Beverly S. Brozanski

Hemodynamic disturbances in premature infants born after chorioamnionitis: Association with cord blood cytokine concentrations

Chorioamnionitis and elevated cord blood inflammatory cytokine concentrations are associated with detectable disturbances of systemic and cerebral hemodynamics in premature newborns. Fifty-five infants (25–31 wk gestation) were enrolled. Chorioamnionitis was defined by placental histology. IL-6, IL-1β, and tumor necrosis factor-α were quantified by ELISA. Blood pressure, heart rate, cardiac output, stroke volume, fractional shortening, and middle cerebral artery blood flow velocities were measured at 3 ± 1 h after birth. Chorioamnionitis was evident in 22 placentas and was associated with increased IL-6 (p < 0.001), IL-1β (p = 0.035), and heart rate (p = 0.027); and with decreased mean and diastolic blood pressure (p = 0.026 and p = 0.019, respectively). IL-6 concentration correlated inversely with systolic, mean, and diastolic blood pressures. Right ventricular cardiac output was elevated (p = 0.028) in infants with fetal vessel inflammation. Maternal temperature ≥38.0°C and newborn immature-to-total white blood cell ratio ≥0.4 were associated with significant decreases in left ventricular fractional shortening (p = 0.001 and p = 0.005, respectively). Neither chorioamnionitis nor elevated cytokine concentrations were associated with changes in middle cerebral artery Doppler blood flow velocities. Chorioamnionitis and elevated cord blood IL-6 concentrations are associated with decreased blood pressure in premature newborns. Inflammation of the fetal vessels and nonspecific indicators of infection are associated with disturbances in cardiac function. Infants with chorioamnionitis and elevated cytokine concentrations do not manifest changes in cerebral Doppler indices within the first few postnatal hours. We speculate that cytokine-associated systemic hemodynamic disturbances in premature infants born after chorioamnionitis predispose such infants to perinatal brain injury.

Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant

We conducted a prospective, randomized, double-blind trial to assess the efficacy and safety of pulse doses of dexamethasone on survival without supplemental oxygen in very low birth weight infants at high risk of having chronic lung disease. Seventy-eight infants with birth weights < or = 1500 gm who were ventilator dependent at 7 days of postnatal age were randomly assigned to receive pulse doses of dexamethasone, 0.5 mg/kg per day, divided twice daily (n = 39), or an equivalent volume of saline solution placebo (n = 39), for 3 days at 10-day intervals until they no longer required supplemental oxygen or assisted ventilation, or reached 36 weeks of postmenstrual age. At study entry, the groups did not differ by birth weight, gestational age, or severity of lung disease. At 36 weeks of postmenstrual age, there was both a significant increase in survival rates without oxygen supplementation (p = 0.03) and a significant decrease in the incidence of chronic lung disease (p = 0.047) in the group that received pulse therapy. Supplemental oxygen requirements were less throughout the study period in the group that received repeated pulse doses of dexamethasone (p = 0.013). The total numbers of deaths and the durations of supplemental oxygen, ventilator support, and hospital stay did not differ between groups. Recorded side effects in the pulse therapy group were minimal and included an increase in the use of insulin therapy for hyperglycemia (p < 0.05). We conclude that in this population of very low birth weight infants, treatment with pulse doses of dexamethasone resulted in improvement in pulmonary outcome without clinically significant side effects.

A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis

BACKGROUND: Pagibaximab, a human chimeric monoclonal antibody developed against lipoteichoic acid, was effective against staphylococci preclinically and seemed safe and well tolerated in phase 1 studies. OBJECTIVE: To evaluate the clinical activity, pharmacokinetics, safety, and tolerability of weekly pagibaximab versus placebo infusions in very low birth weight neonates. PATIENTS AND METHODS: A phase 2, randomized, double-blind, placebo-controlled study was conducted at 10 NICUs. Patients with a birth weight of 700 to 1300 g and 2 to 5 days old were randomly assigned to receive 3 once-a-week pagibaximab (90 or 60 mg/kg) or placebo infusions. Blood was collected for pharmacokinetics, bacterial killing, and safety analyses. Adverse event and clinical outcome data were collected. RESULTS: Eighty-eight patients received pagibaximab at 90 (n = 22) or 60 (n = 20) mg/kg or placebo (n = 46). Groups were not different in demography, mortality, or morbidity. Pagibaximab demonstrated linear pharmacokinetics, a 14.5-day half-life, and nonimmunogenicity. Definite staphylococcal sepsis occurred in 0%, 20%, and 13% (P < .11) and nonstaphylococcal sepsis occurred in 0%, 10%, and 15% (P < .15) of patients in the 90 mg/kg, 60 mg/kg, and placebo groups, respectively. In all patients with staphylococcal sepsis, estimated or observed pagibaximab levels were <500 μg/mL (target level) at infection. CONCLUSIONS: Three once-a-week 90 or 60 mg/kg pagibaximab infusions, in high-risk neonates, seemed safe and well tolerated. No staphylococcal sepsis occurred in infants who received 90 mg/kg. Target levels were only consistently achieved after 2 to 3 doses. Dose optimization should enhance protection.

