JoAnn Harrold

Preliminary reference intervals for cystatin C and beta-trace protein in preterm and term neonates ☆

OBJECTIVE To determine the reference intervals for serum cystatin C (CysC) and beta-trace protein (BTP) as markers of renal function in preterm and term neonates. DESIGN AND METHODS Blood samples of 128 neonates (34% female) admitted to the NICU were analyzed to determine the levels of serum creatinine (enzymatically), CysC and BTP (nephelometric, Siemens Health Care). RESULTS The reference intervals, categorized by age, were reported for the 128 neonates. Median (lower/upper limit) BTP were 1.85 (0.57/3.16) and 1.27 (0.51/2.07) mg/L on days 1 and 3. In keeping with maturation of renal function after birth, CysC and BTP fell from days one to day three after birth, whereas creatinine did not. CONCLUSION Our data provides reference intervals for the levels of creatinine, CysC, and BTP in neonates on days 1 and 3 after birth and demonstrates that CysC and BTP reflect neonatal renal function, whereas creatinine reflects maternal renal function.

Killing the Messenger in the Nick of Time: Persistence of Breast Milk sCD14 in the Neonatal Gastrointestinal Tract

Human breast milk contains several proteins that supplement the newborn mucosal defense system and prevent gastrointestinal illnesses. One of these recently identified breast milk proteins is soluble CD14 (sCD14). By being an important component of the lipopolysaccharide (LPS) receptor complex, it has been suggested that breast milk sCD14 could stimulate the newborn immune system and help reduce gastrointestinal Gram-negative infections. However, to deliver its potential immune benefits to the neonate, sCD14 would have to survive the passage through the gastrointestinal tract and retain its biologic activity. We analyzed the presence of breast milk sCD14 in the neonatal digestive system and found breast milk sCD14 to be absent from the stools of breast-fed infants. In vitro digestion analysis with simulated gastric and pancreatic fluids revealed that sCD14 is likely to survive the pepsin digestion but is more prone to been nicked and digested by pancreatin. These findings suggest that the presence of intact breast milk sCD14 in the upper digestive system could promote innate immunity in this low bacteria density lumen. The low concentration of sCD14 in the LPS-rich environment of the distal gastrointestinal tract (i.e. commensal microflora) could prevent excessive inflammation.

β-trace protein may be a more suitable marker of neonatal renal function.

BACKGROUND To determine the relationship between maternal and neonatal cystatin C (CysC) and β-trace protein (BTP), markers of glomerular filtration rate (GFR) on day 1 of life. METHODS Blood levels of CysC, BTP, and creatinine (Cr) were analyzed from 128 healthy term and preterm neonates admitted to the neonatal intensive care unit (NICU) (36% female) to determine the relationship between gestational age and maternal levels on day 1 of life. RESULTS Maternal Cr correlated positively and significantly with neonatal Cr (r = 0.677, p < 0.0001) and CysC (r = 0.246, p < 0.012) on day 1 of life. Maternal BTP did not correlate with neonatal BTP. Gestational age correlated positively and significantly with neonatal Cr (0.427, p < 0.0001), CysC (r = 0.321, p = 0.001); and with maternal Cr (r = 0.452, p < 0.0001), CysC (r = 0.613, p < 0.0001), and BTP (r = 0.442, p < 0.0001). No correlation was found between gestational age and neonatal BTP. Upon considering the following age groups; 24 - 32, 33 - 36, and ≥ 37 weeks, maternal Cr continued to correlate with neonatal Cr, across all age groups, while no correlation was found with BTP, and CysC correlations were no longer significant. Throughout, neonatal values for CysC and BTP were higher, suggesting that low neonatal GFR was the main determinant for the variance. There was no difference in the median neonatal BTP across all age groups. CONCLUSION Maternal Cr and CysC may both cross the placenta while BTP may not. Placental crossing of Cr seems to be independent of gestational age. The reasons for the different placental handling of BTP and CysC remain unknown.

