Predicting Risk of Infection in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: To predict incident bloodstream infection and urinary tract infection (UTI) in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010-2016. Infants with CDH admitted at 22 participating regional neonatal intensive care units were included; patients repaired or discharged to home prior to admission/referral were excluded. The primary outcome was death or the occurrence of bloodstream infection or UTI prior to discharge. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants. RESULTS: Median gestation and postnatal age at referral in this cohort (n = 1085) were 38 weeks and 3.1 hours, respectively. The primary outcome occurred in 395 patients (36%); and was associated with low birth weight, low Apgar, low admission pH, renal and associated anomalies, patch repair, and extracorporeal membrane oxygenation (P < .001 for all; area under receiver operating curve = 0.824; goodness of fit χ2 = 0.52). After omitting death from the outcome measure, admission pH, patch repair of CDH, and duration of central line placement were significantly associated with incident bloodstream infection or UTI. CONCLUSIONS: Infants with CDH are at high risk of infection which was predicted by clinical factors. Early identification and low threshold for sepsis evaluations in high-risk infants may attenuate acquisition and the consequences of these infections.

A quality improvement initiative standardizing the antibiotic treatment and feeding practices in patients with medical necrotizing enterocolitis.

OBJECTIVE: Evaluate the impact of a multidisciplinary guideline standardizing antibiotic duration and enteral feeding practices following medical necrotizing enterocolitis (mNEC). STUDY DESIGN: For preterm infants with Bell Stage 2 A mNEC and negative blood culture, antibiotic treatment was standardized to 7 days. Trophic feeds of unfortified human milk began 72 h after resolution of pneumatosis. Feeds were advanced by 20 cc/kg/day starting on the last day of antibiotics. Primary outcomes were antibiotic days and days to full feeds, defined as 120 cc/kg/day of enteral nutrition. Secondary outcomes included central line days and length of stay (LOS). RESULTS: Antibiotic duration decreased 23%. Time to start trophic feeds and time to full feeds decreased 33 and 16% respectively. Central line use dropped (98 to 72% of infants) and central line days were reduced by 59%. CONCLUSION: Implementation of a mNEC QI package reduced antibiotic duration, time to full feeds, central line use and CL days.

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.

Gestational Age-Specific Complete Blood Count Signatures in Necrotizing Enterocolitis.

Objective: Necrotizing enterocolitis (NEC) is characterized by peripheral cell abnormalities, yet few studies have analyzed the complete blood count (CBC) specifically by gestational age (GA). Our objective was to describe GA-specific immune abnormalities in NEC through a comprehensive analysis of the CBC differential. Methods: Using a cohort of 246 infants (177 cases, 69 controls) admitted to neonatal intensive care units at a single institution, we retrospectively analyzed CBCs around illness onset in NEC cases compared with controls. Cases included surgical NEC (S-NEC, 34.5%) and medical NEC (M-NEC, 65.5%). Infants were divided into those born at GA <33 and ≥33 weeks. Differences in CBC values were described as absolute and percent changes at NEC onset from baseline and at antibiotic completion after NEC. We used machine learning algorithms based on the CBC at NEC to generate predictive models for diagnosis. Results: At NEC onset, there was an acute drop in monocytes and lymphocytes along with a rise in bands in S-NEC infants born <33 weeks compared with M-NEC. In comparison, both M-NEC and S-NEC ≥33 weeks had a percent drop in neutrophils at diagnosis compared with controls. At antibiotic completion, monocytes in S-NEC <33 weeks significantly rose compared with M-NEC, yet for S-NEC ≥33 weeks, bands significantly dropped compared with M-NEC. Predictive modeling was able to accurately predict S-NEC from M-NEC and controls. Conclusion: There are discrete leukocyte patterns in NEC based on GA. The CBC at diagnosis may be useful in identifying patients who will require surgery.

STEPP IN: Working Together to Keep Infants Warm in the Perioperative Period.

OBJECTIVES: Reduce postoperative hypothermia by up to 50% over a 12-month period in children's hospital NICUs and identify specific clinical practices that impact success. METHODS: Literature review, expert opinion, and benchmarking were used to develop clinical practice recommendations for maintaining perioperative euthermia that included the following: established euthermia before transport to the operating room (OR), standardized practice for maintaining euthermia on transport to and from the OR, and standardized practice to prevent intraoperative heat loss. Process measures were focused on maintaining euthermia during these time points. The outcome measure was the proportion of patients with postoperative hypothermia (temperature ≤36°C within 30 minutes of a return to the NICU or at the completion of a procedure in the NICU). Balancing measures were the proportion of patients with postoperative temperature >38°C or the presence of thermal burns. Multivariable logistic regression was used to identify key practices that improved outcome. RESULTS: Postoperative hypothermia decreased by 48%, from a baseline of 20.3% (January 2011 to September 2013) to 10.5% by June 2015. Strategies associated with decreased hypothermia include >90% compliance with patient euthermia (36.1-37.9°C) at times of OR arrival (odds ratio: 0.58; 95% confidence interval [CI]: 0.43-0.79; P < .001) and OR departure (odds ratio: 0.0.73; 95% CI: 0.56-0.95; P = .017) and prewarming the OR ambient temperature to >74°F (odds ratio: 0.78; 95% CI: 0.62-0.999; P = .05). Hyperthermia increased from a baseline of 1.1% to 2.2% during the project. No thermal burns were reported. CONCLUSIONS: Reducing postoperative hypothermia is possible. Key practices include prewarming the OR and compliance with strategies to maintain euthermia at select time points throughout the perioperative period.

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.

