An interdisciplinary bronchopulmonary dysplasia program is associated with improved neurodevelopmental outcomes and fewer rehospitalizations.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a pulmonary disease associated with poor neurodevelopmental and medical outcomes. Patients with BPD are medically fragile, at high risk for complications and require interdisciplinary care. We tested the hypothesis that a chronic care approach for BPD would improve neurodevelopmental outcomes relative to the National Institute of Child and Human Development Neonatal Research Network (NICHD NRN) and reduce medical complications. STUDY DESIGN: Infants were followed as inpatients and outpatients. Bayley developmental exams were carried out at 18-24 months of age and compared with the NICHD NRN report. Finally, rates of readmission (a proxy for medical complications) were compared before and after implementation of the Comprehensive Center for BPD (CCBPD). RESULT: Developmental scores obtained in 2007 and 2008 show that 12 and 10% of patients with moderate BPD (n=61) had Bayley Scores <70 for mental and motor indices respectively, whereas corresponding national rates were 35 and 26%. For patients with severe BPD (n=46), 15 and 11% of patients within the CCBPD vs 50 and 42% of national patients scored <70 for mental and motor indices, respectively. Finally, readmission rates dropped from 29% in the year before the implementation of the CCPD (n=269) to 5% thereafter (n=866, P<0.0001). CONCLUSION: The encouraging neurodevelopmental outcomes and readmission rates associated with a chronic care approach to BPD suggest these infants may be best served by a comprehensive interdisciplinary approach to care that focuses on neurodevelopment throughout the hospital stay.

Percutaneous central catheters and peripheral intravenous catheters have similar infection rates in very low birth weight infants.

OBJECTIVE: We performed this study to determine if percutaneous central lines (PCLs) were associated with infection more often than peripherally placed intravenous catheters (PIVs). STUDY DESIGN: We conducted a retrospective, cohort study of 53 infants with PCLs inserted from March 1993 to February 1995 for evidence of catheter-related bloodstream infection and 97 cohorts with PIVs who were matched to the infants with PCLs by admission date and birth weight. We considered an infant to have catheter-related bloodstream infection if bacteremia occurred while the PCL or PIV was in place with no other identifiable infection focus. Statistical analyses were performed by using either Student's t test or the Mann-Whitney U test where appropriate. RESULTS: There were eight infections per 1000 catheter days of PCL use and nine infections per 1000 catheter days of PIV use. CONCLUSION: PCLs do not become infected more often than PIVs.

Nitric oxide supplied from a 10% source provides inhaled therapy without lowering inspired oxygen fraction.

The authors designed a low-deadspace system to deliver inhaled nitric oxide from a high-concentration (10%) source. Nitric oxide, nitrogen dioxide, and O2 concentrations were compared under simulated inhaled nitric oxide therapy (in vitro) from low (0.08%, 800 ppm) and high (10%, 100,000 ppm) sources of nitric oxide in nitrogen. O2 concentrations remained above 99% and nitrogen dioxide below 3 ppm for nitric oxide delivered at dosages up to 180 ppm from the 10% source. An acute toxicity trial (in vivo) was also performed in nine rabbits mechanically ventilated with 100% O2 for four hours. Six rabbits received 80 ppm nitric oxide from a 10% source and three control rabbits received only O2. Nitric oxide, nitrogen dioxide, and O2 concentrations were monitored in the ventilator circuit. Methemoglobin, arterial blood gases, arterial blood pressure, and heart rate were sampled every hour. At the 80-ppm nitric oxide dose, an average of 1.1 +/- 0.2 ppm of nitrogen dioxide was produced within the ventilator circuit. Arterial methemoglobin in rabbits that received nitric oxide rose by 0.5% from baseline, compared with a 0.2% rise for controls (p = 0.001). The authors conclude that inhaled nitric oxide therapy can be provided from a high-concentration source. Because this system does not reduce inspired O2 fraction, it may be more appropriate than low-source-concentration nitric oxide delivery systems for testing the efficacy of inhaled nitric oxide as an adjunct to optimal conventional medical therapy.

Thoracic duct function in fetal, newborn, and adult sheep.

