Do prenatal steroids improve the survival of late preterm infants with complex congenital heart defects?

AIM: We evaluated the use of prenatal steroids (PNS) and the effect of that practice on hospital mortality of late preterm infants with complex congenital heart defects (CHD). METHODS: Retrospective review of records of late preterm infants with complex CHD infants that were cared for in a single tertiary perinatal center between 2002 and 2009. Multivariate logistic regression analysis was performed to determine which of the risk factors commonly associated with death prior to discharge from the hospital predict the outcome (hospital death). RESULTS: Of the 106 late preterm infants with complex CHD, 31(29%) died and 15 (14%) received PNS. Endotracheal intubation in the delivery room (42% vs 15%), necrotizing enterocolitis (10% vs 0%) and hypoplastic left heart syndrome (52% vs 25%) were statistically more frequent in non-surviving infants. Non-surviving infants were more frequently treated with PNS (23% vs 11%) but this difference was not statistically significant (p = 0.131). Using logistic regression analysis, delivery room intubation (OR 4.91; 95% CI 1.78 - 13.51) and the hypoplastic left heart syndrome (OR 3.29; 95% CI 1.28 - 8.48), but not prenatal steroids were independently associated with increased risk of hospital death. CONCLUSIONS: In a selected population of late preterm infants with complex CHD, prenatal steroid treatment did not independently influence survival.

Does phenobarbital improve the effectiveness of therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy?

OBJECTIVE: To determine whether phenobarbital (PB) given before therapeutic hypothermia to infants with hypoxic-ischemic encephalopathy (HIE) augments the neuroprotective efficacy of hypothermia. STUDY DESIGN: Records of 68 asphyxiated infants of 36 weeks' gestation, who received hypothermia for moderate or severe HIE were reviewed. Some of these infants received PB prophylactically or for clinical seizures. All surviving infants had later brain magnetic resonance imaging (MRI). The composite primary outcome of neonatal death related to HIE with worsening multiorgan dysfunction despite maximal treatment, and the presence of post-hypothermia brain MRI abnormalities consistent with hypoxic-ischemic brain injury, were compared between the infants who received PB before initiation of hypothermia (PB group, n=36) and the infants who did not receive PB before or during hypothermia (No PB group, n=32). Forward logistic regression analysis determined which of the pre-hypothermia clinical and laboratory variables predict the primary outcome. RESULT: The two groups were similar for severity of asphyxia as assessed by Apgar scores, initial blood pH and base deficit, early neurologic examination, and presence of an intrapartum sentinel event. The composite primary outcome was more frequent in infants from the PB group (PB 78% versus No PB 44%, P=0.006, odds ratio 4.5, 95% confidence interval 1.6 to 12.8). Multivariate analysis identified only the PB receipt before initiation of hypothermia (P=0.002, odds ratio 9.5, 95% confidence interval 2.3 to 39.5), and placental abruption to be independently associated with a worse primary outcome. CONCLUSION: PB treatment before cooling did not improve the composite outcome of neonatal death or the presence of an abnormal post-hypothermia brain MRI, but the long-term outcomes have not yet been evaluated.

The effect of late preterm birth on mortality of infants with major congenital heart defects.

OBJECTIVE: We evaluated the effect of late preterm delivery (34 to 36 weeks) on hospital mortality of infants with congenital heart defects (CHDs). STUDY DESIGN: Retrospective record review of infants with major CHD born at or after to 34 weeks, cared for in a single tertiary perinatal center between 2002 and 2009. Factors associated with death before discharge from the hospital were ascertained using univariate and multivariate analyses. RESULT: Of the 753 infants with CHD, 117 were born at late preterm. Using logistic regression analysis, white race (OR; 95% CI) (0.60; 0.39 to 0.95), late preterm delivery (2.70; 1.69 to 4.33), and need for intubation in the delivery room (3.15; 1.92 to 5.17) were independently associated with hospital death. CONCLUSION: Late preterm birth of infants with major CHDs was independently associated with increased risk of hospital death compared with delivery at more mature gestational ages.

Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns.

OBJECTIVE: The purpose of this observation was to evaluate the safety and efficacy of hydrocortisone (HC) for the treatment of refractory hypotension in term and preterm infants. A secondary purpose was to determine the utility of serum cortisol concentrations in predicting the response to treatment. STUDY DESIGN: This is a retrospective observational study of 117 infants treated with a standardized HC protocol for refractory hypotension. Refractory hypotension was defined as a mean arterial pressure (MAP) less than the gestational age (GA) despite a total inotrope dose of 20 microg per kg per min. Baseline serum cortisol concentrations were determined prior to treatment with stress dose HC. RESULT: Treatment with HC increased the MAP at 2, 6, 12 and 24 h after initiation, decreased the total inotrope dose at 6, 12 and 24 h, and was associated with resolution of oliguria. There was no correlation between the pretreatment baseline cortisol concentration and GA, birth weight or the response to treatment. The incidence of grades III to IV intraventricular hemorrhage, periventricular leukomalacia, bacterial or fungal sepsis and spontaneous intestinal perforation (SIP) after HC treatment was similar to institutional historic controls prior to institution of this standardized HC protocol. CONCLUSION: HC treatment was associated with a rapid resolution of cardiovascular compromise. The incidence of significant side effects was similar to that in previously published reports, including a comparable incidence of SIP. On the basis of our results, measuring baseline serum cortisol concentration to guide the management of refractory hypotension is unwarranted.

Is refractory hypotension in preterm infants a manifestation of early ductal shunting?

BACKGROUND: Clinicians frequently use hydrocortisone (HC) to treat vasopressor-resistant hypotension even before establishing its cause. OBJECTIVE: To identify the etiologic factors leading to development of refractory hypotension, and to assess if patent ductus arteriosus (PDA) is associated with refractory hypotension during the first week of life. STUDY DESIGN: The medical records of 290 consecutively born infants

Are newborns receiving premedication before elective intubation?

AIMS: To determine the extent and type of premedication used for elective endotracheal intubation in neonatal intensive care units (NICUs). METHODS: A pretested questionnaire was distributed via e-mail to the program directors of the neonatology divisions with accredited fellowship programs in Neonatal-Perinatal Medicine in the United States. RESULTS: Of the 100 individuals contacted, 78 (78%) participated in the survey. Only 34 of the 78 respondents (43.6%) always use any premedication for elective intubation. Nineteen respondents (24.4%) reported to have a written policy regarding premedication. Morphine or fentanyl was used most commonly (57.1%), with a combination of opioids and midazolam or other benzodiazepines used less frequently. Fourteen respondents (25%) also use muscle relaxants with sedation for premedication, but only nine respondents combined paralysis with atropine and sedation. CONCLUSION: Most neonatology fellowship program directors do not report always using premedication for newborns before elective endotracheal intubation despite strong evidence of physiologic and practical benefits. Only a minority of the NICUs has written guidelines for sedation, which may preclude effective auditing of this practice. Educational interventions may be necessary to ensure changes in clinical practice.

Extracorporeal membrane oxygenation 2001. The odyssey continues.

Extracorporeal membrane oxygenation was established as a standard of care by demonstrating its ability to save lives in moribund infants. The designs of early studies provided no living cohorts of similarly ill patients by which to measure accurately other (and perhaps to many more important) outcomes of interest: long-term neurodevelopmental outcomes or cost. Prospective cohort studies of neurodevelopmental outcomes post-ECMO demonstrate: (1) because ECMO, as used, saves lives, there will be an increase in the absolute number of handicapped children surviving; (2) there is little evidence that ECMO creates a relative increase in the percent of handicapped children surviving severe respiratory failure. The high direct costs of an ECMO program are measured and well publicized. When such costs are compared with similar therapies in other fields (in such terms as cost per survivor), the cost of ECMO does not seem to be an outlier. Trials of newer therapies, such as iNO, show the capacity to decrease the use of ECMO but have failed to demonstrate either cost-effectiveness or better long-term outcomes. It has not been shown that either society or individual patients have benefited from the decreased need for ECMO.

