Neonatal morbidity occurs despite pulmonary maturity prior to 39 weeks gestation.

OBJECTIVE: To compare outcomes among late-preterm or early-term neonates according to fetal lung maturity (FLM) status. STUDY DESIGN: We conducted a retrospective cohort study of 234 eligible singletons delivered after FLM testing before 39 weeks gestation at our center over a 2-year time period. A primary composite neonatal outcome included death and major morbidities. RESULT: The overall rate of primary composite morbidity was 25/46 (52.2%) and 61/188 (32.4%) in the immature/transitional and mature groups, respectively. After adjustment for confounders including gestational age, the composite outcome was not significantly different; adjusted odds ratio (aOR)=1.4 (confidence interval (CI)=0.7-3.0). The rate of respiratory distress syndrome was significantly higher in the immature/transitional group; odds ratio=3.4 (CI=1.1-10.3) as expected. CONCLUSION: FLM status did not correlate with the spectrum of neonatal morbidities in late-preterm and early-term births. Neonatal complications remained common in both groups.

Outcomes of extremely low birth weight infants given early high-dose erythropoietin.

OBJECTIVE: To evaluate long-term outcomes of 60 extremely low birth weight (ELBW) infants treated with or without three injections of high-dose erythropoietin (Epo). STUDY DESIGN: A retrospective analysis of anthropometric and neurodevelopmental outcome data comparing 30 ELBW infants enrolled in a phase I/II study examining the pharmacokinetics of high-dose Epo (500, 1000 and 2500 U/kg × 3 doses) administered to 30 concurrent controls. RESULT: Birth characteristics and growth from 4 to 36 months were similar for untreated and Epo-treated patients. Multiple linear regression analysis of neurodevelopmental follow-up scores from 17/25 Epo-treated and 18/26 control infants identified that Epo correlated with improvement of cognitive (R=0.22, P=0.044) and motor (R=0.15, P=0.026) scores. No negative long-term effects of Epo treatment were evident. CONCLUSION: Retrospective analysis of the only available long-term follow-up data from ELBW infants given high-dose Epo treatment suggests that Epo treatment is safe and correlates with modest improvement of neurodevelopmental outcomes.

The effect of inhaled nitric oxide on pulmonary function in preterm infants.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) in preterm infants is associated with impaired alveolar growth, inflammation and airway hyperreactivity. In animal models of BPD, inhaled nitric oxide (NO) improves alveolar growth and inhibits airway smooth muscle proliferation. This study was designed to assess the effect of inhaled NO on resistance and compliance in ventilated preterm infants with evolving BPD. STUDY DESIGN: Expiratory resistance and compliance of the respiratory system were measured in 71 ventilated preterm infants, < or = 32 weeks gestation, randomized to NO (n=34) versus placebo (n=37) for > or = 24 days at 7 to 21 days of life. RESULT: At baseline expiratory resistance (231+/-71 versus 215+/-76 cm H(2)O l(-1) s(-1)) and compliance (0.49+/-0.14 versus 0.53+/-0.13 ml cm H(2)O(-1) kg(-1)) were comparable between placebo and NO groups, respectively. There was no effect of NO on expiratory resistance or compliance at 1 h, 1 week or 2 weeks of study gas administration. CONCLUSION: NO had no short- or medium-term effect on expiratory resistance or compliance in ventilated preterm infants.

Ventilatory failure during resistive loaded breathing in the newborn primate.

Previous investigations have shown that ventilatory failure during severe inspiratory resistive loading (IRL) in the 21-day-old infant primate occurs secondary to a decrease in respiratory frequency, that is, central failure. To examine the response of the more immature newborn to IRL, minute ventilation (V'E), arterial blood gases and pH, minute diaphragmatic electromyogram (EMG) activity, peak inspiratory airway pressure, and the centroid frequency (Fc) of the diaphragmatic EMG power spectrum were measured in four unanesthetized tracheotomized 2-day-old monkeys during various levels of IRL, until either 1) ventilatory failure occurred (ventilatory failure run) or 2) normocapnia was sustained for 1 hr (successful trial). During successful trials, minute ventilation, breathing frequency, tidal volume, Fc, and PaCO2 were sustained at baseline levels and an increase in minute EMG activity and peak inspiratory airway pressure were observed. In contrast, during ventilatory failure runs, minute ventilation and tidal volume fell and PaCO2 rose compared to their respective baseline values. Respiratory frequency did not change. The decline in tidal volume occurred despite significant increases in minute diaphragmatic EMG activity and peak inspiratory airway pressure. No shifts in Fc were noted, suggesting that peripheral diaphragmatic fatigue did not occur. We conclude that ventilatory failure during IRL in the 2-day-old monkey is due to the animal's inability to defend tidal volume as opposed to central failure.

