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Nasal ventilation is increasingly used to reduce invasive ventilation in preterm infants. The effects of nasal ventilation and the advantages of synchronized nasal ventilation have not been fully evaluated. The objective was to compare the short-term effects of nasal intermittent mandatory ventilation (NIMV) and synchronized NIMV (S-NIMV) with nasal continuous positive airway pressure (NCPAP) on ventilation, gas exchange, and infant-ventilator interaction. Sixteen clinically stable preterm infants requiring NCPAP (GA, 27.6 ± 2.3 wk; birthweight (BW), 993 ± 248 g; and age, 15 ± 14 d) were exposed to NCPAP, NIMV at 20/min, NIMV at 40/min, S-NIMV at 20/min, and S-NIMV at 40/min for 1 h each (Infant-Star ventilator), in random order. Tidal volume, minute ventilation, and gas exchange did not differ significantly between NCPAP, NIMV, and S-NIMV. Inspiratory effort decreased during S-NIMV compared with NCPAP and NIMV, whereas inspiratory effort during NIMV did not differ from NCPAP. Active expiratory effort and expiratory duration increased during NIMV. Chest wall distortion, apnea and hypoxemia spells, abdominal girth, and comfort did not differ. In conclusion, there were no short-term benefits on ventilation and gas exchange of nasal ventilation compared with NCPAP in clinically stable preterm infants. However, synchronized nasal ventilation reduced breathing effort and resulted in better infant-ventilator interaction than nonsynchronized nasal ventilation.

The Smad2/3 pathway plays a key role in mediating TGF-1 inhibition of branching morphogenesis and induction of connective tissue growth factor (CTGF) expression in embryonic lungs. Because a number of cell-specific interactions have been described between TGF-1-driven Smad signaling and the c-Jun N-terminal kinase (JNK) pathway, we have investigated the effects of JNK inhibition on TGF-1 activation of Smad2, inhibition of branching, induction of CTGF expression, and apoptosis in mouse embryonic lung explants. Mouse embryonic day 12.5 (E12.5) lung explants were treated with TGF-1 in the presence or absence of a specific pharmacologic JNK inhibitor (SP600125) and a specific JNK peptide inhibitor (JNKI). We found that TGF-1 activated the JNK pathway by stimulating c-Jun phosphorylation, which was blocked by JNK inhibitors. Treatment with SP600125 stimulated Smad2 phosphorylation and enhanced TGF-1-induced Smad2 phosphorylation. Treatment with JNK inhibitors also decreased normal branching morphogenesis and induced CTGF expression as well as augmented TGF-1 inhibition of branching and induction of CTGF expression. Furthermore, JNK inhibition-induced apoptosis. Our results demonstrate that inhibition of the JNK pathway promotes TGF-1-driven Smad2 responses in lung branching morphogenesis. These data suggest that the JNK pathway may antagonize TGF-1 dependent Smad2 signaling during mouse embryonic lung development.

High tidal volume (VT) ventilation plays a key role in ventilator induced lung injury and bronchopulmonary dysplasia. However, little is known about the effect of high VTon expression of growth factors that are critical to lung development. In a previous study, we demonstrated that connective tissue growth factor (CTGF) inhibits branching morphogenesis. In this study, we investigated the effect of high VTon CTGF expression in newborn rat lungs. Newborn rats were ventilated with normal VT(10 mL/kg) or high VT(25 mL/kg) for 6 h. Nonventilated animals served as controls. We found that high VTupregulated CTGF expression. To identify the potential signaling pathways mediating high VTinduction of CTGF, newborn rats were ventilated with high VTfor 1 or 3 h. Temporal expression of TGF-βs, p-Smad2, Smad7, and CTGF was analyzed. High VTventilation did not change gene expression of TGF-βs and Smad7 but induced rapid and sustained expression of p-Smad2 that precedes increased CTGF expression. CTGF and p-Smad2 were localized in bronchiolar epithelial cells, alveolar walls and septa. These data suggest that high Vtventilation activates the Smad2 pathway, which may be responsible for downstream induction of CTGF expression in newborn rat lungs.

The ventilatory response to hypoxia is influenced by the balance between inhibitory (GABA, glycine, and taurine) and excitatory (glutamate and aspartate) brainstem amino acid (AA) neurotransmitters. To assess the effects of AA in the nucleus tractus solitarius (NTS) on the ventilatory response to hypoxia at 1 and 2 wk of age, inhibitory and excitatory AA were sampled by microdialysis in unanesthetized and chronically instrumented piglets. Microdialysis samples from the NTS area were collected at 5-min intervals and minute ventilation (VE), arterial blood pressure (ABP), and arterial blood gases (ABG) were measured while the animals were in quiet sleep. A biphasic ventilatory response to hypoxia was observed in wk 1 and 2, but the decrease in VEat 10 and 15 min was more marked in wk 1. This was associated with an increase in inhibitory AA during hypoxia in wk 1. Excitatory AA levels were elevated during hypoxia in wk 1 and 2. Changes in ABP, pH, and ABG during hypoxia were not different between weeks. These data suggest that the larger depression in the ventilatory response to hypoxia observed in younger piglets is mediated by predominance of the inhibitory AA neurotransmitters, GABA, glycine, and taurine, in the NTS.