We measured thoracic duct lymph flow rate versus outflow pressure in 7 chronically catheterized adult sheep and in 6 newborn lambs and compared our results to data previously obtained from 10 fetal sheep. In fetal sheep the thoracic duct lymph flow rate was 34.5 +/- 17.2 ml/hr or 11.7 +/- 6.0 ml/kg/hr. Fetal thoracic duct lymph flow deviated from baseline between 8 and 12 torr outflow pressure and lymph stopped at 18 +/- 2.5 torr. In newborn lambs the thoracic duct lymph flow rate was 49.5 +/- 22.0 ml/hr or 7.4 +/- 2.5 ml/kg/hr. The range of outflow pressures over which newborn lymph flow deviated from baseline was between 15 and 18 torr and lymph flow stopped at 26.2 +/- 6.4 torr. Adult sheep thoracic duct lymph flow rate was 130 +/- 74 ml/hr or 2.3 +/- 1.3 ml/kg/hr. Adult lymph flow deviated from baseline between 25 and 35 torr and stopped at an outflow pressure of 41.7 +/- 6.7 torr. The ability of the thoracic duct to return lymph against an outflow pressure improves with maturation. However, lymph flow rate corrected for body weight is greatest in immature animals. The higher corrected lymph flow rate in conjunction with the decreased ability to pump against an outflow pressure may help account for immature animals predisposition for edema.

Antenatal steroids are associated with less need for blood pressure support in extremely premature infants.

OBJECTIVE: To determine if antenatal steroids decrease the amount of blood pressure support required by extremely premature infants between 23 and 27 weeks' gestation. DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital neonatal intensive care unit from January 1986 to December 1991. PARTICIPANTS: Two hundred forty premature infants between 23 and 27 weeks' gestation who survived at least 48 hours. MAIN OUTCOME MEASURES: The amount of blood pressure support received in the form of dopamine and colloid. Secondary analysis investigated differences in mortality, respiratory support requirements, the incidence of intraventricular hemorrhage, necrotizing enterocolitis, infection, retinopathy of prematurity requiring surgery, and the length of hospitalization. RESULTS: During the first 48 hours of life, premature newborns exposed to antenatal corticosteroids were less likely to receive dopamine for blood pressure support (47% vs 67%), and if they did, the amount of dopamine expressed as a dopamine score was less than that received by those infants not exposed to antenatal corticosteroids (281 +/- 240 vs 407 +/- 281). Those exposed to antenatal corticosteroids also had a lower mortality rate (8% vs 24%) and lower respiratory support requirements. The incidence of grade 3 or 4 intraventricular hemorrhage was 8% in infants exposed to antenatal corticosteroids and 17% in infants not exposed. No difference was found in the incidence of necrotizing enterocolitis, infection, or retinopathy of prematurity requiring surgery, or length of hospitalization. CONCLUSION: Receipt of antenatal corticosteroids is associated with less need for blood pressure support during the first 48 hours after birth in premature infants between 23 and 27 weeks' gestation.

Hydrops in fetal sheep from rapid induction of anemia.

We operated on 14 singleton fetal sheep at 126 +/- 3 d gestation and produced nonimmune anemia in 12 of them to study the mechanisms responsible for hydrops. Two fetuses served as controls. Partial exchange transfusions were performed daily to lower the hematocrit while we measured arterial blood gas tensions; Hb concentration; oxygen saturation; arterial oxygen content; aortic, central venous, and umbilical venous pressures; heart rate; plasma protein concentration; and colloid osmotic pressure. Hydrops developed in six of the fetuses and did not develop in six others, although both groups were anemic to the same degree, had similar total amounts of blood withdrawn based on kilograms of dry weight, and had similar dry weights. The fetuses who had hydrops became anemic more rapidly than the nonhydropic fetus (5.2 +/- 1.9 versus 8.3 +/- 2.7 d; p < 0.05) and had more blood exchanged each day (197 +/- 56 versus 113 +/- 28 mL/kg dry body wt/d; p = 0.008). Umbilical venous pressures increased in both hydropic and nonhydropic fetuses, but the central venous pressure became elevated only in the hydropic fetuses. Changes in heart rate, arterial pH and blood gas tensions, arterial oxygen content, plasma protein concentration, colloid osmotic pressure, and aortic pressure were similar in both groups. At autopsy the hydropic fetuses had 78 +/- 47 mL of ascites and 20 +/- 26 mL of pleural fluid. The water content of the hydropic fetuses and of the hydropic fetuses' placentas was greater than that of the nonhydropic fetuses. We conclude that a more rapid development of anemia is associated with hydrops in fetal sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Feasibility of hepatocellular transplantation via the umbilical vein in prenatal and perinatal lambs.