Alpha-Lactalbumin in Human Milk Alters the Proteolytic Degradation of Soluble CD14 by Forming a Complex

Mothers milk represents a foundational step in the proper development of newborn immunity. This is achieved, in part, through the action of numerous regulatory proteins such as soluble cluster of differentiation 14 (sCD14) found in significant quantities in human milk (∼25–50 μg/mL). In adults, CD14 stimulates cytokine production in response to lipopolysaccharide (LPS), the major lipid component found in the outer membrane of Gram-negative bacteria. However, the fate and function of sCD14 in the neonatal gastrointestinal (GI) tract are unknown and may function differently from adults. Therefore, we administered human sCD14 to experimental animals and observed that it persisted in the upper GI tract after feeding. In our search for potential proteolytic protectants, immunoprecipitation of sCD14 from human milk revealed a 15-kD novel protein that copurified with sCD14. Mass spectrometry analysis of the protein identified alpha-lactalbumin. CD14 was also identified by immunoblot after immunoprecipitation of alpha-lactalbumin from milk. In vitro digestion assays revealed that purified alpha-lactalbumin decreases the proteolytic degradation of human milk derived sCD14 in vitro, suggesting a mechanism by which this key LPS receptor may remain functional in the neonate gut.

Evidence-based neonatology: making a difference beyond discharge from the neonatal nursery.

The number of controlled clinical trials in neonatal medicine has increased steadily over recent years. However, most of these trials examine only short-term outcomes during the initial hospital stay. To determine whether a common neonatal intervention does more good than harm, it is important to study its long-term efficacy and safety. This review summarizes randomized trials of neonatal therapies published between October 2000 and September 2001. Only trials that examine outcomes beyond the initial hospital discharge were considered. Four beneficial interventions were identified: promotion of breast-feeding, comprehensive follow-up care for high-risk, very low birthweight infants, cryotherapy for threshold retinopathy of prematurity, and extracorporeal membrane oxygenation for mature infants with severe respiratory failure. Indomethacin prophylaxis in extremely low birthweight infants is of questionable use. Thyroxine supplementation for premature infants and head cooling for asphyxiated term infants require further study and should not be prescribed outside of rigorous clinical trials.

Examining the effects of a targeted noise reduction program in a neonatal intensive care unit

Objectives To determine whether implementation of a noise reduction policy followed by the addition of direct audit and feedback reduces noise levels in a tertiary-level neonatal intensive care unit (NICU). Study design Noise level data was collected in three phases: (1) baseline (preintervention), (2) immediately postimplementation of our noise reduction policy, (3) postunveiling of direct audit and feedback mechanism. Setting A level 3 NICU in Ontario, Canada. Interventions Noise reduction policy and a direct audit and feedback mechanism. Main outcome measures Average noise level. Results The baseline level of noise in our unit consistently exceeds guidelines with an average baseline noise of 49 dB (±1.4). Our intervention resulted in a significant reduction in noise levels for one of the four areas in our NICU [−1.06 dB (−1.52, −0.6)], with a trend towards reduction in a second area (−0.21 dB (−0.6, 0.18)). Unexpectedly, two other areas experienced a significant increase in noise (2.05 dB (1.18, 2.94); 0.85 dB (0.11, 1.59)). Conclusions The baseline noise in the NICU consistently exceeds guidelines, but reductions in noise levels are achievable. Nonetheless, more work is needed to find the optimal NICU design and noise reduction strategy.

Reduction of noise in the neonatal intensive care unit using sound-activated noise meters

Objectives To determine if sound-activated noise meters providing direct audit and visual feedback can reduce sound levels in a level 3 neonatal intensive care unit (NICU). Design/methods Sound levels (in dB) were compared between a 2-month period with noise meters present but without visual signal fluctuation and a subsequent 2 months with the noise meters providing direct audit and visual feedback. Results There was a significant increase in the percentage of time the sound level in the NICU was below 50 dB across all patient care areas (9.9%, 8.9% and 7.3%). This improvement was not observed in the desk area where there are no admitted patients. There was no change in the percentage of time the NICU was below 45 or 55 dB. Conclusions Sound-activated noise meters seem effective in reducing sound levels in patient care areas. Conversations may have moved to non-patient care areas preventing a similar change there.