Administration of Escherichia coliendotoxin attenuates the ventilatory response to hypoxia (VRH) in newborn piglets, but the mechanisms responsible for this depression are not clearly understood. Nitric oxide (NO) production increases during sepsis and elevated NO levels can inhibit carotid body function. The role of endothelial NO on the VRH during endotoxemia was evaluated in 26 young rats. Minute ventilation (VE) and oxygen consumption (Vo2) were measured in room air (RA) and during 30 min of hypoxia (10% O2) before and after E. coliendotoxin administration. During endotoxemia, animals received placebo (PL, n8); a nonselective nitric oxide synthase (NOS) inhibitor (NG-nitro-L-arginine methyl ester, L-NAME, n9), or a neuronal NOS (nNOS) inhibitor (7-nitroindazole, 7-NI, n9). During endotoxemia, a larger increase in VEwas observed only during the first min of hypoxia in the L-NAME group when compared with PL or 7-NI (p< 0.001). VRH was similar in the PL and 7-NI groups. A larger decrease in Vo2at 30 min of hypoxia was observed in L-NAME and 7-NI groups when compared with PL (p< 0.03). These data demonstrate that the attenuation of the early VRH during endotoxemia is in part mediated by an inhibitory effect of endothelial NO on the respiratory control mechanisms.

Apnea is a common complication of respiratory syncytial virus (RSV) infection in young infants. The purpose of this study was to determine whether this infection affects apnea triggered by sensorineural stimulation in weanling rats. We also studied which neurotransmitters are involved in this response and whether passive prophylaxis with a specific neutralizing antibody (palivizumab) confers protection against it. Weanling rats were inoculated intranasally with RSV, adenovirus, or virus-free medium. Changes in respiratory rate and apnea in response to nerve stimulation with increasing doses of capsaicin were measured by plethysmography. Capsaicin-induced apnea was significantly longer in RSV-infected rats at postinoculation days 2 (upper airways infection) and 5 (lower airways infection), and apnea-related mortality occurred only in the RSV-infected group. Reduction in the duration of apnea was observed after selective inhibition of central -aminobutyric acid (GABA) type A receptors and neurokinin type 1 receptors for substance P. Prophylactic palivizumab protected against apnea and apnea-related mortality. These results suggest that sensorineural stimulation during RSV infection is associated with the development of apnea and apnea-related death in early life, whose mechanism involves the release of GABA acting on central GABA type A receptors and substance P acting on neurokinin type 1 receptors.

NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus(GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4–10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 × 108CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p< 0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p< 0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates.

An endothelin-converting enzyme mediates the conversion from low-potency pro-endothelin to potent endothelin-1 (ET-1). Increased ET-1 levels have been observed in pulmonary hypertension of various etiologies in infants. We hypothesized that increased ET-1 levels induce pulmonary hypertension during group B Streptococcus(GBS) infusion, and this can be attenuated by the administration of an endothelin-converting enzyme inhibitor (ECEI). Twenty-two unanesthetized, chronically instrumented newborn piglets received a continuous infusion of GBS (3.5 × 108colony-forming units/kg/min) while exposed to 100 O2. They were randomly assigned to receive a placebo (PL) or an ECEI (phosphoramidon, 30 mg/kg i.v.) 15 min after sustained pulmonary hypertension. Comparison of hemodynamic measurements and arterial blood gases at baseline and over the first 210 min from the onset of pulmonary hypertension was performed between groups. GBS infusion caused significant increases in mean pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), and PVR/SVR, and significant decreases in cardiac output, pH, and base excess. After the administration of ECEI, a significant reduction in pulmonary artery pressure (p< 0.0001), PVR (p< 0.001), and PVR/SVR (p< 0.01) and an improvement in cardiac output (p< 0.01) were observed during GBS infusion. The decrease in pH (p< 0.001) and base excess (p< 0.001) during GBS infusion was less marked after the administration of ECEI compared with the PL. Plasma ET-1 levels were obtained in 20 additional piglets; levels were significantly lower in the ECEI compared with PL after 3 h of GBS infusion (p< 0.02). All animals in the ECEI group survived the study period as opposed to 25 survival in the PL group (p< 0.001). These data suggest that the increased circulating ET-1 levels mediate, in part, the GBS-induced pulmonary hypertension.