Hepatocellular transplantation has previously been performed in experimental animals by infusion of hepatocyte suspensions into the spleen or portal venous system. Cells injected into these sites flow to the liver and engraft within the hepatic parenchyma. We designed this study to evaluate the feasibility of hepatocellular transplantation through the umbilical vein in the prenatal or perinatal periods. Allogeneic sheep hepatocytes were harvested, stained with the vital fluorescent dye DiI, and injected into the umbilical vein of fetal lambs at 85% gestation and term. Hemodynamic studies performed to assess the physiological impact of transplantation on the recipient animal demonstrated that the procedure was well tolerated. No significant short-term complications were encountered and no lesions were found by conventional histological examination at necropsy 1-17 days after transplantation. Engrafted cells were identified within the liver by fluorescent microscopy and flow cytometry in 4/7 animals constituting 1.2-5% of the hepatocyte population. Fluorescent cellular material with the morphology of hepatocytes, noncellular material, and fluorescent phagocytic cells were seen occasionally in other organs including lung, brain, adrenal, and placenta. These studies demonstrate the feasibility of performing hepatocellular transplantation in the fetus via the umbilical vein in experimental animals.

Thoracic duct lymph flow in fetal sheep with increased venous pressure from electrically induced tachycardia.

The intent of this study was to investigate thoracic duct lymph flow, as it is related to the development of hydrops fetalis during rapid atrial pacing. We studied 6 fetal sheep at 128 +/- 6 days of gestation who had chronically placed thoracic duct catheters, aortic and superior vena cava catheters, and atrial pacing electrodes. Atrial pacing at 317 beats/min caused an elevation in central venous pressure from a baseline value of 3 Torr to 7 Torr without affecting pH, arterial blood gas tensions, aortic blood pressure, total protein concentration, or colloid osmotic pressure, although there was a small rise in hematocrit. The thoracic duct lymph flow rate at baseline was 41 +/- 6 ml/h. After atrial pacing for 6 h, the lymph flow rate as measured over at least three consecutive 10-min intervals, and presumably the transvascular fluid filtration rate, increased to 67 +/- 7 ml/h if it was collected at an outflow pressure of 3 Torr, equal to the venous pressure prior to the onset of atrial pacing. However, if the lymph was collected instead at an outflow pressure of 7 Torr, equal to the actual venous pressure measured with rapid atrial pacing, then the lymph flow rate diminished to 48 +/- 5 ml/h. This difference in lymph flow secondary to the increase in venous pressure could account for a maximum of 19 ml/h of edema that accumulates in fetal interstitium and body cavities with atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of outflow pressure upon thoracic duct lymph flow rate in fetal sheep.

Edema develops when lymph does not return to the venous circulation at a rate equal to the rate of capillary filtration. Fetal sheep develop edema as well as an increased central venous pressure while undergoing atrial pacing at 320 beats per min. We hypothesized that the increased central venous pressure augmented the appearance of fetal edema by impairing the return of thoracic duct lymph to the venous circulation. To investigate this hypothesis, we studied the effect of outflow pressure upon thoracic duct lymph flow in 10 unanesthetized fetal sheep who had low resistance lymph catheters placed in the cervical thoracic duct near its junction with the left jugular vein. After the ewe and fetus recovered for 5 d, we altered the outflow pressure of the lymph catheter by adjusting its height with respect to amniotic fluid pressure and measured the resultant change in thoracic duct lymph flow rate. We found that lymph flow rate was constant over the range of outflow pressures (central venous pressures) normally encountered but decreased in a linear fashion at pressures greater than 0.68 kPa (5.1 torr). Lymph flow stopped at an outflow pressure of 2.40 kPa (18 torr). The data points are best fit by two lines obtained by a piecewise linear regression rather than a single line obtained from a linear regression. We conclude that fetal thoracic duct lymph flow is sensitive to elevations in outflow pressure. Lymph flow begins to diminish at outflow pressures corresponding to central venous pressures commonly encountered in pathologic conditions and may augment the appearance of fetal edema.

Reduction in plasma protein does not affect body water content in fetal sheep.

We performed this study to determine if isolated hypoproteinemia and low colloid osmotic pressure cause formation of fetal edema. We successfully operated on six sets of twin fetal sheep at 114 d gestation to insert catheters into arteries and veins of both fetuses, allowing us to chronically perform partial exchange transfusions. One twin underwent protein reduction by repeated partial exchange transfusion over 3 d, and the other twin underwent simultaneous sham procedures. We removed an average of 18 g of protein, causing a 41% decrease in plasma protein concentration and a 44% decrease in colloid osmotic pressure. Vascular pressures, heart rate, hematocrit, plasma osmolarity, arterial pH, and arterial PO2 were not affected by protein reduction or by sham procedure, whereas PCO2 increased by a small amount in both groups. At autopsy, none of the fetuses in either group were edematous. Measurements of total body water by the wet to dry method, chloride space, and amniotic and allantoic fluid volumes were similar in both groups. We conclude that hypoproteinemia of a short duration does not affect the body water content of fetal sheep.

