Joseph B. Philips

Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants

BACKGROUND Septicemia is a major antecedent of morbidity and mortality in very low birth weight (501- to 1500-g) infants. Our purpose was to determine prospectively the incidence, clinical presentation, laboratory features, risk factors, morbidity and mortality associated with late onset septicemia in infants 501 to 1500 g. METHODS Clinical data were prospectively collected for 2416 infants enrolled in a multicenter trial to determine the efficacy of intravenous immunoglobulin in preventing nosocomial infections. Septicemia was confirmed by positive blood culture in 395 symptomatic infants. Multivariate analyses of factors associated with septicemia were performed. RESULTS Sixteen percent of VLBW infants developed septicemia at a median age of 17 days. Factors associated with septicemia by logistic regression included male gender, lower gestational age and birth weight and decreased baseline serum IgG concentrations. Increasing apnea (55%), feeding intolerance, abdominal distension or guaiac-positive stools (43%), increased respiratory support (29%), lethargy and hypotonia (23%) were the dominant presenting features of septicemia. An abnormal white blood cell count (46%), unexplained metabolic acidosis (11%) and hyperglycemia (10%) were the most common laboratory indicators. Septicemic infants, compared with nonsepticemic infants, had significantly increased mortality (21% vs. 9%), longer hospital stay (98 vs. 58 days) and more serious morbidity, including severe intraventricular hemorrhage, bronchopulmonary dysplasia and increased ventilator days (P < 0.001). CONCLUSIONS Late onset septicemia is common in very low birth weight infants, and the rate is inversely proportional to gestational age and birth weight. Septicemia is more common in males and those with low initial serum IgG values. A set of clinical signs (apnea, bradycardia, etc.) and laboratory values (leukocytosis, immature white blood cells and neutropenia) increase the probability of late onset sepsis, but they have poor positive predictive value.

A Randomized, Controlled Trial of Very Early Prophylactic Ligation of the Ductus Arteriosus in Babies Who Weighed 1000 g or Less at Birth

We speculated that prophylactic ligation of the ductus arteriosus would reduce mortality and morbidity in very-low-birth-weight infants. To test this hypothesis, we randomly assigned 84 babies who weighed 1000 g or less at birth and required supplemental oxygen either to receive standard treatment (n = 44) or to undergo prophylactic surgical ligation of the ductus arteriosus on the day of birth (n = 40). The ductus was ligated in babies in the control group only if the shunt was hemodynamically important. All the babies were followed for one year. The incidence of necrotizing enterocolitis was reduced in the group that underwent prophylactic ligation (3 of 40 [8 percent]) as compared with the control group (13 of 44 [30 percent]; P = 0.002). The frequency of death, bronchopulmonary dysplasia, retinopathy of prematurity, and intraventricular hemorrhage was similar in both groups. Because early enteral feeding may have increased the incidence of necrotizing enterocolitis, we analyzed separately the babies who were fed early. Among the infants who were fed within 14 days of birth, those who underwent prophylactic ligation had a lower incidence of necrotizing enterocolitis (1 of 11 [9 percent]) than those who did not (13 of 24 [54 percent]; P = 0.001). Within the control group, the infants who were fed within 14 days of birth and whose ductus was ligated for medical reasons within 5 days of birth had a lower incidence of necrotizing enterocolitis (2 of 10 [20 percent]) than those whose ductus was ligated later or not at all (11 of 14 [79 percent]; P = 0.004). We conclude that early surgical closure of the ductus arteriosus reduces the risk of necrotizing enterocolitis in infants of very low birth weight who require supplemental oxygen.

A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants

BACKGROUND Nosocomial infections are a major cause of morbidity and mortality in premature infants. As a rule, their low serum gamma globulin levels at birth subsequently decline to hypogammaglobulinemic values; hence, prophylactic administration of intravenous immune globulin may reduce the rate of hospital-acquired infections. METHODS In this prospective, multicenter, two-phase controlled trial, 2416 infants were stratified according to birth weight (501 to 1000 g and 1001 to 1500 g) and randomly assigned to an intravenous immune globulin group (n = 1204) or a control group (n = 1212). Control infants were given placebo infusions during phase 1 of the study (n = 623) but were not given any infusions during phase 2 (n = 589). Infants weighing 501 to 1000 g at birth were given 900 mg of immune globulin per kilogram of body weight, and infants weighing 1001 to 1500 g at birth were given a dose of 700 mg per kilogram. The immune globulin infusions were repeated every 14 days until the infants weighed 1800 g, were transferred to another center, died, or were sent home from the hospital. RESULTS Nosocomial infections of the blood, meninges, or urinary tract occurred in 439 of the 2416 infants (18.2 percent): 208 (17.3 percent) in the immune globulin group and 231 (19.1 percent) in the control group (relative risk, 0.91; 95 percent confidence interval, 0.77 to 1.08). Septicemia occurred in 15.5 percent of the immune globulin recipients and 17.2 percent of the controls. During phase 1 the rate of nosocomial infections was 13.4 percent in the immune globulin group and 17.8 percent in the control group; the respective rates during phase 2 were 21.0 percent and 20.4 percent. The predominant organisms included gram-positive cocci (53.0 percent), gram-negative bacilli (22.4 percent), and candida species (16.0 percent). Adverse reactions were rarely observed during the infusions. Immune globulin therapy had no effect on respiratory distress syndrome, bronchopulmonary dysplasia, intracranial hemorrhage, the duration of hospitalization, or mortality. The incidence of necrotizing enterocolitis was 12.0 percent in the immune globulin group and 9.5 percent in the control group. CONCLUSIONS Prophylactic use of intravenous immune globulin failed to reduce the incidence of hospital-acquired infections in very-low-birth-weight infants.