During proportional assist ventilation (PAV), the ventilator pressure is servocontrolled throughout each spontaneous inspiration such that it instantaneously increases in proportion to the airflow (resistive unloading mode), or inspired volume (elastic unloading mode), or both (combined unloading mode). The PAV pressure changes are generated in a closed-loop feedback circuitry commonly using a pneumotachographic signal. In neonates, however, a pneumotachograph increases dead space ventilation, and its signal may include a substantial endotracheal tube leak component. We hypothesized that respiratory inductive plethysmography (RIP) can replace pneumotachography to drive the ventilator during PAV without untoward effects on ventilation or respiratory gas exchange. Ten piglets and five rabbits were supported for 10-min (normal lungs) or 20-min (meconium injured lungs) periods by each of the three PAV modes. In each mode, three test periods were applied in random order with the ventilator driven by the pneumotachograph signal, or the RIP abdominal band signal, or the RIP sum signal of rib cage and abdomen. Interchanging the three input signals did not affect the regularity of spontaneous breathing, and gas exchange was achieved with similar peak and mean airway pressures (ANOVA). However, the RIP sum signal worked adequately only when the relative gains of rib cage and abdominal band signal were calibrated. We conclude that an RIP abdominal band signal can be used to generate PAV, avoiding increased dead space and endotracheal tube leak problems.

Thoracoabdominal asynchrony (TAA) and chest wall distortion (CWD) are commonly seen in preterm infants secondary to a highly compliant rib cage and poor compensation of distorting forces by inspiratory rib cage muscles. Continuous positive airway pressure (CPAP) reduces TAA and CWD by stenting the chest wall. We hypothesized that application of positive airway pressure only during inspiration and in proportion to an infant’s inspiratory effort should have a similar but more pronounced effect than CPAP alone. A ventilator providing airway pressure changes in proportion to flow and volume generated by an infant (proportional assist ventilation) was used to unload the respiratory pump during inspiration. Ten preterm infants were studied birth weight, 745 (635–1175) g; gestational age, 26.5 (24–31) wk; postnatal age 3 (1–7) d; medium (range). TAA and CWD were determined by respiratory inductive plethysmography. TAA was expressed as the phase angle between the rib cage and abdominal motion and CWD as the total compartmental displacement ratio. In addition, we measured tidal volume with a pneumotachograph and esophageal and airway pressure deflections with pressure transducers. Measurements were obtained during alternating periods of CPAP and two different degrees of support (Gain 1 1.09 ± 0.68, Gain 2 1.84 ± 0.84 cm H2O/mL) that were provided by a proportional assist ventilator. Phase angle and the total compartmental displacement ratio decreased with increasing gain compared with CPAP alone. Peak airway pressure increased from 0.6 to 3.8 to 7.6 cm H2O above positive end-expiratory pressure (PEEP) with CPAP, Gain 1, and Gain 2, respectively, as tidal volume increased from 2.8 to 4.1 to 4.7 mL/kg. Esophageal pressure changes decreased only little with increasing gain. Chest wall excursion increased and abdominal movement decreased, indicating a redistribution of tidal volume between chest and abdomen. We conclude that proportional assist ventilation reduces TAA and CWD by generating a small increase in airway pressure that occurs in synchrony and in proportion to each inspiratory effort.

Hypothermic newborn piglets have a depressed ventilatory response to hypoxia, and this may be due to an increase in CNS -aminobutyric acid (GABA) levels. To evaluate the effects of GABAAreceptor blockade on the ventilatory response to hypoxia in hypothermic piglets, 31 anesthetized paralyzed mechanically ventilated newborn piglets (2–7 d) were studied at a brain temperature of 38.5 ± 0.5°C normothermia (NT), n15 or 34 ± 0.5°C hypothermia (HT), n16. The central respiratory output was evaluated by measuring burst frequency and moving time average area of phrenic nerve activity. Measurements of minute phrenic output (MPO), arterial blood pressure, heart rate, oxygen consumption, and arterial blood gases were obtained at room air and during 20 min of isocapnic hypoxia fraction of expired oxygen (Fio2) 0.10. After 10 min of hypoxia, a bolus injection of 20 L of bicuculline methiodide (BM; 10 g) or Ringer’s solution was administered into the cisterna magna over a 1-min period, and the piglets remained in hypoxia for an additional 10 min. There was an initial increase of 50 ± 6 in MPO during the first minute of hypoxia followed by a decrease to values 24 ± 8 above baseline at 10 min in the NT group. In contrast, in the HT group, the initial increase in MPO with hypoxia was eliminated, and, at 10 min, there was a decrease to a mean value 35 ± 4 below baseline level (NT versusHT, p< 0.03). After administration of BM, a significant increase in MPO with hypoxia was observed in both groups compared with their placebo groups (p< 0.002 in NT-BM group, p< 0.0001 in HT-BM group). However, the magnitude of the increase in MPO during hypoxia was significantly greater in the HT group after administration of BM (NT versusHT, p< 0.0001). Changes in oxygen consumption, arterial blood pressure, heart rate, pH, partial pressure of oxygen (Pao2), and base excess with hypoxia were not different between NT and HT groups before and after the administration of BM. The cardiorespiratory response to hypoxia was not modified after administration of Ringer’s solution to NT and HT placebo groups. These data suggest that the depression in hypoxic ventilatory response produced by HT is in part modulated by an increased CNS GABA concentration.