Antimicrobial Prophylaxis for Cesarean Delivery Before Skin Incision

OBJECTIVE: To estimate the effect of a hospital-wide change in the timing of antimicrobial prophylaxis in cesarean deliveries on maternal and neonatal infections. METHODS: In November 2004, our institution instituted guidelines recommending that the administration of antimicrobial prophylaxis for cesarean delivery be administered before skin incision rather than after umbilical-cord clamping. We reviewed all cesarean deliveries from two time periods. Group 1 received antibiotics after umbilical-cord clamping (July 2002 to November 2004). Group 2 received antibiotics before skin incision (June 2005 to August 2007). Rates of maternal and neonatal infectious complications were compared between groups. RESULTS: There were 4,229 cesarean deliveries in group 1 and 4,781 cesarean deliveries in group 2. Compared with women receiving antimicrobial prophylaxis after umbilical-cord clamping, those administered antimicrobial prophylaxis before skin incision had lower rates of postpartum endometritis (2.2% compared with 3.9%) and wound infection (2.5% compared with 3.6%). After multivariable logistic regression, antimicrobial prophylaxis before skin incision remained associated with lower rates of endometritis (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.47–0.79) and wound infection (OR 0.70, 95% CI 0.55–0.90). Antimicrobial prophylaxis before skin incision had no adverse effect on neonatal infection rates or on the evaluation of the neonate. CONCLUSION: Antimicrobial prophylaxis before skin incision, compared with after cord clamping, resulted in lower rates of maternal infections and had no effect on neonatal infections. Antimicrobial prophylaxis for cesarean delivery should occur before skin incision, consistent with basic tenets of surgical antimicrobial prophylaxis. LEVEL OF EVIDENCE: II

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 &mgr;g/mL for 50% of the dose interval and >2 &mgr;g/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148). Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

Low blood pressure among very-low-birth-weight infants with fetal vessel inflammation

OBJECTIVE: To test the hypothesis that fetal vessel inflammation (FVI: funisitis and/or fetal vasculitis) is associated with lower blood pressure (BP) over the first week of life and an increased risk of periventricular leukomalacia (PVL) among premature infants.STUDY DESIGN: A total of 255 infants born at <1350 g to normotensive mothers were stratified by gestational age (GA) and grouped by presence/absence of FVI on placental pathology. Daily highest (Hi) and lowest (Lo) systolic BP (BPsys), mean BP (BPmn) and diastolic BP (BPdia) over first 7 days of life were analyzed by repeated measures ANOVA and regression analysis. Cranial ultrasounds were obtained at 2 weeks of life.RESULTS: Infants ≥30 weeks gestation with FVI had lower HiBPsys, HiBPmn, HiBPdia, LoBPsys, LoBPmn and LoBPdia (p<0.001) than did infants without FVI. Infants with PVL (all ≤27 weeks gestation) had lower LoBPmn and LoBPdia (p<0.01) than controls. FVI did not increase the risk of PVL in these infants.CONCLUSION: FVI and PVL are associated with reduced BP over the first week of life.

Postnatal development of phrenic motoneurons in the cat

The postnatal growth of phrenic motoneurons in the cat was studied using retrograde transport of horseradish peroxidase (HRP). The mean somal surface area of these developing motoneurons increased 2.5 times from day 3 to adult while the mean somal volume increased four-fold. This change in mean somal surface area during postnatal development was found to be correlated with the change in mean axonal conduction velocity measured from phrenic motoneurons.

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections.

BACKGROUND Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections. METHODS Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score. RESULTS Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%. CONCLUSIONS Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success. CLINICAL TRIALS REGISTRATION NCT00621192.

Use of polymerase chain reaction as a diagnostic tool for neonatal sepsis can result in a decrease in use of antibiotics and total neonatal intensive care unit length of stay

Objective:To retrospectively determine if a negative 16S ribosomal RNA (rRNA) polymerase chain reaction (PCR) (PCR(−)) could lead to a decrease in the number of antibiotic doses and neonatal intensive care unit (NICU) length of stay (LOS) for infants admitted to the NICU for presumed early-onset sepsis (EOS) with negative blood culture results (BC(−)).Study design:Analysis included 419 infants, greater than 35 weeks gestational age, with PCR(−), BC(−) and LOS>48 h. Both the investigators and clinical care team were unaware of the PCR results. The actual number of antibiotic doses (AAD) administered was compared to an estimated number of antibiotics doses (EAD) that would have been given until PCR(−) results were available by 18 h. The number of antibiotic doses saved was calculated as (AAD−EAD). The actual NICU LOS in hours (aLOS) for a subset of infants who remained in the hospital primarily for antibiotic therapy was compared to an estimated LOS (eLOS) if infants with PCR(−) were discharged from the NICU when clinically stable. The number of hours saved was calculated as (aLOS−eLOS).Results:Approximately eight antibiotic doses and 85 NICU hours per infant could be saved using PCR(−) results available at 18 h.Conclusions:Use of 16S rRNA PCR could decrease the number of antibiotics doses and NICU LOS for infants admitted for EOS. This may facilitate: (1) earlier NICU discharge; (2) parental satisfaction; and (3) decreased health care costs.

Prophylactic Indomethacin Reduces Grades III and IV Intraventricular Hemorrhages when Compared to Early Indomethacin Treatment of a Patent Ductus Arteriosus

OBJECTIVE: To determine the relative risk of severe intraventricular hemorrhage (IVH) between two very early indomethacin treatment strategies.STUDY DESIGN: Retrospective chart review of infants <29 weeks gestation and <1350 g who received either indomethacin prophylaxis or very early echocardiography with indomethacin treatment only if the ductus arteriosus was patent.RESULTS: A total of one hundred and two infants received prophylactic indomethacin (pINDO). Echochardiography was performed on 158 infants, of whom 117 received indomethacin. Infants receiving pINDO had lower gestational age, but similar birth weight, gender, race, antenatal steroid exposure, delivery mode, Apgar scores, and need for resuscitation as infants evaluated by echocardiography. Grades III to IV IVH was observed less frequently in infants who received pINDO (OR 0.27, 95% CI 0.10 to 0.77, p=0.014). Frequency of side effects and recurrent patent ductus arteriosus did not differ between treatment groups.CONCLUSION: pINDO reduces severe IVH when compared to an early echocardiography strategy.