Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system.

The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT(1) receptor (AT(1)-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO(2) = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT(1)-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT(1)-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT(1)-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT(1)-R staining, but C animals showed weak iNOS and AT(1)-R staining. Macrophages of L and P animals showed moderate and weak AT(2)-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT(1)-R blockade. We suggest that AT(1)-R blockade might act through AT(2)-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT1 receptor (AT1-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO2 = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT1-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT1-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT1-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT1-R staining, but C animals showed weak iNOS and AT1-R staining. Macrophages of L and P animals showed moderate and weak AT2-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT1-R blockade. We suggest that AT1-R blockade might act through AT2-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

Effects of instrumental dead space reduction during weaning from synchronized ventilation in preterm infants.

OBJECTIVE: A majority of the modalities of synchronized ventilation in preterm infants require the use of flow sensors that can increase dead space and may adversely affect ventilator weaning. The objective of this study was to assess the effects of flow sensor dead space during synchronized intermittent mandatory ventilation (SIMV) weaning in preterm infants. STUDY DESIGN: Twelve preterm infants (gestational age 25+/-2 weeks, birth weight 705+/-158 g, age: 31+/-186 days, SIMV rate: 25+/-8 breaths min(-1), peak inspiratory pressure 18+/-2 cm H(2)O, positive end-expiratory pressure: 5+/-0.5 cm H(2)O, pressure support: 9+/-3 cm H(2)O, fraction of inspired oxygen: 34+/-6%) underwent two 2.5-h weaning periods during which SIMV rate was reduced twice by 5 breaths min(-1) at 30-min intervals as tolerated, with and without reduction of flow sensor dead space, in random sequence. A 30-min baseline was obtained before each weaning period. Dead space was reduced by flushing the flow sensor with a continuous gas leak flow in the endotracheal tube connector. RESULT: Transcutaneous CO(2) tension during SIMV weaning periods without and with reduced dead space did not differ from baseline, whereas total minute ventilation and tidal volume were lower during the SIMV weaning period with reduced dead space. Three infants did not tolerate SIMV weaning without while one infant did not tolerate weaning with reduced dead space. CONCLUSION: SIMV weaning elicited a compensatory rise in spontaneous ventilation. When flow sensor dead space was reduced during SIMV weaning, gas exchange was maintained with lower minute ventilation. Instrumental dead space imposes a ventilatory burden during SIMV weaning in small preterm infants.

Mechanical ventilatory support in preterm infants.

A large proportion of premature infants presents with acute respiratory failure after birth and require mechanical ventilatory support. In addition to conventional mechanical ventilation, an increasing number of these infants are currently supported by newer modes including synchronized, volume targeted and noninvasive mechanical ventilation. While these new modes have improved weaning from mechanical ventilation they have not had a consistent impact on respiratory outcome or other morbidities. This is a review of the different modes of invasive and noninvasive mechanical ventilation used to support premature infants with respiratory failure.

Antenatal exposure to magnesium sulfate and the incidence of patent ductus arteriosus in extremely low birth weight infants.

OBJECTIVE: Magnesium sulfate (MgSO(4)) is the most commonly used tocolytic agent in the US and is also employed as a prophylactic agent against seizures in pre-eclamptic women. MgSO(4) crosses the placenta and its concentration in the newborn usually exceeds that of maternal levels. The purpose of this study was to explore the relationship between antenatal exposure to MgSO(4) and the incidence of patent ductus arteriosus (PDA) in extremely low birth weight infants. STUDY DESIGN: A total of 954 neonates with birth weights between 500 and 1000 g, born at the University of Miami/Jackson Memorial Hospital between January 1995 and December 2004 and surviving for more than 3 days, were followed until death or discharge from the hospital. The incidence of PDA in infants exposed to MgSO(4) was compared with those not exposed and comparisons were also made between infants exposed to different maternal doses of MgSO(4). RESULTS: The incidence of PDA was significantly higher in the group of infants exposed to MgSO(4) compared with the unexposed control group (67 vs. 60%, P<0.018). When stratified by gestational age the differences were significant only in the group of infants with a gestational age of >or=26 weeks (58 vs. 49%, P<0.039). Logistic regression analysis to adjust for co-variables indicated an increased risk of PDA with higher doses of MgSO(4) (odds ratio 1.33 confidence interval (CI) 1.12 to 1.58, per 50 g of MgSO(4)). CONCLUSION: Antenatal exposure to MgSO(4) is associated with a higher risk of PDA in extremely low birth weight infants and this effect is more significant and dose-related in more mature infants.