In order to evaluate the influence of leukotrienes on group B streptococcal (GBS) sepsis we studied the effect of a leukotriene antagonist, FPL 57231, on the early hemodynamic changes occurring secondary to an infusion of live GBS. Paralyzed, mechanically ventilated piglets received a continuous intravenous infusion of bacteria (5 × 108org/kg/min) while systemic arterial pressure and pulmonary artery pressure were measured continuously. Cardiac output was measured by thermodilution; and plasma samples for determination of thromboxane B2and 6-keto-PGF1αwere taken at preset intervals. In addition to GBS, treatment animals received a continuous infusion of FPL 57231 starting 15 min after the bacterial infusion was begun. Study animals as a whole responded to bacteria within 15 min with a marked elevation in pulmonary artery pressure from 13.6 ± 4 to 44.6 ± 6 mm Hg (p< 0.001), and a decline in PaO2(79 ± 9 to 44 ± 5 mm Hg) (p< 0.001) and a cardiac output (0.27 ± 0.07 to 0.15 ± 0.06 liter/min/kg) (p< 0.0001). In animals treated with FPL 57231 these changes were reversed or significantly attenuated by 60 min. In the control group pH deteriorated significantly to 7.17 ± 0.1 compared to baseline values (p< 0.01) by 60 min, while treatment group animals maintained a pH of 7.3 ± 0.23. Thromboxane B2and 6-keto PGF1αwere similar in both groups and did not change during the study period. In addition, survival was significantly longer in treatment (191 ± 44 min) compared to control animals (100 ± 32 min) (p< 0.01). These data suggest that FPL 57231 may attenuate the early cardiovascular changes accompanying GBS infection and positively influence survival without modifying thromboxane or 6-keto PGF1αlevels. These results imply that leukotrienes influence the early hemodynamic manifestations of GBS sepsis.

The effects of the cyclooxygenase inhibitor, indomethacin, and the leukotriene receptor antagonist, FPL 57231, on changes in dynamic lung compliance and pulmonary resistance associated with a 1-h infusion of live group B streptococci were evaluated in mechanically ventilated piglets. To define mediators of early changes in lung function, animals were given an infusion of either FPL 57231 or indomethacin beginning 15 min after the infusion of group B streptococci was begun. These groups were compared to an untreated group who received only group B streptococci. Within 15 min of starting the bacterial infusion, all groups showed significant increases in pulmonary artery pressure, pulmonary artery wedge pressure, total pulmonary resistance, transpulmonary pressure, and thromboxane B2, and decreases in tidal volume, dynamic lung compliance, and PaO2. After treatment with indomethacin there were significant decreases in pulmonary artery pressure (mean ± SEM; 48 ± 1 to 22 ± 3 mm Hg, p < 0.001), pulmonary artery wedge pressure (7.5 ± 1.3 to 2.2 ± 0.4 mm Hg, p < 0.001) and thromboxane B2 (6.51 ± 1.56 to 1.01 ± 0.27 ng/ml, p < 0.01) and an increase in dynamic lung compliance (1.10 ± 0.10 to 1.28 ± 0.14 ml/ cm H2O/kg, p < 0.01) over the study period. Total pulmonary resistance decreased significantly (18.7 ± 1.8 to 15.7 ± 1.5 cm H2O/liter/s, p < 0.02) only at 60 min. In animals treated with FPL 57231 only pulmonary artery pressure (46 ± 3 to 30 ± 2 mm Hg, p < 0.05) and pulmonary artery wedge pressure (7.5 ± 0.8 to 4.0 ± 0.9 mm Hg, p < 0.01) decreased. These data suggest that cyclooxygenase products of arachidonic acid metabolism play a role in the early changes in pulmonary mechanics in group B streptococci sepsis.

Functional residual capacity (FRC) was determined in 50 infants by a simplified N2washout method. Fourteen infants were preterm, four full-term newborns and the rest were 1 month to 5 yr of age. Weight ranged from 1.19 to 25.8 kg. The method gave well reproducible values with a mean coefficient of variation of 3.9. The FRC values are equally well correlated to weight and length (r= 0.98). The correlation with weight is linear, intercepting the x axis (FRC = 0) at a weight of 480 g, the one with length is best described by a power curve. The course of the regression lines reflects the observation that FRC per kg weight or per cm length is lower in neonates than in larger infants. The FRC measurements are in the same range as values obtained by other investigators using the N2washout or He-dilution techniques. The values are significantly smaller than thoracic gas volume measurements obtained by plethysmography. This difference may be due to air trapping or to possible methodological problems with the plethysmographic technique. The data demonstrate that FRC can be measured easily and accurately in preterm and older infants using a N2washout technique.

