Ronald S. Cohen

Once-daily gentamicin dosing in newborn infants

Objective. We developed a simplified gentamicin dosing protocol for all neonates using a loading dose and once-daily dosing that would have an equal or lower incidence of toxicity and an equal or improved effectiveness compared with a regimen with no loading dose that included use of divided daily dosing. Methods. All neonatal intensive care unit patients with a postnatal age ≤7 days and started on gentamicin therapy at the discretion of the attending neonatologist were evaluated in this comparative cohort study. All peak and trough serum drug levels (SDL), pertinent demographic data, and markers of potential nephrotoxicity, ototoxicity, and cure were tracked prospectively during 132 consecutive, nonrandomized courses of therapy on a new gentamicin protocol. These were compared with data retrieved retrospectively throughout 103 consecutive, nonrandomized courses of therapy in a control group. Results. Initial measured peak SDL were higher (7.8 ± 1.1 μg/mL vs 6.1 ± 1.0 μg/mL) and trough SDL were lower (0.9 ± 0.2 μg/mL vs 2.7 ± 0.6 μg/mL) in the protocol term subset, compared with the control term subset (gestational age, ≥37 weeks; weight, ≥2500 g). One hundred percent of the initial and maintenance peak SDL in term protocol neonates were 5 to 12 μg/mL; compared with 84% of the initial and 61% of maintenance peak SDL in the term control group. One hundred percent of the initial and maintenance trough SDL were in the desired range of <2 μg/mL in term protocol neonates; compared with 70% of the initial and 94% of maintenance trough SDL in the term control group. No significant differences were found in any SDL in low birth weight neonates (gestational age <37 weeks or weight <2500 g and >1500 g) in the protocol compared with the control group. The very low birth weight (weight <1500 g) protocol neonates had a significantly higher mean initial trough SDL (2.3 ± 0.7 μg/mL vs 1.5 ± 0.6 μg/mL) and a lower incidence of initial trough SDL <2.0 μg/mL (30% vs 95%) than very low birth weight neonates in the control group. No differences were seen between groups in incidence of significant rise in serum creatinine or failure of hearing screen. Conclusion. A loading dose followed by once-daily dosing was shown to result in SDL in the safe and therapeutic range in all term neonates in this study. In low birth weight neonates, this regimen resulted in peak and trough SDL throughout therapy that were similar to those observed in the control group. Delaying the initiation of maintenance once-daily dosing until 36 to 48 hours after the loading dose would be expected to result in a higher incidence of initial trough SDL in target range for very low birth weight neonates.

Improved outcomes with a standardized feeding protocol for very low birth weight infants.

Objective:The objective of this study was to evaluate the impact of a standardized enteral feeding protocol for very low birth weight (VLBW) infants on nutritional, clinical and growth outcomes.Study Design:Retrospective analysis of VLBW cohorts 9 months before and after initiation of a standardized feeding protocol consisting of 6–8 days of trophic feedings, followed by an increase of 20 ml/kg/day. The primary outcome was days to reach full enteral feeds defined as 160 ml/kg/day. Secondary outcomes included rates of necrotizing enterocolitis and culture-proven sepsis, days of parenteral nutrition and growth end points.Result:Data were analyzed on 147 VLBW infants who received enteral feedings, 83 before (‘Before’) and 64 subsequent to (‘After’) feeding protocol initiation. Extremely low birth weight (ELBW) infants in the After group attained enteral volumes of 120 ml/kg/day (43.9 days Before vs 32.8 days After, P=0.02) and 160 ml/kg/day (48.5 days Before vs 35.8 days After, P=0.02) significantly faster and received significantly fewer days of parenteral nutrition (46.2 days Before vs 31.3 days After, P=0.01). Necrotizing enterocolitis decreased in the After group among VLBW (15/83, 18% Before vs 2/64, 3% After, P=0.005) and ELBW infants (11/31, 35% Before vs 2/26, 8% After, P=0.01). Late-onset sepsis decreased significantly in the After group (26/83, 31% Before vs 6/64, 9% After, P=0.001). Excluding those with weight <3rd percentile at birth, the proportion with weight <3rd percentile at discharge decreased significantly after protocol initiation (35% Before vs 17% After, P=0.03).Conclusion:These data suggest that implementation of a standardized feeding protocol for VLBW infants results in earlier successful enteral feeding without increased rates of major morbidities.