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn.

BACKGROUND: Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed. METHODS: To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome (n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) ("other": n = 43), and congenital diaphragmatic hernia (n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [PaO2] < 60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater. RESULTS: Baseline oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively (p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation (p < 0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%). CONCLUSIONS: We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN.

Association of elevated umbilical cord blood creatine kinase and myoglobin levels with the presence of cocaine metabolites in maternal urine.

STUDY OBJECTIVE: To determine whether an association exists between antenatal cocaine exposure and elevated levels of creatine kinase (CK) and myoglobin in umbilical cord blood collected upon delivery. STUDY POPULATION: 105 anonymous maternal urines with corresponding infant umbilical cords bloods. METHODS: Maternal urines were screened for cocaine metabolites by the Syva EMIT assay, with positive specimens confirmed by gas chromatography/mass spectrometry. For all 8 positives, plus the first 47 of the negatives collected, matched infant cord blood specimens were analyzed for myoglobin by radioimmunoassay and CK by kinetic enzyme activity assay. Cord bloods matched to the remaining 50 cocaine-negative urines were not analyzed. A two-tailed Mann-Whitney test was used to evaluate the significance of differences in CK and myoglobin levels between the two groups. RESULTS: CK levels were evaluated twofold in the cocaine-positive group as compared to the cocaine negative group (mean 383 +/- 260 vs. 189 +/- 68 IU/L, p = 0.005). Myoglobin levels were twofold higher in the cocaine-positive group compared to the cocaine negative group (mean 55.9 +/- 37.1 vs. 33.3 +/- 26.8 ng/mL, p = 0.077). CONCLUSION: Antenatal cocaine exposure is associated with elevated cord blood CK, and possibly with elevated cord blood myoglobin. Additional studies, using larger study populations and more sensitive methods of detecting antenatal cocaine exposure, along with detailed follow-up examination of infants, are indicated.

Effect of nitric oxide synthase inhibition during group B streptococcal sepsis in neonatal piglets.

Nitric oxide (NO), an important vasodilatory modulator of systemic and pulmonary vascular tone, is synthesized from L-arginine by the enzyme NO synthase in vascular endothelial and smooth muscle cells. L-Arginine analogs, such as N omega-nitro-L-arginine methyl ester (L-NAME), are competitive antagonists of NO synthase and inhibit NO synthesis. Group B streptococcus (GBS) causes pulmonary hypertension, hypoxemia, lung vascular injury, and reduced cardiac output in both human newborns and neonatal piglets. Lung vascular injury associated with prolonged GBS infusion in piglets may attenuate NO production and thus promote severe pulmonary hypertension. We studied the effect of the NOS inhibitor, L-NAME and the precursor of NO, L-arginine, on pulmonary and systemic hemodynamics during late-phase GBS sepsis in the piglet model. Neonatal piglets were anesthetized, ventilated with room air, and randomized to receive a continuous infusion of saline (n = 5) or GBS (n = 5) for 4 h. After 3 h of infusion, both groups received a bolus of L-NAME (3 mg/kg). Hemodynamic and gas exchange indices were measured at baseline, 30 min, and 3 h of infusion, and 30 min and 1 h after L-NAME treatment. L-NAME treatment caused 1) significant increases in mean pulmonary arterial pressure, pulmonary vascular resistance, mean systemic arterial pressure, and systemic vascular resistance for both groups; 2) a similar percentage of increase in pulmonary vascular resistance for the two groups; 3) greater reduction in cardiac output and SV in the GBS compared with the control group; and 4) no significant alterations in arterial partial pressure of oxygen or the difference between alveolar and arterial partial pressure of oxygen for either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Repair of a laryngotracheoesophageal cleft in an infant by means of extracorporeal membrane oxygenation.

Few survivors have been reported following attempted repair of laryngotracheoesophageal clefts (LTECs). The major challenge is maintaining oxygenation, both during the surgical repair and during the postoperative period of healing. We report a neonate with an LTEC extending to the carina whose successful repair was facilitated by extracorporeal membrane oxygenation (ECMO) begun intraoperatively and continued postoperatively for 11 days. The intraoperative surgical exposure of the defect was excellent. Postoperative trauma to the fresh tracheal repair from ventilatory pressures and endotracheal tube motion was eliminated through the use of ECMO. The patient was discharged without a tracheotomy and with a normal voice, cry, and swallow. According to this result, the use of ECMO may represent a significant advance in facilitating the correction of major laryngotracheoesophageal anomalies. The rationale, advantages, disadvantages, and potential pitfalls of this approach are presented, as well as preoperative and postoperative documentation of our results.

