortality rates for the participating neonatal units over the 4 study years. Our findings highlight the need to promote intrauterine transport and improve neonatal transport as well as the management of these infants in the delivery room and within the first 28 days of life.

Seudohipoaldosteronismo tipo I múltiple: presentación y seguimiento / Multiple type I pseudohypoaldosteronism: neonatal management and outcome

El seudohipoaldosteronismo (PHA) tipo I múltiple es un síndrome de resistencia mineralocorticoide, de herencia autosómica recesiva, que afecta a túbulo renal, glándulas salivales y sudoríparas y mucosa del colon. Caso 1. Recién nacida con hermana que falleció a los 10 días de vida con hiperpotasemia. A los 7 días de vida presenta deshidratación, hiponatremia, hiperpotasemia, acidosis metabólica e hipernatriuria. El diagnóstico se basó en la presencia de aldosterona en plasma, actividad de renina plasmática (ARP) y eliminación de sal en sudor muy elevadas. Precisó rehidratación y tratamiento con sal, bicarbonato, resinas de intercambio iónico y dieta pobre en potasio. Durante el primer año de vida requirió hospitalización por descompensaciones repetidas. Tras 7 años de evolución, aún precisa suplementos de sal y bicarbonato y resinas de intercambio iónico. El desarrollo psicomotor y el crecimiento son adecuados. Caso 2. Recién nacida de 8 días con antecedente de consanguinidad en la familia materna. Al ingreso presenta deshidratación severa con hiponatremia, hiperpotasemia, acidosis metabólica e hipernatriuria, con aldosterona, ARP y sal en sudor muy elevados. Precisa rehidratación, suplementos de sal y bicarbonato y resinas de intercambio iónico. Permanece ingresada durante 6 meses por descompensaciones múltiples, siendo posible posteriormente control ambulatorio. Al año de edad, la curva de peso y el desarrollo psicomotor son adecuados. Conclusiones. Se debe sospechar PHA I múltiple en recién nacidos con síndrome pierde-sal e hiperpotasemia, sin virilización, hiperpigmentación ni déficit glucocorticoide, que no responde al tratamiento con mineralocorticoides. La labilidad en el primer año de vida obliga al ingreso hospitalario prolongado. A edades posteriores es susceptible de control ambulatorio (AU)