Lack of vancomycin-associated nephrotoxicity in newborn infants: a case-control study.

OBJECTIVE: The purpose of this study was to compare the incidence of nephrotoxicity, defined as doubling of baseline serum creatinine concentration, in newborn infants with peak vancomycin serum concentrations 40 microg/mL. A secondary objective was to correlate concomitant disease states and potentially nephrotoxic drug therapy with rises in serum creatinine in vancomycin recipients. METHODS: Newborn infants with culture-proven Staphylococcus aureus or coagulase-negative staphylococcal septicemia who received vancomycin therapy for >3 days between 1985 and 1995 were identified from an existing database and a review of medical record. All 69 patients included in the study had serial serum creatinine determinations, including a baseline value within 48 hours of starting treatment with vancomycin, and serum vancomycin concentrations determined after at least three doses, with peak and trough concentrations determined 1 hour after a 60-minute infusion and 15 to 30 minutes before a dose, respectively. Infants with congenital renal or cardiac anomalies were excluded. Demographic characteristics, vancomycin dosing regimen, serum vancomycin concentrations and sample times, concomitant drug therapy, and disease states were recorded. Patients were divided into group A (peak vancomycin concentration 40 microg/mL). The change in serum creatinine concentration between the start and end of vancomycin therapy was determined. Nephrotoxicity was identified if serum creatinine doubled at any time from the start to the end of vancomycin therapy. Alternative definitions of nephrotoxicity (any rise in serum creatinine to >0.6 mg/dL or new abnormalities of urine sediment) were used in additional analyses. RESULTS: A total of 69 evaluable patients (gestational age, 28.9 +/- 3.0 weeks; birth weight, 1219 +/- 516 g) were identified, 61 in group A and 8 in group B. Six patients in group A underwent doubling of serum creatinine concentration during vancomycin therapy, whereas none in group B did so. Serum creatinine doubled to >0.6 mg/dL in only 3 infants (all in group A). Any increase in serum creatinine to >0.6 mg/dL was seen in 10 infants, 9 of whom were in group A. No confounding variable, including previous or concomitant underlying disease states associated with renal dysfunction or treatment with other potentially nephrotoxic agents, were associated with a significant rise in serum creatinine. CONCLUSION: Vancomycin-associated nephrotoxicity is rare in neonates, even with serum peak concentrations >40 microg/mL.

Group C streptococcal infection in a term newborn infant.

Group C streptococci were recovered from the cerebrospinal fluid of a term infant with symptoms whose mother had received intrapartum antibiotic therapy for chorioamnionitis. This case highlights that beta-hemolytic streptococci of Lancefield groups other than A or B can be isolated from a normally sterile site and should be considered as pathogens. It also underscores the potential importance of sampling cerebrospinal fluid in an infant with symptomatic suspected sepsis, especially in the setting of exposure to maternal antimicrobial agents.

Comparison of two methods of surfactant administration and the effect on dosing-associated hypoxemia.

OBJECTIVE: The purpose of our study was to test the hypothesis that surfactant dosing through a proximal sideport adapter on an endotracheal tube leads to more dosing-associated hypoxemia compared with a method of dosing that uses a double-lumen endotracheal tube. STUDY DESIGN: Using adequate sample size to compare significant changes in O2 saturation (power > 0.8, alpha < 0.05) we enrolled 36 infants with respiratory distress syndrome in this randomized trial. A 10% change in O2 saturation was considered clinically significant. Nineteen infants received 38 doses of surfactant through the sideport adapter. Seventeen infants received 31 doses of surfactant through the nonventilation lumen of a double-lumen endotracheal tube. Two main outcome measures were assessed: time-averaged O2 saturation values 30 minutes after dosing and the largest absolute fall in O2 saturation for each patient. RESULTS AND CONCLUSIONS: Time-averaged O2 saturation measures were higher in the proximal sideport group (p = 0.02), but the magnitude of difference was probably not clinically significant. No significant difference was detected between groups when we compared largest absolute drop in O2 saturation. Secondary analyses found no effect of birth weight or dose number (second vs third dose) on either outcome measure.