Effect of group B streptococcal sepsis on diaphragmatic function in young piglets.

Recent studies indicate that diaphragmatic pressure generation (Pdi) is impaired by bacterial infection. However, group B streptococcus (GBS) had no effect on Pdi when infused into 4-wk-old piglets. As responsiveness to GBS is age-dependent, we therefore studied the acute effect of GBS infusion on Pdi, using a younger, 2-wk-old piglet model. Using trans-Pdi with phrenic nerve stimulation, we studied the effect of continuous GBS infusion in seven anesthetized, spontaneously breathing 2-wk-old piglets. Pdi was measured under baseline conditions (50% O2/50% N2) and at 1, 2, and 4 h of GBS infusion. GBS was infused at a rate which caused a doubling of the pulmonary artery pressure but which avoided hypotension or acidosis--both of which can decrease Pdi. In addition, the piglets were kept hyperoxic [PaO2 > 13.3 kPa (100 torr)], and no piglet with hypercapnia [PaCO2 > 8.7 kPa (65 torr)] was included, as hypoxia and hypercapnia can also cause respiratory muscle dysfunction. For the GBS group, diaphragmatic contractility declined significantly by 1 h at 30-, 50-, and 100-Hz stimulation frequency and, by 2 h, was significantly decreased at all frequencies. We conclude that 2-wk-old piglets, in contrast to 4-wk-old piglets, demonstrate a decline in Pdi during GBS infusion. These data demonstrate an age-related response to GBS in the piglet.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of methylxanthines on diaphragmatic fatigue in the piglet.

Studies in adult animal and human subjects have suggested that the methylxanthine drugs can delay the onset or attenuate the severity of diaphragmatic fatigue. We have investigated the effect of aminophylline and caffeine on the pressure-generating capacity of the fatigued diaphragm in 1-mo-old piglets. Measurements of ventilation, transdiaphragmatic pressure, blood gases and pH, diaphragmatic electromyogram, diaphragmatic pressure-frequency curve (PdiFC), diaphragmatic blood flow, and end-expiratory lung volume were obtained at baseline, after 90 min of inspiratory resistive loaded breathing (IRL), and again 30 min after methylxanthine infusion while still on IRL. IRL resulted in a significant decrease in minute ventilation secondary to a fall in tidal volume. Spontaneously generated transdiaphragmatic pressure increased 7-fold from baseline. EMG activity increased to both segments of the diaphragm. Abdominal expiratory muscle activity was noted after the onset of IRL and was accompanied by a fall in end-expiratory lung volume. The PdiFC was significantly decreased from baseline after 90 min of IRL, demonstrating diaphragmatic fatigue. Aminophylline did not alter the PdiFC of the diaphragm. Diaphragmatic electromyogram and tidal volume increased. No change in diaphragmatic blood flow was demonstrated after infusion of aminophylline. Serum theophylline levels averaged 117 +/- 11 mumol/L (21 +/- 2 micrograms/mL). Caffeine administration did not alter the PdiFC or the diaphragmatic electromyogram during IRL. Blood flow to both segments of the diaphragm decreased after caffeine infusion. Serum caffeine levels averaged 86 +/- 30 mumol/L (16.6 +/- 5.9 micrograms/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inspiratory resistive loaded breathing and hypoxemia on diaphragmatic function in the piglet.