IL-1 is purported to be a proximal mediator in the cascade leading to septic shock. To characterize its hemodynamic effects and to ascertain whether its blockade would ameliorate the deleterious consequences of sepsis, an IL-1 receptor antagonist (IL-1ra) was administered to 16 anesthetized, mechanically ventilated piglets that received a continuous infusion of group B streptococci (GBS) (7.5 X 107colony-forming units/kg/min). Systemic (Psa), pulmonary artery (Ppa), and wedge (Pwp) pressures and cardiac output were measured pre-GBS and every 30 min during GBS infusion. After 15 min of bacterial infusion the control group received normal saline, whereas the treatment group received a bolus of IL-1ra (40 mg/kg) followed by a continuous infusion of IL-1ra (60 μg/kg/min). In comparing IL-1ra-treated animals with controls from the 15-min GBS baseline to the succeeding septic study period (45–120 min), the following treatment effects were noted (120-min values shown): mean Psa remained elevated in treatment compared with control animals (12.7 ± 2.5 versus9 ± 3.5 kPa; p< 0.001) as did CO (0.21 ± 0.07 versus0.13 ± 0.08 L/min/kg; p< 0.001). Pwp decreased in the treatment compared to the control group over the study period (1 ± 0.3 versus1.6 ± 0.7 kPa; p< 0.02). Mean Ppa and mean Pra were not different between groups over time. Median length of survival was significantly longer (p= 0.04) in treated (226 min) compared with control animals (150 min). These data suggest that IL-1 plays an important role in GBS sepsis and septic shock, and that IL-1ra may in part ameliorate the cardiovascular alterations associated with GBS sepsis in the neonate.

Cardiovascular responses to the calcium antagonists verapamil and nifedipine were evaluated in a piglet model of hypoxic pulmonary hypertension. All animals were mechanically ventilated and paralyzed. Cardiac output (CO), pulmonary artery (Ppa) and aortic blood pressure (AoP), pulmonary wedge pressure, right atrial pressure (Pra), and arterial blood gases were measured prior to and after pulmonary hypertension was induced by hypoxia and after administration of calcium-blocking agents. Results were compared to a control group of piglets subjected to a similar period of hypoxia. Verapamil infusion (0.15 mg/kg) resulted in a rapid decrease in Ppa, AoP and pulmonary vascular resistance (p<0.05) which returned to baseline values by 15 min. Nifedipine (100 µg/ kg) resulted in a decrease in Ppa at 1 min (p<0.05) which remained significantly lower than controls throughout the study period. AoP declined precipitously during the same time period (p<0.01). No significant change in Ppa was noted when nifedipine was administered at a dose of 10 µg/kg. For the most part, these drugs have a transient vasodilatory action on pulmonary as well as systemic circulation in this animal model; however, they might in higher doses be associated with significant systemic hypotension. For this reason, the use of these drugs in the treatment of hypoxic pulmonary hypertension in the neonate should be approached with caution.

To evaluate the relationship between brain blood flow and ventilatory response to hypoxia, seventeen sedated, spontaneously breathing newborn piglets were studied. Minute ventilation (E) was measured by pneumotachograph, cardiac output by thermodilution and total brain and brain stem blood flows with radiolabeled microspheres. Measurements were performed while the animals were breathing room air and after 10 min of hypoxia induced by breathing 10 O2. Two patterns of ventilatory response to hypoxia were observed in the study animals. All animals increasedEduring the 1st min of hypoxia, but nine (mean ± SD; age 5 ± 1.3 d; wt 1828 ± 437 g) sustained increased Eafter 10 min of hypoxia (↑Egroup). The remaining eight animals (age 5 ± 1.2 d; wt 1751 ± 168 g) had decreased Eat 10 min of hypoxia to values less than their room air baseline (↓Egroup). The decrease in PaO2during hypoxia was similar in both groups, however the PaCO2decreased significantly only in the ↑Egroup. Although cardiac output increased significantly during hypoxia in both groups, the values during normoxia and hypoxia were lower in the ↓Egroup (p<0.001). Arterial blood pressure increased significantly during hypoxia only in the ↑Egroup. The increase in total brain and brain stem blood flows with hypoxia was similar in both groups, despite the two different patterns of ventilatory response to hypoxia. These data suggest that in this animal model the distinct patterns of ventilatory response to hypoxia are not related to the changes in total brain or brain stem blood flows that occur during hypoxia.