Treatment of parenteral nutrition-associated cholestasis with cholecystokinin-octapeptide.

The authors investigated whether parenteral nutrition-associated cholestasis (PNAC) in surgical neonates could be alleviated by the administration of cholecystokinin-octapeptide (CCK). Two groups of infants were studied, after major abdominal or cardiac surgery in the newborn period. The low-dose group consisted of three infants with PNAC who received cholecystokinin-octapeptide (Sincalide) at a dose of 0.02 micrograms/kg intravenously (IV), twice daily. The high-dose group comprised eight infants with PNAC who received an initial dose of 0.02 micrograms/kg IV or intramuscularly, three times daily on the first day, followed by a daily doubling of the dose up to as high as 0.32 micrograms/kg. In the low-dose group, direct bilirubin levels declined a mean of 50.2 +/- 14.5%. In the high-dose group, direct bilirubin levels declined a mean of 23.4 +/- 14.3%. In three patients in the high-dose group, no decline occurred. All three had clinical signs of overt liver failure and died of liver failure within 2 months after treatment with CCK. By excluding these patients from the high-dose group, the decline in bilirubin levels increased to 49.6 +/- 10.9%. Side effects from CCK occurred in two patients and consisted of abdominal pain and feeding intolerance. Treatment with CCK appears to be associated with a decline in direct bilirubin levels, provided overt liver failure has not developed.

Extracorporeal life support for neonatal respiratory failure. A 20-year experience.

OBJECTIVE: The authors reviewed their experience with extracorporeal life support (ECLS) in neonatal respiratory failure; they define changes in patient population, technique, and outcomes. SUMMARY BACKGROUND DATA: Extracorporeal life support has progressed from laboratory research to initial clinical trials in 1972. Following a decade of clinical research, ECLS is now standard treatment for neonatal respiratory failure refractory to conventional pulmonary support techniques. Our group has the longest and largest experience with this technique. METHODS: Between 1973 and 1993, 460 neonates with severe respiratory failure were treated using ECLS. The records of all patients were reviewed. RESULTS: Overall survival was 87%. Primary diagnoses were meconium aspiration syndrome (MAS; 169 cases [96% survival]), respiratory distress syndrome/hyaline membrane disease (91 cases [88% survival]), persistent pulmonary hypertension of the newborn (37 cases [92%]), pneumonia/sepsis (75 cases [84% survival]), congenital diaphragmatic hernia (CDH; 67 cases [67% survival]), and other diagnoses (21 cases [71% survival]). Common mechanical complications included clots in the circuit (136; 85% survival); air in the circuit (67; 82% survival); cannula problems (65; 83% survival) and oxygenator failure (34; 65% survival). Patient-related complications included intracranial infarct or bleed (54 cases; 61% survival), major bleeding (48 cases; 81% survival), seizures (88 cases; 76% survival), metabolic abnormalities (158 cases; 71% survival) and infection (21 cases; 48% survival). Since 1989, treatment groups have been expanded to include premature infants (13 cases; 62% survival), infants with grade I intracranial hemorrhage (28 cases; 54% survival) and "non-honeymoon" CDH patients (15 cases; 27% survival). Since 1990, single-catheter venovenous access has been used in 131 patients (97% survival) and currently is the preferred mode of access. Follow-up ranges from 1 to 19 years; 80% of patients are growing and developing normally. CONCLUSIONS: Extracorporeal life support has become standard treatment for severe neonatal respiratory failure in our center (460 cases; 87% survival), and worldwide (8913 cases; 81% survival). The availability of ECLS makes the evaluation of other innovative methods of treatment, such as late elective repair of diaphragmatic hernia and new pulmonary vasodilators, possible. The application of ECLS is now being extended to premature and low-birth weight infants as well as older children and adults.