Effects of Targeting Higher or Lower Oxygen Saturations in Centers with More Versus Less Separation between Median Saturations.

Subgroup analysis of the Canadian Oxygen Trial to compare outcomes of extremely preterm infants in centers with more versus less separation between median arterial oxygen saturations in the two target ranges. Centers with more separation observed lower rates of death or disability in the 85%-89% range than in the 91%-95% target range.

A mixed methods evaluation of the maternal-newborn dashboard in Ontario: dashboard attributes, contextual factors, and facilitators and barriers to use: a study protocol

BackgroundThere are wide variations in maternal-newborn care practices and outcomes across Ontario. To help institutions and care providers learn about their own performance, the Better Outcomes Registry & Network (BORN) Ontario has implemented an audit and feedback system, the Maternal-Newborn Dashboard (MND), for all hospitals providing maternal-newborn care. The dashboard provides (1) near real-time feedback, with site-specific and peer comparison data about six key performance indicators; (2) a visual display of evidence-practice gaps related to the indicators; and (3) benchmarks to provide direction for practice change. This study aims to evaluate the effects of the dashboard, dashboard attributes, contextual factors, and facilitation/support needs that influence the use of this audit and feedback system to improve performance. The objectives of this study are to (1) evaluate the effect of implementing the dashboard across Ontario; (2) explore factors that potentially explain differences in the use of the MND among hospitals; (3) measure factors potentially associated with differential effectiveness of the MND; and (4) identify factors that predict differences in hospital performance.Methods/designA mixed methods design includes (1) an interrupted time series analysis to evaluate the effect of the intervention on six indicators, (2) key informant interviews with a purposeful sample of directors/managers from up to 20 maternal-newborn care hospitals to explore factors that influence the use of the dashboard, (3) a provincial survey of obstetrical directors/managers from all maternal-newborn hospitals in the province to measure factors that influence the use of the dashboard, and (4) a multivariable generalized linear mixed effects regression analysis of the indicators at each hospital to quantitatively evaluate the change in practice following implementation of the dashboard and to identify factors most predictive of use.DiscussionStudy results will provide essential data to develop knowledge translation strategies for facilitating practice change, which can be further evaluated through a future cluster randomized trial.

Free thyroxine and thyroid-stimulating hormone reference intervals in very low birth weight infants at 3-6 weeks of life with the Beckman Coulter Unicel DxI 800.

OBJECTIVES To establish reference intervals for thyroid stimulating hormone (TSH) and free thyroxine (FT4) at 3-6 weeks of age in very low birth weight (VLBW) infants with the Beckman Coulter Unicel DxI 800 by gender, birth weight (BW) and gestational age (GA) subgroups. DESIGN AND METHODS A 4 year retrospective cohort of 308 VLBW infants (GA=27.9 weeks, BW=992.3g) was studied. All blood samples for TSH and FT4 were analyzed using the modified fTSH2 (TSH) and two-step competitive enzyme immunoassay (FT4). Reference intervals were evaluated according to the most recent Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS The study provides non-parametric 95% reference intervals with associated 90% confidence intervals for FT4 and TSH derived from 308 infants screened at a median of 31 days. The reference intervals for this population are TSH=1.14-11.04 mIU/L and FT4=10.9-21.4 pmol/L. TSH statistically differed according to birth weight (<1000 g vs 1000-1499 g) while FT4 differed according to gender and gestational age at time of testing (<32 weeks vs ≥ 32 weeks); however, these differences were not clinically significant and a single reference interval for each analyte is reported. CONCLUSION The results of this study highlight the importance and complexity of establishing appropriate reference intervals for thyroid function testing for the preterm population.