Biochemical manifestations of oxygen toxicity in the newborn lamb.

The purpose of this project was to study the role of lipid peroxidation in oxygen-induced lung injury in the newborn lamb. It was our hypothesis that injury to the microvascular bed of the lung by oxygen would coincide with a burst of peroxidative activity and would be accompanied by an increased rate of excretion of ethane and pentane in expired gas. We measured vascular pressures, the rate of lung lymph flow and concentrations of ethane and pentane in exhaled gas in 10 newborn lambs that breathed greater than 95% oxygen continuously. Our marker for oxygen-induced lung injury was an increase in the permeability of the microvascular bed of the lung to protein (an increase in the rate of lung lymph flow accompanied by an increase in the protein concentration in lymph). Although all 10 lambs demonstrated an abrupt increase in microvascular permeability to protein within 48 to 96 h of exposure to greater than 95% oxygen, the rates of ethane and pentane excretion remained unchanged throughout the entire experimental period. Lung tissue concentrations of glutathione decreased by 40% in the oxygen-exposed lambs and the concentrations of glutathione disulfide increased 85% relative to air-breathing controls. Activities of glutathione reductase and superoxide dismutase were lower in the lungs of the oxygen-exposed lambs than in controls, whereas the activities of glutathione peroxidase and catalase were not changed. We conclude that, in the lamb, changes in the rates of excretion of ethane and pentane do not correlate with the timing of injury to the microvascular bed of the lung.

Reversal of venous blood flow with atrial tachycardia and hydrops in fetal sheep.

The purpose of this project was to characterize the reversal of blood flow in the proximal inferior vena cava (IVC) seen in fetal sheep with pacing-induced atrial tachycardia and hydrops. We successfully operated on seven pregnant ewes at 118-130 d gestation to attach ECG and pacing wires, insert vascular catheters, and place Doppler flow probes around the common aortic trunk and the IVC. We also performed two-dimensional and Doppler ultrasonographic exams at baseline, after initiation of pacing, and daily thereafter. All fetuses developed hydrops. Ultrasonographic appearance of ascites and pleural effusion occurred within 4 h in four fetuses and within 48 h in all fetuses. Atrial pacing did not affect arterial pH or arterial O2 tension, but arterial CO2 tension increased by a small amount. Mean IVC pressure increased 75%, whereas mean aortic pressure remained the same. Concentrations of plasma protein and albumin and the hematocrit did not change with atrial pacing. Doppler ultrasound examination and Doppler IVC flow tracings showed that flow reversal began immediately with atrial pacing and disappeared immediately with cessation of pacing. Reversed flow was 21% of forward flow. Inspection of simultaneous recordings of ECG, Doppler aortic and IVC flows, and aortic and IVC pressure tracings revealed that the reversed blood flow occurred in diastole in conjunction with atrial contraction and, therefore, could not be due to tricuspid insufficiency. Our findings of increased venous pressure and reversed venous blood flow suggest that ventricular function is impaired and further suggest that oxygen supply to the ventricles may not be sufficient for the increased demand.

Atrial tachycardia causes hydrops in fetal lambs.

The purpose of this project was to study mechanisms responsible for edema formation in fetuses with hydrops. We produced hydrops fetalis in 28 fetal sheep [gestational age of 125 +/- 5 days (mean +/- SD)] by pacing their atria at 300-320 beats/min for 68 +/- 40 (SD) h. All fetuses developed peripheral edema and ascites [volume of ascitic fluid was 134 +/- 75 (SD) ml; total protein concentration was 3.10 +/- 0.6 (SD) g/dl, and total albumin concentration was 1.68 +/- 0.3 (SD) g/dl]. Pacing did not affect aortic pressure but increased venous pressure from 4 +/- 1 to 8 +/- 1 (SE) Torr. Pacing did not affect pH, arterial partial pressure of O2 (PaO2), or Na+ but increased PaCO2 from 53 +/- 1 to 55 +/- 1 (SE) Torr and K+ from 3.9 +/- 0.1 to 4.3 +/- 0.1 (SE) meq/l. Hematocrit increased from 29 +/- 1 to 32 +/- 1 (SE)% acutely with pacing but returned to base line by the last day of the experiment. Plasma protein concentration decreased slightly from 3.7 +/- 0.1 to 3.5 +/- 0.1 (SE) g/dl by the last day of the experiment; plasma albumin concentration did not change. Plasma volume decreased acutely from 271 +/- 19 to 238 +/- 16 (SE) ml and then remained decreased throughout the experiment. Red blood cell mass and the turnover time for albumin were not affected by pacing. We found no consistent relationship between edema formation and changes in arterial blood gas tensions, plasma protein concentrations, or the turnover time for albumin.2

Effects of arginine vasopressin on hemodynamics and lung fluid balance in lambs.