The efficacy of extracorporeal life support in premature and low birth weight newborns.

Based on data obtained early in the development of neonatal extracorporeal life support (ECLS), contraindications to the use of ECLS have included low estimated gestational age (EGA) and low birth weight (BW). However, multiple improvements in the technical and management aspects of neonatal ECLS have been implemented since those early data were evaluated. The purpose of this study, therefore, is to assess in the "modern era" the efficacy of prolonged extracorporeal support in premature and low birth weight newborns. Examination of the Extracorporeal Life Support Organization (ELSO) Registry showed that between 1988 and 1991 ECLS was utilized in 158 premature (PREM, EGA < or = 34 weeks), 4,128 full-term (FT, EGA > or = 35 weeks), 26 low birth weight (LBW, BW < 2.0 kg), and 4,333 normal birth weight (NBW, BW > or = 2.0 kg) patients with respiratory failure. Data were evaluated for variables thought to be associated with a decrease in survival or an increase in the incidence of intracranial hemorrhage (ICH). A logistic regression model was developed to evaluate the ability of EGA and BW to predict survival. The incidence of survival (SURV) was decreased (63% v 84%) and ICH increased (37% v 14%) significantly in PREM when compared with FT newborns (P < .001). However, respectable survival rates in PREM patients with EGA > 32 weeks were documented. In addition, both survival and ICH in PREM patients have improved substantially when compared with past reports (Past: SURV = 25% and ICH = 100%; current: SURV = 63% and ICH = 37%; ICH P < .001; SURV P = .056). Survival was significantly decreased in LBW when compared to NBW neonates (65% v 83%, P < .05), but there was no significant difference in ICH.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal membrane oxygenation in term newborns. A prospective cost-benefit analysis.

Clinicians reserve ECMO for neonates at > 80% predicted mortality risk. The authors hypothesized that ECMO instituted at lower (50%) mortality risk would result in fewer intensive care unit days and a lower hospital cost compared with conventional therapy (including ECMO at high mortality risk). This was a randomized control trial, cost-benefit analysis in an academic newborn intensive care unit. The patients were a prospectively studied, consecutive sample of 41 term neonates with 1) age 24-72 hours, 2) "maximal medical management" for > 6 hours, 3) oxygenation index (OI) values > 25 but < 40. (Severity of illness measured by OI = ((mean airway pressure x FiO2 x 100) PaO2)). All eligible patients entered. Thirty-two of 37 survivors were evaluated at 1 year. Intervention occurred when OI = 25. Patients were randomized to ECMO or continued medical management (ECMO possible at OI = 40). Planned primary outcome measures were ICU days and hospital charges. Secondary measures were pulmonary and neurologic outcomes at discharge and 1 year. Twenty-two early ECMO patients, 19 controls, 14/19 met late ECMO criteria. Four patients died (two each group). No statistically significant difference was seen in hospital charges (early ECMO = $49,500 versus control = $53,7000), (95% confidence intervals = -$3200 to +$5100 more for controls) or ICU days (early = 14 + 5 days versus control = 19 + 12 days) (95% CI = -0.8 to +10 more for controls). At 1 year the early group had a higher mental developmental index score (115 + 11) versus (103 + 18), (p = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal membrane oxygenation. Will this therapy continue to be as efficacious in the future?

The efficacy of ECMO has been discussed. If only a dichotomous live/die outcome is used as a measure of utility, ECMO is efficacious for infants with a greater than 20% mortality rate. Using a Bayesian approach and neonatal follow-up data, one concludes that ECMO, as used at present, is effective. Future measures of efficacy will vary depending on utility measures used, the populations studied, and the relative efficacy of alternative therapies.

