Accumulation of transforming growth factor-beta2 and nitrated chondroitin sulfate proteoglycans in cerebrospinal fluid correlates with poor neurologic outcome in preterm hydrocephalus.

BACKGROUND: Progressive post-hemorrhagic hydrocephalus in preterm infants strongly predicts abnormal neurologic development, and often accompanies cystic periventricular leukomalacia (cPVL). Transforming growth factor-beta1 (TGF-beta1), associated with hydrocephalus, can upregulate the chondroitin sulfate proteoglycan (CSPG) synthesis. To date, CSPG and their nitrated metabolites (NT-CSPG) have not been evaluated in hydrocephalus. OBJECTIVES: We hypothesized that TGF-beta1, TGF-beta2, CSPG, and NT-CSPG would accumulate in cerebrospinal fluid (CSF) in preterm hydrocephalus, and their concentrations would correlate with poor long-term outcomes. METHODS: TGF-beta1, TGF-beta2, CSPG, and NT-CSPG concentrations in CSF were measured prospectively by ELISA in 29 preterm newborns with (n=22) or without (n=34) progressive post-hemorrhagic hydrocephalus, and correlated with progressive neonatal hydrocephalus and neurologic outcome. Only concentrations from each patient's initial CSF sample were used for statistical analysis. RESULTS: Compared to neonates without hydrocephalus, CSF [TGF-beta1], [TGF-beta2], [CSPG] and [NT-CSPG] were significantly greater by >3-, >35-, >8-, and >3-fold, respectively. Unlike CSF [TGF-beta2] and [CSPG], [TGF-beta1] correlated with CSF [total protein]. Only CSF [NT-CSPG] correlated with cPVL. Unlike [TGF-beta2] or [CSPG], [NT-CSPG] correlation with preterm progressive post-hemorrhagic hydrocephalus (PPHH) was explained entirely by the presence of cPVL among these patients. [TGF-beta2] was >20-fold greater in preterm survivors who required a ventriculoperitoneal shunt for PPHH (n=9), as compared to survivors who did not require a shunt (n=2), or those without hydrocephalus (n=12). [TGF-beta2] and [NT-CSPG] correlated inversely with Bayley Index Scores (15.0 months median adjusted age). CONCLUSIONS: This is the first report that [TGF-beta2], [CSPG], and [NT-CSPG], measured well before term, accumulate abnormally in preterm progressive post-hemorrhagic hydrocephalus CSF, and correlate with adverse neurologic outcome.

Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants?

OBJECTIVE: A wide variability in the incidence of severe retinopathy of prematurity (ROP) is reported by different centers. The altered regulation of vascular endothelial growth factor from repeated episodes of hyperoxia and hypoxia is 1 important factor in the pathogenesis of ROP. Strict management of O(2) delivery and monitoring to minimize these episodes may be associated with decreased rates of ROP. The objective of this study was to compare the incidence of and need for surgery for severe ROP (stages >or=3) in infants of 500 to 1500 g birth weight before and after the implementation of a new clinical practice of O(2) management in a large level 3 neonatal intensive care unit (NICU). METHODS: An oxygen management policy that included strict guidelines in the practices of increasing and weaning of fraction of inspired oxygen (FIO(2)) and the monitoring of O(2) saturation parameters in the delivery room, during in-house transport of infants to the NICU, and throughout hospitalization was implemented in April 1998. The main objectives were to monitor oxygenation levels more precisely and to avoid hyperoxia and repeated episodes of hypoxia-hyperoxia in very low birth weight infants. Included in the policy were equipment for monitoring, initiation of monitoring at birth, avoidance of repeated increases and decreases of the FIO(2), minimization of "titration" of FIO(2), modification of previously used alarm limits, and others. After an educational process, each staff member signed an agreement stating understanding of and future compliance with the guidelines. Examinations were performed by experienced ophthalmologists following international classification and American Academy of Pediatrics recommendations. ROP data from January 1997 to December 2002 for infants of 500 to 1500 g were analyzed as usual and also have been reported to Vermont Oxford Network since 1998. RESULTS: The incidence of ROP 3 to 4 at this center decreased consistently in a 5-year period from 12.5% in 1997 to 2.5% in 2001. The need for ROP laser treatment decreased from 4.5% in 1997 to 0% in the last 3 years. CONCLUSION: We observed a significant decrease in the rate of severe ROP in very low birth weight infants in association with an educational program provided to all NICU staff and the implementation and enforcement of clinical practices of O(2) management and monitoring. Although several confounders cannot be excluded, it is likely that differences in these clinical practices may be, at least in part, responsible for the documented intercenter variability in rates of ROP.

Are tidal volume measurements in neonatal pressure-controlled ventilation accurate?

Bedside pulmonary mechanics monitors (PMM) have become useful in ventilatory management in neonates. These monitors are used more frequently due to recent improvements in data-processing capabilities. PMM devices are often part of the ventilator or are separate units. The accuracy and reliability of these systems have not been carefully evaluated. We compared a single ventilatory parameter, tidal volume (V(t)), as measured by several systems. We looked at two freestanding PMMs: the Ventrak Respiratory Monitoring System (Novametrix, Wallingford, CT) and the Bicore CP-100 Neonatal Pulmonary Monitor (Allied Health Care Products, Riverside, CA), and three ventilators with built-in PMM: the VIP Bird Ventilator (Bird Products Corp., Palm Springs, CA), Siemens Servo 300A (Siemens-Elema AB, Solna, Sweden), and Drager Babylog 8000 (Drager, Inc., Chantilly, VA). A calibrated syringe (Hans Rudolph, Inc., Kansas City, MO) was used to deliver tidal volumes of 4, 10, and 20 mL to each ventilator system coupled with a freestanding PMM. After achieving steady state, six consecutive V(t) readings were taken simultaneously from the freestanding PMM and each ventilator. In a second portion of the bench study, we used pressure-control ventilation and measured exhaled tidal volume (V(te)) while ventilating a Bear Test Lung with the same three ventilators. We adjusted peak inspiratory pressure (PIP) under controlled conditions to achieve the three different targeted tidal volumes on the paired freestanding PMM. Again, six V(te) measurements were recorded for each tidal volume. Means and standard deviations were calculated.The percentage difference in measurement of V(t) delivered by calibrated syringe varied greatly, with the greatest discrepancy seen in the smallest tidal volumes, by up to 28%. In pressure control mode, V(te) as measured by the Siemens was significantly overestimated by 20-95%, with the biggest discrepancy at the smallest V(te), particularly when paired with the Bicore PMM. V(te), as measured by the VIP Bird and Drager paired with the Ventrak PMM, had a tendency to underestimate V(t) by up to 25% at the smallest V(te). However, when paired with the Bicore PMM, these same two ventilators read over target by up to 18%. Under controlled laboratory conditions, we demonstrated that true delivered V(te), as measured by the three ventilators and two freestanding PMM, differed markedly. In general, decreasing dynamic compliance of the tubing was not associated with greater inaccuracy in V(te) measurements.