Effect of booster blood transfusions on oxygen utilization in infants with bronchopulmonary dysplasia

To assess the impact of booster transfusions on oxygen utilization in infants with bronchopulmonary dysplasia, we noninvasively measured oxygen consumption (VO2) and the variables of systemic oxygen transport (SOT) before and 24 hours after transfusion therapy in 10 oxygen-dependent infants with bronchopulmonary dysplasia. The infants had been born with a mean gestational age of 27.6 weeks and a mean birth weight of 0.88 kg. Study weight averaged 1.24 +/- 0.35 kg, and study age averaged 5.5 +/- 2.4 weeks. Requirements for fractional concentration of inspired oxygen averaged 0.41 +/- 0.15 to maintain an oxygen saturation of 0.93 +/- 0.02. The VO2 was measured by means of a commercially available analyzer through a flow-through circuit and pump connected to a hood or in line with the ventilator. Cardiac output was calculated by means of pulsed Doppler ultrasonography. Oxygen saturation was measured by means of transcutaneous pulse oximetry. The coefficient of oxygen utilization was calculated as VO2/SOT. Transfusion consisted of packed erythrocytes (10 ml/kg). Oxygen utilization fell in all subjects after transfusion (p less than 0.01), but it fell more substantially in subjects with higher coefficients of oxygen utilization (r = -0.80, p less than 0.01), suggesting a physiologic benefit in selected patients, particularly those with higher levels of oxygen utilization. There was also a significant increase in overall systemic oxygen transport (p less than 0.01) and decrease in VO2 (p less than 0.02). Hemoglobin levels alone did not correlate with overall systemic oxygen transport, VO2, or level of oxygen use before transfusion, and thus did not predict which subjects would have a physiologic benefit from transfusion as reflected by falls in oxygen utilization.

Use of sodium nitroprusside in neonates: efficacy and safety.

Sodium nitroprusside was administered to 58 neonates, including 11 with severe respiratory distress syndrome, 15 with persistent pulmonary hypertension of the newborn, 28 with clinical shock, three with systemic hypertension, and two with pulmonary hypoplasia, all refractory to conventional intensive therapy. Nitroprusside was infused at 0.2 to 6.0 micrograms/kg/min for periods of 10 minutes to 126 hours. Infants with severe respiratory distress syndrome had increased PaO2 and decreased PaCO2 or peak inspiratory pressure, and nearly all (82%) survived. Infants with persistent pulmonary hypertension of the newborn had variable responses; improvement did not correlate with survival, but survival (47%) was identical to that in an earlier series of infants given tolazoline. Infants in shock had improved perfusion, urine output, and serum bicarbonate levels, and these responses were significantly related to survival. Hypertension was controlled in all three hypertensive infants. Adverse effects were very uncommon. Toxic effects were not observed. Sodium nitroprusside is effective and can be used safely in circulatory disorders in the neonate.

Understanding Neonatal Jaundice: A Perspective on Causation

Neonatal jaundice can be best understood as a balance between the production and elimination of bilirubin, with a multitude of factors and conditions affecting each of these processes. When an imbalance results because of an increase in circulating bilirubin (or the bilirubin load) to significantly high levels (severe hyperbilirubinemia), it may cause permanent neurologic sequelae (kernicterus). In most infants, an increase in bilirubin production (e.g., due to hemolysis) is the primary cause of severe hyperbilirubinemia, and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and/or polymorphism. Combining information about bilirubin production and genetic information about bilirubin elimination with the tracking of bilirubin levels means that a relative assessment of jaundice risk might be feasible. Information on the level of bilirubin production and its rate of elimination may help to guide the clinical management of neonatal jaundice.

Impact of Donor Milk Availability on Breast Milk Use and Necrotizing Enterocolitis Rates.

OBJECTIVES: To examine the availability of donor human milk (DHM) in a population-based cohort and assess whether the availability of DHM was associated with rates of breast milk feeding at NICU discharge and rates of necrotizing enterocolitis (NEC). METHODS: Individual patient clinical data for very low birth weight infants from the California Perinatal Quality Care Collaborative were linked to hospital-level data on DHM availability from the Mothers’ Milk Bank of San José for 2007 to 2013. Trends of DHM availability were examined by level of NICU care. Hospitals that transitioned from not having DHM to having DHM availability during the study period were examined to assess changes in rates of breast milk feeding at NICU discharge and NEC. RESULTS: The availability of DHM increased from 27 to 55 hospitals during the study period. The availability increased for all levels of care including regional, community, and intermediate NICUs, with the highest increase occurring in regional NICUs. By 2013, 81.3% of premature infants cared for in regional NICUs had access to DHM. Of the 22 hospitals that had a clear transition to having availability of DHM, there was a 10% increase in breast milk feeding at NICU discharge and a concomitant 2.6% decrease in NEC rates. CONCLUSIONS: The availability of DHM has increased over time and has been associated with positive changes including increased breast milk feeding at NICU discharge and decrease in NEC rates.

Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production

A total of 45 infants, including 20 appropriate-size-for-gestational-age infants (AGAs), 19 large-size-for-gestational-age infants (LGAs) and 6 infants of diabetic mothers (IDMs), had determinations of their pulmonary excretion rate of carbon monoxide (VeCO) in the first postnatal week as an index of bilirubin production. We calculated a ratio (Rw) of birth weight to ideal weight (50th percentile for gestational age) as a relative measure of infant size. We also measured maternal glycosylated hemoglobin (Hb AIc) in the postpartum period as a reflection of the time-integrated blood glucose level over the weeks preceding delivery. Mean values for maternal Hb AIc in the postpartum period, infant Rw, and VeCO were all significantly increased for the LGAs and IDMs compared to the normal AGAs. Nine LGAs had mothers whose Hb AIc levels were >2 S.D. higher than the mean Hb AIc level for mothers of normal AGAs. The infants whose mothers had the highest Hb AIc levels were not always the ones with the highest bilirubin production rates. These findings suggest that maternal Hb AIc in the postpartum period, infant size, and bilirubin production are associated phenomena, but that a postpartum time-integrated measure of blood glucose level over the weeks preceding parturition may not reflect changes in other associated factors which can affect infant erythropoiesis. The LGAs are not a homogeneous group, and some may have mothers with missed abnormalities of gestational glucose metaoblism.

Breath hydrogen analysis: a review of the methodologies and clinical applications.

Hydrogen gas (H2) is a product of the fermentation of dietary carbohydrate (CHO) by bacteria in the lumen of the gastrointestinal tract in man. Thus, H2 is actually an exogenously produced gas, which either is passed as flatus, or diffuses into the body and is exhaled. In the adult, a fairly constant fraction is expired, providing a reliable indicator of total colonic H2 production. Breath H2 analysis currently represents a useful clinical means of testing adults and older children for the malabsorption of CHO. Noninvasive and easy procedures for the collection of expired air have encouraged their increasingly widespread use in pediatrics. Evidence to date suggests that breath H2 analysis may provide the best available method for estimating semiquantitatively the degree of CHO malabsorption. The association of the results of breath H2 analysis with other clinical measures of CHO digestion and absorption is expected, but discrepancies can also be anticipated based on the nature of this particular trace gas method. The interpretation of the results of breath H2 analysis in neonates and young infants remains especially problematic because of confounding variables which are difficult to control and are measured infrequently.

Neonatal Bilirubin Production Estimated from “End-Tidal” Carbon Monoxide Concentration

The relationship between the pulmonary excretion rate of carbon monoxide (VECO) and the concentration of CO, in a sample of breath, drawn through a nasopharyngeal catheter at end-expiration, was assessed in 25 studies of nine preterm and 14 term infants. The VECO and this approximate end-tidal sample of CO (ETCO) correlated significantly over a wide range of CO elimination rates: VECO = 10.45 ETCO + 2.25 (n = 25, r = 0.95). The ETCO correctly predicted elevations in VECO > 2 SD of the mean VECO for normal infants (13.9 ± 3.5 μl/kg/h), with 90% sensitivity and 73% specificity (p < 0.01). Three subjects with Rh isoimmune hemolytic disease were easily identified by the ETCO as well as the VECO. The ETco is a simple, noninvasive measurement for rapidly identifying infants with significant hemolytic disease.

Retrospective review of serological testing of potential human milk donors

Objective To estimate the prevalence of positive serology among potential donors to a human milk bank. Design Retrospective review of our experience with donor serological testing at our milk bank over a 6-year interval. Setting Not-for-profit, regional human milk bank. Patients Volunteer, unpaid potential donors of human milk. Interventions Serological testing for syphilis, HIV, hepatitis B, hepatitis C, human T cell lymphotropic virus type 1 (HTLV-1) and human T cell lymphotropic virus type 2 (HTLV-2). Main outcome measures Results of serological screening tests performed on potential donors. Results Of 1091 potential donors, 3.3% were positive on screening serology, including 6 syphilis, 17 hepatitis B, 3 hepatitis C, 6 HTLV and 4 HIV. Conclusions There is a significant incidence of positive serology among women interested in donating human milk. This implies that there may be significant risk associated with peer-to-peer distribution of human milk from unscreened donors.