Fatal meconium aspiration syndrome occurring despite airway management considered appropriate

A combined obstetric-pediatric approach to tracheal toilet is said to prevent serious cases of the potentially fatal meconium aspiration syndrome. After delivery of the head a DeLee trap is used to suction the oropharynx and nasopharynx. Immediately following delivery, endotracheal suction is performed in an effort to remove any remaining meconium-stained amniotic fluid. Although routinely using this approach, we continue to have occasional cases of fatal meconium aspiration syndrome. Therefore, we reviewed the outcome of infants born through meconium-stained fluid. During a 5-year period, 1420 (15%) of 9299 live-born infants had meconium-stained fluid. Thirty (2.1%) of these 1420 developed meconium aspiration syndrome and 12 (40%) died; eight received a postmortem examination. Four had unequivocal evidence of meconium aspiration, two had large numbers of intra-alveolar squamous cells, and two had no evidence of aspiration. We conclude that aggressive airway management during and immediately after delivery does not always prevent fatal meconium aspiration syndrome.

A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome

OBJECTIVE To compare the efficacy of two surfactants, Exosurf Neonatal (Burroughs Wellcome Co.) and Survanta (Ross Laboratories), for the treatment of neonatal respiratory distress syndrome. DESIGN Multicenter randomized trial. SETTING Eleven tertiary care university neonatal intensive care units participating in the National Institute of Child Health and Human Development Neonatal Research Network. PATIENTS Newborn infants (n = 617) weighing 501 to 1500 gm with respiratory distress syndrome who were receiving assisted ventilation with 30% oxygen or more within 6 hours of birth were enrolled between January 1991 and January 1992. INTERVENTIONS Infants were randomly assigned to receive up to four intratracheal doses of either Exosurf Neonatal (n = 309) or Survanta (n = 308). MAIN OUTCOME MEASURES The occurrence of death or bronchopulmonary dysplasia 28 days after birth and the average fraction of inspired oxygen (FIO2) and mean airway pressure (MAP) during the first 72 hours after treatment. RESULTS Death or bronchopulmonary dysplasia occurred in 67% of the infants in the Exosurf group and 62% of those in the Survanta group (adjusted relative risk, 1.07; 95% confidence interval, 0.96 to 1.20). During the 72 hours after the first surfactant dose, the average FIO2 (+/- SEM) was 0.50 +/- 0.01 for Exosurf and 0.42 +/- 0.01 for Survanta (difference, 0.08; 95% confidence interval, 0.05 to 0.11); the average MAP (+/- SEM) was 7.64 +/- 0.21 cm H2O for Exosurf and 6.93 +/- 0.21 cm H2O for Survanta (difference, 0.71 cm H2O; 95% confidence interval, 0.13 to 1.29 cm H2O). There was no difference between the groups in the incidence of other neonatal morbidities or in the duration of hospitalization, assisted ventilation, or supplemental oxygen administration. CONCLUSION We found no difference between treatment groups in the incidence of death or bronchopulmonary dysplasia, although we did observe a difference in the initial response to treatment as measured by FIO2 and MAP.

Antibiotic susceptibility profiles for group B streptococci isolated from neonates, 1995-1998

Antibiotic susceptibility profiles were analyzed for 119 invasive and 227 colonizing strains of group B streptococci isolated from neonates at 6 US academic centers. All strains were susceptible to penicillin, vancomycin, chloramphenicol, and cefotaxime. The rate of resistance to erythromycin was 20.2% and to clindamycin was 6.9%. Resistance to erythromycin increased in 1997. Type V strains were more resistant to erythromycin than were type Ia (P=.003) and type Ib (P=.004) strains and were more resistant to clindamycin than were type Ia (P<.001), type Ib (P=.01), and type III (P=.001) strains. Resistance rates varied with geographic region: in California, there were high rates of resistance to erythromycin and clindamycin (32% and 12%, respectively), and low rates in Florida (8.5% and 2.1%, respectively). Penicillin continues to be the drug of choice for treatment of group B streptococcus infection. For women who are penicillin intolerant, however, the selection of an alternative antibiotic should be guided by contemporary resistance patterns observed in that region.