Evaluating the near-term infant for early onset sepsis: progress and challenges to consider with 16S rDNA polymerase chain reaction testing.

Although the rate of early onset sepsis in the near-term neonate is low (one to eight of 1,000 cases), the rate of mortality and morbidity is high. As a result, infants receive multiple, broad-spectrum antibiotic therapy, many for up to 7 days despite blood cultures showing no growth. Maternal intrapartum antibiotic prophylaxis and small blood volume collections from infants are cited as reasons for the lack of confidence in negative culture results. Incorporating an additional, more rapid test could facilitate a more timely diagnosis in these infants. To this end, a 16S rDNA polymerase chain reaction (PCR) assay was compared to blood culturing for use as a tool in evaluating early onset sepsis. Of 1,751 neonatal intensive care unit admissions that were screened, 1,233 near-term infants met inclusion criteria. Compared to culture, PCR demonstrated excellent analytical specificity (1,186 of 1,216, 97.5%) and negative predictive value (1,186 of 1,196, 99.2%); however, PCR failed to detect a significant number of culture-proven cases. These findings underscore the cautionary stance that should be taken at this time when considering the use of a molecular amplification test for diagnosing neonatal sepsis. The experience gained from this study illustrates the need for changes in sample collection and preparation techniques so as to improve analytical sensitivity of the assay.

High surgical burden for infants with severe chronic lung disease (sCLD).

BACKGROUND/PURPOSE: Infants with severe chronic lung disease (sCLD) may require surgical procedures to manage their medical problems; however, the scope of these interventions is undefined. The purpose of this study was to characterize the frequency, type, and timing of operative interventions performed in hospitalized infants with sCLD. METHODS: The Children's Hospital Neonatal Database was used to identify infants with sCLD from 24 children's hospital's NICUs hospitalized over a recent 16-month period. RESULTS: 556 infants were diagnosed with sCLD; less than 3% of infants had operations prior to referral and 30% were referred for surgical evaluation. In contrast, 71% of all sCLD infants received ≥1 surgical procedure during the CHND NICU hospitalization, with a mean of 3 operations performed per infant. Gastrostomy insertion (24%), fundoplication (11%), herniorrhaphy (13%), and tracheostomy placement (12%) were the most commonly performed operations. The timing of gastrostomy (PMA 48±10 wk) and tracheostomy (PMA 47±7 wk) insertions varied, and for infants who received both devices, only 33% were inserted concurrently (13/40 infants). CONCLUSIONS: A striking majority of infants with sCLD received multiple surgical procedures during hospitalizations at participating NICUs. Further work regarding the timing, coordination, perioperative complications, and clinical outcomes for these infants is warranted.

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.

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 µg/mL for 50% of the dose interval and >2 µg/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.

A pulmonary score for assessing the severity of neonatal chronic lung disease.

BACKGROUND: Limited data are available to describe the spectrum of severity of neonatal chronic lung disease. In the multicenter Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial, all infants had some degree of pulmonary dysfunction, because eligibility required a median oxygen saturation of < or =94% with room air. Infants randomized to the supplemental oxygen group (oxygen saturation target of 96-99%) had more pulmonary morbidity than did those in the conventional group (oxygen saturation target of 88-94%). This prompted the retrospective development of a pulmonary severity score to compare the baseline status of the 2 groups. OBJECTIVES: To describe a pulmonary score that reflects the severity of neonatal lung disease and to evaluate the association of the score and its components with subsequent pulmonary morbidity through 3 months of corrected age. DESIGN AND METHODS: A pulmonary score was developed empirically by a consensus panel of 3 neonatologists and was defined as the fraction of inspired oxygen (Fio2) x (support) + (medications), where Fio2 is the actual or "effective" (for nasal cannula) Fio2; support is 2.5 for a ventilator, 1.5 for nasal continuous positive airway pressure, or 1.0 for nasal cannula or hood oxygen; and medications is 0.20 for systemic steroids for bronchopulmonary dysplasia, 0.10 each for regular diuretics or inhaled steroids, and 0.05 each for methylxanthines or intermittent diuretics. The scores could range from 0.21 to 2.95. Pulmonary morbidity was defined as any of the following occurring from randomization at a mean of 35.4 weeks' postmenstrual age through 3 months of corrected age: death or rehospitalization with a pulmonary cause; an episode of pneumonia/sepsis/exacerbation of chronic lung disease; or continued hospitalization, supplemental oxygen therapy, diuretic treatment, or systemic steroid therapy at 3 months. Between-group differences were tested with the Kruskal-Wallis or chi2 test. RESULTS: Data through death or the 3-month corrected age examination were available for 588 infants. Enrolled infants represented a wide spectrum of severity of chronic lung disease, with baseline pulmonary scores at randomization ranging from 0.21 to 2.6. The median pulmonary score at enrollment did not differ between the conventional and supplemental groups (0.42 and 0.45, respectively). However, higher baseline pulmonary scores were observed for infants who did versus did not develop subsequent pulmonary morbidity (0.48 vs 0.38). The pulmonary score was associated with subsequent pulmonary morbidity. Regression analyses adjusting for Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity group assignment, gestational age at birth, race, gender, and postmenstrual age at randomization revealed that the score was a significant independent predictor of subsequent pulmonary morbidity (odds ratio: 7.2; 95% confidence interval: 3.6-14.4). CONCLUSIONS: The pulmonary score, calculated near term, reflects a wide spectrum of bronchopulmonary dysplasia severity and is associated with subsequent pulmonary morbidity through corrected age of 3 months. This simple score could prove useful in clinical and research settings. Validation of the score requires additional study.