Continuous positive airway pressure: early, late, or stay with synchronized intermittent mandatory ventilation?

Mechanical ventilation is associated with significant short- and long-term morbidity in small preterm infants. Continuous positive airway pressure applied through nasal prongs is an effective, less-invasive method to improve gas exchange and reduce apnea in these infants. A large number of studies have evaluated the possibility of reducing the need or duration of mechanical ventilation by early use of nasal continuous positive airway pressure shortly after birth and by applying it after extubation. Although results of these trials have not been consistent, most of the evidence suggests that nasal continuous positive airway pressure is a viable alternative to mechanical ventilation in many preterm infants and that its use after extubation contributes to maintain better lung function and reduces apnea. Despite this, there is no evidence that these beneficial short-term effects translate into lower rates of long-term morbidity such as bronchopulmonary dysplasia and neurologic sequelae or mortality rates.

Proportional assist ventilation in infants.

Proportional assist ventilation and respiratory mechanical unloading is a new mode of respiratory assistance that produces similar gas exchange with lower airway pressures than conventional ventilation in infants. This is achieved by tailoring the ventilator pressure contour to the specific derangements in lung mechanics and by a near perfect synchronization with the infant's own inspiratory effort. In contrast to conventional ventilation, PAV only amplifies the effect on ventilation of the spontaneous respiratory effort and relies on the subject's respiratory control. Whether PAV will reduce the incidence of acute complications and chronic pulmonary sequelae in infants needs to be evaluated in randomized controlled trials.

Closed-loop controlled inspired oxygen concentration for mechanically ventilated very low birth weight infants with frequent episodes of hypoxemia.

BACKGROUND: Mechanically ventilated very low birth weight infants often present with frequent episodes of hypoxemia, and maintaining arterial oxygen saturation by pulse oximetry (SpO(2)) within a normal range by manual fraction of inspired oxygen (FIO(2)) adjustments is difficult and time consuming. OBJECTIVES: An algorithm for closed-loop FIO(2) control (cFIO(2)) to maintain SpO(2) within a target range was compared with continuous manual FIO(2) (mFIO(2)) adjustments by a nurse in a group of ventilated infants who presented with frequent episodes of hypoxemia. RESULTS: Fourteen infants (birth weight: 712 +/- 142 g; gestational age: 25 +/- 1.6 weeks; age: 26 +/- 11 days; synchronized intermittent mandatory ventilation rate: 24 +/- 10 b/m; peak inspiratory pressure: 17.5 +/- 2.0 cmH(2)O; positive end-expiratory pressure: 4.3 +/- 0.5 cmH(2)O) were studied for 2 hours on each mode in random sequence. Both modes aimed to maintain SpO(2) between 88% and 96%. There were 15 +/- 7 and 16 +/- 6 hypoxemic episodes/hour (SpO(2) <88%, >5 s) during mFIO(2) and cFIO(2), respectively; episode duration was 41 +/- 23 and 32 +/- 15 s, totaling 19 +/- 16% and 17 +/- 12% of recording time. There were 13 +/- 10 and 10 +/- 8 hyperoxemic episodes/hour (SpO(2)>96%, >5 s) during mFIO(2) and cFIO(2,) respectively; episode duration was 27 +/- 15 and 24 +/- 19 s, totaling 15 +/- 14% and 10 +/- 9% of recording time. Mean SpO(2) and FIO(2) levels were similar during both modes. The nurse made 29 +/- 17 adjustments/hour during mFIO(2). There was a significant increase in the duration of normoxemia (SpO(2) between 88%-96%) during cFIO(2) (75 +/- 13 vs 66 +/- 14% of recording time). CONCLUSION: In this group of infants, cFIO(2) was at least as effective as a fully dedicated nurse in maintaining SpO(2) within the target range, and it may be more effective than a nurse working under routine conditions. We speculate that during long-term use, cFIO(2) may save nursing time and reduce the risks of morbidity associated with supplemental oxygen and episodes of hypo- and hyperoxemia.

Bronchopulmonary dysplasia and surfactant.