Several amino acids (AA) act as neurotrans—mitters and mediate the ventilatory response to carbon dioxide and hypoxia in adult human beings and animals. To evaluate the influence of AA on the neonatal ventilatory response to hypoxia, 29 newborn piglets less than 5 d old were randomly assigned to a control diet or protein-free diet for 7–10 d. Minute ventilation, arterial blood pressure, oxygen consumption, and arterial blood gases were measured in sedated, spontaneous breathing piglets while they breathed room air and at 1, 5 and 10 min of hypoxia (fraction of inspired oxygen concentration — 0.10) before and after 4 h of AA (Trophamine, 3 g/kg, i.v.) or 10 dextrose infusion. The administration of AA solution in protein-deprived piglets resulted in a significant increase in minute ventilation after 10 min of hypoxia (26 ± 19) in comparison with their ventilatory response before AA infusion (10 ± 12; p< 0.02). Similar increase in the ventilatory response to hypoxia was observed in the control diet group after A A infusion (23 ± 17 versus 11 ± 11; p< 0.05). Changes in arterial blood pressure, oxygen consumption, and arterial blood gases during hypoxia were similar before and after AA infusion. The ventilatory response to hypoxia in both protein-free and control diet animals were similar before and after the 10 dextrose infusion. These results stress the importance of nutritional factors in the neonatal control of breathing.

The purpose of this study was to evaluate the relationship between changes in minute ventilation (VE) and oxygen consumption (Vo2) in response to acute hypoxia in the newborn piglet. Twenty-five (mean ± SD; age, 4.7 ± 1.1 d; weight, 1451 ± 320 g) sedated, spontaneously breathing newborn piglets were studied. VE was measured by pneumotachography, and Vo2was measured by the open-circuit technique. Measurements were performed while the animals breathed room air and repeated after 10 min of hypoxia, which was induced by breathing 10 oxygen. Although the mean VE values during hypoxia displayed a typical biphasic ventilatory response, the individual pattern of this ventilatory response to hypoxia was variable. Thirteen animals sustained VE above baseline after 10 min of hypoxia, whereas the 12 remaining animals decreased VE after 10 min of hypoxia to values below their room air baseline. The Vo2values did not differ between groups during normoxia, and a similar decrease in Vo2occurred in both groups after 10 min of hypoxia. Further-more, no correlation was observed between changes in VE and Vo2during hypoxia either in absolute values or in the percent change from room air baseline. Arterial Po2decreased similarly in both groups, but Paco2decreased significantly only in the group that sustained VE above baseline after 10 min of hypoxia. These data demonstrate that in this animal model the hypoxic ventilatory depression is not determined by the decrease in Vo2that occurs during hypoxia.

Pentoxifylline (PTXF) is a methylxanthine that modifies leukocyte function and inhibits cytokine release. To evaluate its effects on the cardiovascular manifestations of sepsis secondary to group B streptococci, 14 anesthetized, mechanically ventilated piglets were studied over a 240-min period. Animals were randomly assigned to a treatment group that received a PTXF bolus (20 mg/kg) followed by a continuous infusion of 5 mg/kg/h before and during group B streptococci (1 x 108colony forming units/kg/min) administration and a control group that received saline as a placebo. Comparison of the hemodynamic measurements and arterial blood gases during the first 90 min of PTXF treatment with those of the control group resulted in the following 90 min values: systemic arterial blood pressure was significantly higher in the PTXF group (89 ± 10 versus56 ± 30 mm Hg; P < 0.005) as was cardiac output (0.18 ± 0.04 versus0.10 ± 0.07 L/kg/min; p < 0.005). Pulmonary vascular resistance remained lower in the PTXF-treated animals (135 ± 117 versus248 ± 119 mm Hg/L/min/kg; P < 0.001), and these animals were less acidotic as measured by pH (7.07 ± 0.2 versus7.31 ± 0.1; p < 0.05) and base deficit (-15 ± 9 versus−5 ± 2 mmol/ L;p < 0.05). Median survival time was significantly longer in the PTXF group (210 versus90 min; p < 0.002). These data demonstrate that PLXF can ameliorate some of the deleterious hemodynamic manifestations of group B streptococci sepsis and result in improved survival in a young animal model. (Pediatr Res31: 596–600, 1992)