The combined effects of inspiratory resistive loaded breathing (IRL) and hypoxemia on transdiaphragmatic pressure (Pdi) in nine 1-mo-old Yorkshire piglets were studied. IRL was adjusted to increase spontaneously generated Pdi five to six times above baseline but maintain arterial PCO2 < 70 Torr to prevent hypercapnic depression of diaphragmatic contractility. Measurements of ventilation, blood gases and pH, Pdi, diaphragmatic electromyogram, Pdi during phrenic nerve stimulation, diaphragmatic blood flow, and end-expiratory lung volume were obtained at baseline, after 2 h of IRL, and then after 1 h of hypoxemia (arterial PO2 approximately 40 Torr) combined with IRL. Diaphragmatic muscle samples were obtained after study completion and immediately frozen in liquid nitrogen for determination of tissue ATP, phosphocreatine, lactate, and glycogen levels. Ten 1-mo-old piglets were subjected to IRL alone and served as controls. IRL alone resulted in significant impairment of Pdi generation. The addition of hypoxemia for 1 h did not further compromise Pdi in comparison to control animals who were subjected to IRL alone. Blood flow to both the costal and crural segments of the diaphragm increased significantly during IRL; the addition of the hypoxemic stress resulted in further significant augmentation of blood flow to both segments of the diaphragm. No differences were noted in diaphragmatic muscle tissue ATP, phosphocreatine, or glycogen between control and IRL animals or between control and IRL plus hypoxemia animals. Muscle lactate levels increased significantly in the IRL plus hypoxemia animals only. The data from this study suggest that moderate hypoxemia during resistive-loaded breathing in the piglet does not accentuate diaphragmatic fatigue.

Group B streptococcus has no effect on piglet diaphragmatic force generation.

Recent studies indicate that diaphragmatic contractility is adversely affected by bacterial infection. Using transdiaphragmatic pressure (Pdi) with phrenic nerve stimulation, the effect of continuous Group B Streptococcus (GBS) infusion on diaphragmatic force output was studied in seven anesthetized, spontaneously breathing 1-month old piglets. Pdi was measured under baseline condition (50% O2/50% N2) and at 1, 2, and 4 h of GBS infusion. The GBS was infused at a level that caused a doubling of the pulmonary artery pressure and a 32% decrease in cardiac output but which avoided hypotension or acidosis--both of which can decrease diaphragmatic contractility. In addition, the piglets were kept hyperoxic (PaO2 greater than 100) and no piglet with hypercapnia (PaCO2 greater than 65) was studied, as hypoxia and hypercapnia also can cause respiratory muscle dysfunction. Pdi in response to phrenic nerve stimulation did not change during GBS infusion. We conclude that GBS infusion, in the absence of hypotension, hypercapnia, hypoxia, or acidosis, has no effect on diaphragmatic force generation in the piglet.

Cocaine and the use of alcohol and other drugs during pregnancy.

Recent reports of adverse pregnancy outcomes associated with prenatal cocaine exposure have raised questions about the actual numbers of infants who are exposed to cocaine in utero. Whereas toxicologic urine screens obtained at delivery can detect cocaine use in the preceding few days, they fail to yield a comprehensive picture of use during and immediately before pregnancy. According to postpartum self-report, 15% of a teaching hospital sample and 3% of a private hospital sample of mothers had used cocaine during pregnancy or in the previous month (total = 876). Rates at the teaching hospital reflect a fifteenfold increase over the past 12-year period, when compared with previously obtained data. Cocaine users were significantly more likely to report that they drank alcohol, smoked cigarettes, and took other illicit drugs during pregnancy than women who denied using cocaine. Mothers at highest risk for cocaine use were those who were black (20%), were single-separated-divorced (24% to 33%), and had less than a high school education (21%).

Diaphragmatic force and substrate response to resistive loaded breathing in the piglet.

Inspiratory resistive loaded (IRL) breathing results in hypoventilation and diaphragmatic fatigue in the piglet. We studied the effects of 6 h of IRL on ten 1-mo-old piglets. The load was adjusted to increase spontaneously generated transdiaphragmatic pressure five to six times baseline. Six 1-mo-old piglets acted as controls and were identically instrumented but were not subjected to IRL. Measurements of ventilation, blood gases and pH, diaphragmatic electromyogram, force-frequency curve, blood flow, and end-expiratory lung volume were obtained hourly. Diaphragmatic muscle samples were obtained after 6 h for determination of ATP, phosphocreatine, lactate, and glycogen levels. No changes occurred in the control animals. IRL resulted in a significant decrease in ventilation, an increase in diaphragmatic EMG, onset of abdominal expiratory muscle activity, and a fall in end-expiratory lung volume by 1 h. The force-frequency curve adjusted for lung volume change fell by 20% at all frequencies of stimulation at 1 h and by 40% at 6 h. Blood flow to the costal and crural diaphragm increased by 51 and 141%, respectively. No differences were noted in ATP, phosphocreatine, lactate, or glycogen between control and IRL animals. It is concluded that submaximal spontaneous contractions of the piglet diaphragm over a 6-h period cause a substantial decrease in its maximal force-generating capacity that is not related to substrate depletion.

Respiratory mechanics of the piglet during the first month of life.