The purpose of this project was to study the effects of increased plasma concentrations of arginine vasopressin (AVP) on hemodynamics and lung fluid balance in lambs. We studied 16 unanesthetized newborn lambs during a base-line period and while infusing AVP into a hindlimb vein at 1.65 +/- 0.12 and 2.98 +/- 0.15 mU.kg-1.min-1. We measured aortic, pulmonary arterial, and left atrial pressures and heart rate continuously and cardiac output at frequent intervals. In five additional experiments, we collected samples of pure lung lymph during a base-line period and while infusing AVP at 2.02 +/- 0.15 mU.kg-1.min-1. AVP infusion increased plasma concentrations of AVP to 11.3 +/- 5.2 and 19.9 +/- 5.2 microU/ml at the low and high rates of infusion, respectively. Both aortic and left atrial pressures increased at the low rate of infusion (11 and 3 Torr, respectively) but remained unchanged at the higher rate. Systemic vascular resistance increased, and heart rate and cardiac output decreased at each rate of infusion. In fact, at the higher rate of infusion cardiac output decreased 38% when compared with base line. Neither pulmonary artery pressure nor pulmonary vascular resistance was affected by infusion of AVP. Despite the increase in left atrial pressure, the rate of lung lymph flow was not affected by the infusion of AVP, whereas the lymph-to-plasma protein ratio decreased slightly but significantly from 0.64 +/- 0.02 to 0.60 +/- 0.02.(ABSTRACT TRUNCATED AT 250 WORDS)

Inspiratory airway obstruction does not affect lung fluid balance in lambs.

The purpose of this study was to examine the effects of inspiratory airway obstruction on lung fluid balance in newborn lambs. We studied seven 2- to 4-wk-old lambs that were sedated with chloral hydrate and allowed to breathe 30-40% O2 spontaneously through an endotracheal tube. We measured lung lymph flow, lymph and plasma protein concentrations, pulmonary arterial and left atrial pressures, mean and phasic pleural pressures and airway pressures, and cardiac output during a 2-h base-line period and then during a 2- to 3-h period of inspiratory airway obstruction produced by partially occluding the inspiratory limb of a nonrebreathing valve attached to the endotracheal tube. During inspiratory airway obstruction, both pleural and airway pressures decreased 5 Torr, whereas pulmonary arterial and left atrial pressures each decreased 4 Torr. As a result, calculated filtration pressure remained unchanged. Inspiratory airway obstruction had no effect on steady-state lung lymph flow or the lymph protein concentration relative to that of plasma. We conclude that in the spontaneously breathing lamb, any decrease in interstitial pressure resulting from inspiratory airway obstruction is offset by a decrease in microvascular hydrostatic pressure so that net fluid filtration remains unchanged.

Hypoxia and angiotensin II infusion redistribute lung blood flow in lambs.

To assess the effects of alveolar hypoxia and angiotensin II infusion on distribution of blood flow to the lung we performed perfusion lung scans on anesthetized mechanically ventilated lambs. Scans were obtained by injecting 1-2 mCi of technetium-labeled albumin macroaggregates as the lambs were ventilated with air, with 10-14% O2 in N2, or with air while receiving angiotensin II intravenously. We found that both alveolar hypoxia and infusion of angiotensin II increased pulmonary vascular resistance and redistributed blood flow from the mid and lower lung regions towards the upper posterior region of the lung. We assessed the effects of angiotensin II infusion on filtration pressure in six lambs by measuring the rate of lung lymph flow and the protein concentration of samples of lung lymph. We found that angiotensin II infusion increased pulmonary arterial pressure 50%, lung lymph flow 90%, and decreased the concentration of protein in lymph relative to plasma. These results are identical to those seen when filtration pressure increases during alveolar hypoxia. We conclude that alveolar hypoxia and angiotensin II infusion both increase fluid filtration in the lung by increasing filtration pressure. The increase in filtration pressure may be the result of a redistribution of blood flow in the lung with relative overperfusion of vessels in some areas and transmission of the elevated pulmonary arterial pressure to fluid-exchanging sites in those vessels.

Oxygen toxicity and other ventilatory complications of treatment of infants with persistent pulmonary hypertension.

While current ventilator therapy has greatly improved the outlook for infants with persistent pulmonary hypertension, it brings with it substantial risk for serious lung injury from oxygen toxicity, barotrauma, and alveolar rupture. This article discusses the mechanisms by which these complications occur and methods by which they can be prevented.