Respiratory training of premature infants was performed to determine whether improved respiratory muscle strength and/or endurance would result. Twenty-two premature infants were randomized into control and training groups for 2 wk, using inspiratory flow-resistive loads for training (75 cm H2O-L-1-s in wk 1 and 90 cm H2O-L-1-s in wk 2). Respiratory endurance was assessed by the time interval required for the development of a 5-torr rise in transcutaneous CO2tension during the hypoventilation induced by loaded breathing, using a moderately severe resistive load (250 cm H2O-L-1-s at 1 L-min-1). Respiratory strength was assessed by the maximum negative airway pressure generated during occluded breaths, a pressure-time integral, and an effort index. Results revealed that respiratory muscle endurance, which was not initially different between control and trained groups, increased significantly after 2 wk in the trained group by 137 (median value, p< 0.05), whereas it remained unchanged in the control group (-24). The trained group of infants also showed a significant decrease in baseline breathing frequency between the initial and final measurements taken 2 wk apart when compared with controls (p< 0.05) and a lesser increase in inspiratory time with loading in the final measurement as compared with the initial value (p< 0.05). There was no significant difference between the control and trained groups in initial or subsequent measures of respiratory muscle strength. Inspiratory flow-resistive load training appears to improve the respiratory endurance of premature infants in whom respiratory muscle fetigue has been described to play a role in the development of respiratory failure. (Pediatr Res31: 613–618, 1992)

The effect of the cyclooxygenase inhibitor, indomethacin, on choroidal (ChBF) and retinal (RBF) blood flow during hypercarbia was examined in 16 paralyzed and mechanically ventilated piglets less than 8 d old. The animals were randomly assigned to a control group (mean ± SEM: wt, 1.66 ± 0.1 kg; n= 8) that received a placebo infusion or to an indomethacin treatment group (wt, 1.68 ± 0.2 kg; n= 8) that received an infusion of indomethacin (5 mg/kg i.v. over 30 min). Baseline ChBF and RBF were measured using radiolabeled microspheres in room air before and 15 min after the administration of placebo or indomethacin. Animals were then exposed to 30 min of hypercarbia (6–7 CO2, arterial CO2pressure 8–10 kPa) and measurements were repeated. There were no significant differences in RBF between control (40 ± 3 mL/ min/100 g) and indomethacin-treated animals (40 ± 3 mL/ min/100 g) before administration of placebo or indomethacin. However, RBF decreased significantly in the indomethacin-treated animals (28 ± 2 mL/min/100 g) compared to the control group (42 ± 4 mL/min/100 g) 15 min after administration of placebo or indomethacin. Furthermore, an increase in RBF occurred during hypercarbia in the control group (86 ± 6 mL/min/100 g), but this change was blunted in the indomethacin-treated animals (33 ± 5 mL/min/100 g) (p< 0.001). In contrast, ChBF did not differ significantly between the control and indomethacin groups during the periods studied. These results suggest that the increase in RBF during hypercarbia is at least partially mediated by cyclooxygenase by-products of ara-chidonic acid metabolism. The change in ChBF appears to be less influenced by these mediators.

Low dose ATP-MgCl2is reported to cause selective pulmonary vasodilation during hypoxic and thromboxane mimetic-induced constriction. In addition, it has been shown to increase cardiac output and improve cellular function during circulatory shock. Based on these properties we hypothesized that ATP-MgCl2might ameliorate the cardiopulmonary manifestations of sepsis secondary to group B streptococci (GBS). We studied 14 anesthetized, mechanically ventilated piglets who received a continuous infusion of GBS (7.5× 107colony-forming units/kg/min) and were randomly assigned to a treatment group that received a continuous infusion of ATP-MgCl2at 0.6 μmol/kg/min or a control group that received normal saline as placebo. Comparison of the hemodynamic measurements, pulmonary mechanics, and arterial blood gases over the first 120 min of ATP-MgCl2infusions with those of the control group revealed the following: GBS infusion caused significant increases in mean pulmonary artery pressure, pulmonary vascular resistance(PVR), mean systemic arterial blood pressure, systemic vascular pressure(SVR), and PVR/SVR ratio with decreases in cardiac output and stroke volume. ATP-MgCl2caused significant reduction in mean pulmonary artery pressure (p< 0.001), PVR (p< 0.0001), mean systemic arterial blood pressure (p< 0.003), SVR (p< 0.01), and PVR/SVR ratio (p< 0.03) with improvement in cardiac output (p< 0.001) and stroke volume (p< 0.01). The partial pressure of arterial O2(p< 0.04), and pH (p< 0.001) were higher and the partial pressure of arterial CO2(p< 0.02) lower in ATP-MgCl2-treated animals. Also dynamic lung compliance was higher (p< 0.001) and pulmonary airway resistance lower (p< 0.001) in treated animals. Median survival in control animals was 153 min, whereas all treated animals survived to 240 min (p< 0.001). These data demonstrate that ATP-MgCl2ameliorates the deletrious cardiopulmonary manifestations of GBS sepsis and results in improved survival in a young animal model.