Venovenous extracorporeal membrane oxygenation: early CT alterations following use in management of severe respiratory failure in neonates.

PURPOSE: To describe brain CT alterations occurring after neonatal venovenous extracorporeal membrane oxygenation (V-V ECMO). METHODS: CT studies were prospectively obtained after V-V ECMO in 31 neonates with severe respiratory failure. Images were scored for cerebrospinal fluid space size, hemorrhage, and regions of decreased attenuation. RESULTS: Subarachnoid space enlargement at the interhemispheric fissure, frontal, temporal, or parietal convexity occurred in 21 of the 31 patients. When subarachnoid space enlargement was asymmetric (six of the 21), it was always isolated to or greater on the right. Ventricular enlargement was demonstrated in seven of the 31. Hemorrhage occurred in seven and regions of low brain attenuation in 11 of the 31 neonates. CONCLUSIONS: Increased sagittal sinus pressure caused by internal jugular vein ligation and cannulation of the superior vena cava may contribute to subarachnoid space enlargement by decreasing cerebrospinal fluid resorption at the arachnoid villi. Reduced incidence of cerebral hemorrhage with V-V ECMO, as compared with venoarterial (V-A) ECMO, may relate to sparing of the right common carotid artery (it is ligated with V-A ECMO), and to routing of oxygenated blood to the right atrium with V-V ECMO rather than to the arterial circuit as with V-A ECMO.

Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) may affect the pharmacokinetics of certain drugs. The objectives of this study were to determine (1) the pharmacokinetics of gentamicin in neonates on ECMO and compare them to reported values for a similar patient population not on ECMO, (2) if the pharmacokinetics of gentamicin differ between venous-venous and venous-arterial bypass, and (3) if the pharmacokinetics of gentamicin are affected by oxygenator surface area (0.6 m2 vs 0.8 m2 oxygenators). The medical records of 29 term neonates who received gentamicin while on ECMO were reviewed. Data collected included gentamicin dosage, peak and trough serum concentrations determined at steady state, duration of treatment, time on ECMO, daily weights, and pertinent laboratory values. An initial dosage of gentamicin 2.5 mg/kg every 18 hours is suggested for term neonates on ECMO. Dosage adjustments should be based on gentamicin serum concentrations, and modifications may also be required after ECMO.

Follow-up of infants treated with extracorporeal membrane oxygenation for newborn respiratory failure.

Follow-up studies were conducted to assess the medical and developmental outcome of 92 infants treated with extracorporeal membrane oxygenation at the University of Michigan. Of 118 near-term (greater than 34 weeks' gestation) infants who received extracorporeal membrane oxygenation, 103 (87%) were surviving and available for follow-up at between 1 and 7 years of age. Ninety-two of these children were seen on at least one occasion. Each visit included a history and physical examination, an evaluation by a physical therapist, and developmental testing by a pediatric psychologist. Medical outcome during year 1 found 31% of the children rehospitalized, primarily with respiratory illness. Outpatient-treated lower respiratory tract illness was seen in an additional 31% of the children. New or nonstatic neurologic problems were noted in 6% of the children. Abnormal growth during year 1 occurred in 26% of the children. At last clinic visit 16% of the children exhibited moderate-to-severe neurologic abnormalities, and 8% had moderate-to-severe cognitive delay. Sensorineural hearing loss occurred in 4% of children. Nine percent of the children were receiving speech and language therapy; screening tests showed that an additional 6% had speech and language delay. Overall, at last visit 16 (20%) of the children exhibited some type of handicap. A review of the literature on follow-up studies of non-extracorporeal membrane oxygenation-treated infants with persistent pulmonary artery hypertension produced an impairment rate of 18.5%. Outcome post-extracorporeal membrane oxygenation appears similar to that seen in less ill cohorts of infants treated with more "conventional" therapy. Long-term follow-up of all such infants remains essential.