Bronchopulmonary dysplasia (BPD) is the most common respiratory complication in preterm infants who survive prolonged mechanical ventilation. Exogenous surfactant administration clearly reduces the severity of respiratory distress syndrome (RDS) and consequently the need for aggressive ventilation and prolonged oxygen therapy. However, the overall incidence of BPD has not decreased but in fact may even have increased after the introduction of surfactant therapy. There are several reasons for the lack of effect on the incidence of BPD. First, surfactant therapy and antenatal steroids have markedly increased survival of the smallest infants, i.e. those at higher risk of BPD. Second, there has been a change in the pathogenesis and the presentation of BPD. While the classic BPD was mainly the consequence of barotrauma and oxygen toxicity, the new BPD seen in the surfactant era results from the interaction of many factors that lead to prolonged mechanical ventilation and colonization of the airway with pathogens that may trigger an inflammatory cascade. While the overall incidence of BPD has not been substantially modified by surfactant therapy, the more severe cases of BPD have become less common. The data regarding the effect of surfactant administration on the incidence and severity of BPD is conflicting. There is substantial evidence that the administration of exogenous surfactant, either as prophylaxis or as a treatment in infants with established RDS, can reduce neonatal mortality and the occurrence of BPD or death. The data also suggest that prophylactic or early administration is more effective than late treatment in reducing mortality and BPD or death. No clear difference has been documented between natural or synthetic surfactant treatment in terms of their effect on incidence of BPD or mortality. The lack of consistency in the results with surfactant replacement may reflect the changing pathogenesis of BPD and the multiplicity of factors involved among which surfactant deficiency is only one.

Changes in the pathogenesis and prevention of chronic lung disease of prematurity.

With the increasing survival of extremely premature infants there is a large number of them who are developing chronic lung disease (CLD), but the severity of the lung damage is considerably less than that observed in the classic form of bronchopulmonary dysplasia (BPD). Because many of these infants have only a mild initial respiratory distress and therefore do not receive aggressive ventilation, it is clear that factors other than oxygen toxicity and barotrauma are involved in the pathogenesis of this new milder type of CLD. CLD results from the interaction of multiple factors that can injure the immature lung. For this reason the prevention must be based on the elimination of all the factors implicated in its pathogenesis. Clinical and epidemiological data strongly suggest that infections, either prenatal or nosocomial, and the presence of a patent ductus arteriosus (PDA) play a major role in the development of CLD in these infants. For this reason, efforts to prevent CLD in extremely low birth weight infants should include an aggressive approach to the prevention and treatment of prenatal and neonatal infections and an early closure of the PDA.

Inductance plethysmography: an alternative signal to servocontrol the airway pressure during proportional assist ventilation in small animals.

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.

Proportional assist ventilation decreases thoracoabdominal asynchrony and chest wall distortion in preterm infants.

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 H(2)O/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 H(2)O 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.

Effects of anti-CD18 monoclonal antibody, R15.7, on the cardiopulmonary manifestations of group B streptococcal sepsis in piglets.

We hypothesized that anti-CD18 monoclonal antibody, R15.7, a murine IgG(1) antibody which blocks leukocyte-endothelial cell adherence, might ameliorate the cardiopulmonary manifestations of sepsis secondary to group B streptococci (GBS). Twenty-six anesthetized, mechanically ventilated newborn piglets received a continuous infusion of GBS (7.5 x 10(9) cfu/kg/min) and were randomly assigned to a treatment group receiving R15.7 (1 mg/kg i.v.) 15 min prior to GBS infusion or to a control group. Cardiopulmonary measurements, arterial blood gases and peripheral blood leukocytes were obtained over 120 min of R15.7 infusion. GBS infusion caused significant increases in pulmonary artery and systemic arterial blood (Psa) pressures, pulmonary vascular (PVR) and systemic vascular (SVR) resistances, and PVR/SVR ratio with decreases in cardiac output and stroke volume. R15.7-treated piglets maintained significantly higher Psa (p < 0.003), dynamic lung compliance (p < 0.04), PaO2 and pH (p < 0.05), and lower total lung resistance (p < 0.01) and PaCO2 (p < 0.04). A longer median survival time was observed in the treatment group (p < 0.01). These data suggest that administration of a CD18-blocking agent prolongs survival in a young animal model of GBS sepsis, possibly secondary to improved tissue perfusion, lung mechanics and acid-base status.

Effects of GABA receptor blockade on the ventilatory response to hypoxia in hypothermic newborn piglets.

Hypothermic newborn piglets have a depressed ventilatory response to hypoxia, and this may be due to an increase in CNS gamma-aminobutyric acid (GABA) levels. To evaluate the effects of GABA(A) receptor 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 degrees C [normothermia (NT), n = 15] or 34 +/- 0.5 degrees C [hypothermia (HT), n = 16]. 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 microL of bicuculline methiodide (BM; 10 microg) 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 versus HT, 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 versus HT, 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.