Fourteen preterm infants with apnea (body weight, 1052 ± 44 g; gestational age, 30.2 ± 0.5 wks; and postnatal age, 9.9 ± 1.5 days) were studied in an effort to evaluate the effects of aminophylline on respiratory center output and respiratory reflex activity in the preterm infant with idiopathic apnea. This was done by using the airway occlusion technique. The infants were studied before and 48 h after aminophylline was begun as a treatment for apnea. Occlusion pressure, which reflects respiratory center output, was measured at 100 msec after occlusion started (P100) and at its maximum (Pmo). P100 increased from 2.4 ± 0.2 to 3.1 ± 0.2 cmH2O (P< 0.005), and Pmo from 6.1 ± 0.7 to 8.8 ± 1.0 cmH2O (P< 0.001) after aminophylline therapy was started.

Leukotrienes have been implicated in the pathogenesis of hypoxic pulmonary hypertension in adult animals and in persistent pulmonary hypertension with accompanying hypoxemia in the neonate. In order to elucidate the role of leukotrienes in hypoxic pulmonary hypertension in a young animal model, the effects of a leukotriene antagonist, FPL 57231, were evaluated in anesthetized piglets. Cardiac output and vascular pressures were measured and pulmonary and systemic vascular resistances calculated prior to and during hypoxia. These measurements were compared during continued hypoxia between a control and treatment group which received FPL 57231. FPL 57231 infusion resulted in significant decreases in mean pulmonary artery pressure (p<0.04), pulmonary vascular resistance (p<0.01) and the ratio of pulmonary/systemic vascular resistance (p<0.01). Systemic vascular resistance fell approximately 25 from hypoxic baseline (p<0.01) while PVR decreased 54. There were no differences between groups in mean systemic arterial pressure, cardiac output, pH, or PaCO2. In addition, pretreatment with FPL 57231 attenuated the hemodynamic response to hypoxia. These data suggest that leukotrienes may, in part, mediate hypoxic pulmonary vasoconstriction in piglets. (Pediatr Res 19 1201-1205, 1985)

An open circuit N2washout technique is described for the determination of functional residual capacity in infants. Either 100 O2or any oxygen/helium mixture can be used as the washing gas. The subject breathes the washing gas through a T-tube and the washed out nitrogen is mixed with this gas in a mixing chamber, placed into the exhalation part of the circuit. The N2concentration of the mixed gas is analyzed continuously, and the concentration signal is electronically integrated over time. Calibration of the system is accomplished by injecting known amounts of nitrogen or room air into the circuit. The gas flow through the system must remain constant and is adjusted to approximate peak inspiratory flow of the infant. In vitro testing of the system showed that the technique gives reproducible values (coefficient of variance 1.0) and that the integrated signal output has a close linear correlation with the amount of N2washed out (r0.99). In vivo measurements in 10 cats confirmed the accuracy and reproducibility of the method when compared with N2collection. The technical advantages of the system are simplicity of components, absence of valves, easy calibration, low dead space, and no need to collect or measure expired gases. For the infant this means no added resistance during washout and no risk of hypoxia, hyperoxia, or hypercapnea. In the presence of pulmonary disease and poor gas mixing the washout period can be prolonged as needed. There is no lower limit of weight or size for functional residual capacity measurements in small infants or animals. (Pediatr Res 19 1165-1169, 1985)

Seventeen piglets were infected with a continuous intravenous infusion of live group B β-hemolytic streptococci (GBS). Hemodynamic changes were recorded, and blood samples were drawn for measurement of thromboxane B2(TxB2) (stable metabolite of thromboxane A2) and 6-keto-PGF1α(stable metabolite of prostacyclin). Control animals (n9) received only bacteria, while treatment animals (n8) received indomethacin, 3 mgkg IV, 15 min after the start of the bacterial infusion. Control animals responded to the bacteria within 15 min with marked elevation in mean pulmonary artery pressure (Ppa) from 15 ± 8 to 39 ± 6 mm Hg and decline in Pao2from 80 ± 11 to 51 ± 6 mm Hg and cardiac output (CO) from 0.24 ± 0.07 to 0.13 ± 0.07 litersmin kg. Mean arterial blood pressure (AoP) significantly decreased from baseline value of 95 ± 13 to 51 ± 32 mm Hg by 180 min. In animals treated with indomethacin, these changes were reversed or significantly attenuated. The hemodynamic changes were associated temporally with elevations in plasma concentrations of TxB2or 6-keto-PGF1α. In he first 60 min, TxB2levels in both groups correlated with Ppa (r0.72, p<0.001) and Pao2(r-0.60, p<0.001). A strong negative correlation between TxB2and CO was observed over the first 180 min (r-0.73, p<0.001). There was a statistically significant correlation between AoP and 6-keto-PGF1αconcentration between 60 and 180 min (r-0.54, p<0.002). Indomethacin improved the hemodynamic function in this model of GBS sepsis. This improvement was related in part to inhibition of synthesis of thromboxane A2and prostacyclin.