Piglets at 3, 14, and 30 days of age were studied to assess the postnatal changes in lung, chestwall, and total respiratory system compliance associated with normal growth. Static deflation compliance of the lung and total respiratory system increased significantly with age; there was no change in chestwall compliance. When normalized for body weight or lung volume, all measures of compliance tended to decrease with postnatal age. Measures of lung and chestwall compliance obtained with an end-inspiratory occlusion technique were less than the static compliance measures, but demonstrated the same relative changes with postnatal maturation. Chestwall compliance at 3 days of age was only 1.3 times greater than lung compliance and there was no significant change in this ratio with postnatal age. In contrast to the trend for the human infant, the piglet's chestwall at 3 days of age is stiff relative to the lung and does not become stiffer with age over the first 4 weeks of life.

The ventilatory pump: neonatal and developmental issues.

This review documents the current knowledge with regard to the structure and function of the developing ventilatory pump. We note that while the neonate's compliant rib cage and diaphragmatic configuration may predispose the newborn to pump failure, its diaphragmatic endurance properties and ability to recruit accessory muscles of respiration may protect against such impairment. We also share evidence that central neural failure can lead to an inability to defend minute ventilation during periods of heightened respiratory effort. Nevertheless, our fund of knowledge remains limited and at this juncture it is unclear which factors or interplay of factors contribute to the development of ventilatory failure in the human neonate and infant. The ventilatory pump is a vital component of the respiratory system. As such, our understanding of the pathogenesis and reversal of ventilatory pump impairment is crucial to improving our management of respiratory failure. We are only beginning to develop such an understanding within a neonatal and developmental context. Future research endeavors will enlarge our fund of knowledge regarding the thorax, the respiratory muscles, and the central neural respiratory-related neurons that control them. From such an understanding will emerge clinically relevant information that has therapeutic implications for the care of newborns and infants with respiratory disease.

Effect of aminophylline on diaphragmatic contractility in the piglet.

Minute ventilation, arterial blood gases, arterial pH, cardiac output, and transdiaphragmatic force generation, both during spontaneous ventilation and in response to phrenic nerve stimulation during airway occlusion at end expiration, were measured in nine anesthetized, tracheostomized piglets before and 30 min after parenteral infusion of 20 mg/kg aminophylline. Serum theophylline levels averaged 109 +/- 21 mumol/L (19.7 +/- 3.7 micrograms/mL) at 30 min postinfusion. No significant changes were noted in pH, blood gases, blood pressure, or ventilatory measures after aminophylline. Aminophylline infusion also had no effect on transdiaphragmatic force generation at any frequency of phrenic nerve stimulation studied. It is concluded that aminophylline has no effect on diaphragmatic contractility in the quietly breathing, nonfatigued piglet.

Estimation of intrapleural pressure in the newborn.

We examined the changes in esophageal (Pes), proximal airway (Paw), and direct intrapleural (Ppl) pressure measurements following end-expiratory airway occlusion in anesthetized spontaneously breathing newborn piglets. Simultaneous occluded pressure measurements were obtained during resting ventilation, inspiratory resistive loaded (IRL) breathing, and bilateral transvenous phrenic nerve stimulation. During spontaneous resting ventilation, occluded Paw/Ppl averaged 104 +/- 4% and occluded Pes/Ppl averaged 89 +/- 3%. Similar values were found for occluded spontaneous breaths with IRL. During phrenic nerve stimulation at end-expiratory lung volume, occluded Paw/Ppl averaged 104 +/- 6% while occluded Pes/Ppl decreased to 70 +/- 22%. We conclude that proximal airway pressure more accurately reflects intrapleural pressure than esophageal pressure with occlusion in newborn swine. During phrenic nerve stimulation, esophageal pressure measures are grossly inaccurate estimates of intrapleural pressure with occlusion.

The effect of aminophylline on diaphragm blood flow in the piglet.

The effect of aminophylline on diaphragmatic blood flow was investigated in two groups of newborn piglets. Six animals were studied during spontaneous breathing and seven additional animals were paralyzed and ventilated to assess the effect of aminophylline on blood flow to the nonworking diaphragm. Arterial blood gases and pH, cardiac output, and diaphragmatic blood flow were measured before and 20 min after infusion of 20 mg/kg aminophylline. Blood theophylline concentrations averaged 117 mumols/L (21 micrograms/mL) in both groups of animals. Heart rate increased significantly in all animals. Cardiac output increased significantly only in spontaneously breathing animals. Aminophylline had no effect on blood flow to the costal or crural portions of the diaphragm in either the paralyzed or spontaneously breathing animals.