Level of Maternal IgG Anti-Group B Streptococcus Type III Antibody Correlated with Protection of Neonates against Early-Onset Disease Caused by This Pathogen

The present study estimates the level of maternal immunoglobulin (Ig) G anti-group B streptococcus (GBS) type III required to protect neonates against early-onset disease (EOD) caused by this pathogen. Levels of maternal serum IgG anti-GBS type III, measured by enzyme-linked immunosorbent assay, in 26 case patients (neonates with EOD caused by GBS type III) and 143 matched control subjects (neonates colonized by GBS type III who did not develop EOD) of > or = 34 weeks gestation were compared. The probability of EOD decreased with increasing levels of maternal IgG anti-GBS type III (P = .01). Neonates whose mothers had > or = 10 microg/mL IgG anti-GBS type III had a 91% lower risk for EOD, compared with those whose mothers had levels of < 2 microg/mL. A vaccine that induces IgG anti-GBS type III levels of > or = 10 microg/mL in mothers can be predicted to offer a significant degree of protection against EOD caused by this pathogen.

The Role of Patent Ductus Arteriosus Ligation in Bronchopulmonary Dysplasia: Reexamining a Randomized Controlled Trial

OBJECTIVE To reexamine data from a randomized controlled trial of prophylactic ductus ligation to determine whether ligation contributes directly to the development of bronchopulmonary dysplasia (BPD) in extremely low birth weight infants. STUDY DESIGN The control group underwent ligation only if they had development of a symptomatic patent ductus arteriosus (PDA). The Prophylactic Ligation group underwent ligation within 24 hours of birth regardless of the presence or absence of symptoms of a PDA. We hypothesized that the incidence of BPD would be higher in the prophylactic ligation group because more ligations were performed than in the control group. RESULTS Prophylactic ligation significantly increased the incidence of BPD (defined as a supplemental oxygen requirement at 36 weeks postmenstrual age) and the incidence of mechanical ventilation at 36 weeks. The groups were statistically similar in gestation, sex, race, fluid administration, intraventricular hemorrhage, pulmonary air leaks, and survival to 36 weeks. The lower incidence of BPD in the control group occurred despite the fact that the incidence of necrotizing enterocolitis (a known risk factor for BPD) was significantly elevated in the control group. Only infants who had previously undergone a PDA ligation had development of BPD in the control group. CONCLUSION Prophylactic ligation, while eliminating the PDA, increases the risk for BPD.

Level of Maternal Antibody Required to Protect Neonates against Early-Onset Disease Caused by Group B Streptococcus Type Ia: A Multicenter, Seroepidemiology Study

Because of the difficulty of conducting efficacy trials of vaccines against group B streptococcus (GBS), the licensure of these vaccines may have to rely on studies that measure vaccine-induced antibody levels that correlate with protection. This study estimates the level of maternal antibody required to protect neonates against early-onset disease (EOD) caused by GBS type Ia. Levels of maternal serum IgG GBS Ia antibodies, measured by ELISAs in 45 case patients (neonates with EOD caused by GBS Ia) and in 319 control subjects (neonates colonized by GBS Ia but without EOD) born at > or =34 weeks gestation were compared. The probability of developing EOD declined with increasing maternal levels of IgG GBS Ia antibody (P = .03). Neonates whose mothers had levels of IgG GBS Ia antibody > or =5 microg/mL had an 88% lower risk (95% confidence interval, 7%-98%) of developing type-specific EOD, compared with those whose mothers had levels < 0.5 microg/mL. A vaccine that induces IgG GBS Ia antibody levels > or =5 microg/mL in mothers can be predicted to confer a high degree of type-specific immunity to EOD to their infants.

Capsular Polysaccharide Types of Group B Streptococcal Isolates from Neonates with Early-Onset Systemic Infection

The distribution of serotypes of group B streptococci (GBS) isolated from 67 infants with early-onset sepsis are described. Case-infants were assembled from 13 hospitals across the United States from 15 July 1995 to 5 February 1997 through prospective active surveillance. The distribution of GBS serotypes was Ia, 40%; Ib, 9%; II, 6%; III, 27%; V, 15%; and nontypeable, 3%. Type V occurred more frequently in the northeast region (New York and New Jersey) than in other regions (29% vs. 9%, P = .06). Conversely, type III occurred significantly less frequently in the northeast region than other regions (10% vs. 35%, P = .04). GBS types Ia, III, and V accounted for 82% of the isolates. This report supports previous observations about the emergence of GBS type V, but our data caution that conclusions about serotype distributions based on one geographic location or on a small number of patients may not be generally applicable. Continued monitoring seems necessary for the design of a GBS vaccine.