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.

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.

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.

Effect of L-aspartate on the ventilatory response to hypoxia in sedated newborn piglets.

L-aspartate (L-ASP) acts as an excitatory amino acid neurotransmitter at the synapses of brain stem respiratory neurons. In order to determine the effect of L-ASP on the neonatal ventilatory response to hypoxia, 9 control piglets [age 4.3 +/- (SD) 0.9 days, weight 1.9 +/- 0.5 kg] and 9 L-ASP-treated animals [age 5.0 +/- (SD) 1.4 days, weight 2.1 +/- 0.7 kg] were studied. Minute ventilation, oxygen consumption, arterial blood pressure, and blood gases were measured in sedated piglets while spontaneously breathing room air and during 1, 5, and 10 min of hypoxia (O2 concentration in inspired gas 0.10). Measurements were obtained before and 60 min after the administration of L-ASP (580 mg/kg i.v. over 1 h) or 5% dextrose solution. In the control animals, the ventilatory response to hypoxia was similar before and after dextrose infusion. In contrast, a significant and sustained increase in ventilation was observed at 1, 5, and 10 min of hypoxia after the administration of L-ASP. Changes in oxygen consumption, heart rate, arterial blood pressure, pH, and arterial O2 tension with hypoxia were similar before and after the L-ASP infusion, while the arterial CO2 tension decreased significantly during hypoxia after the administration of L-ASP. These data suggest that the excitatory amino acid L-ASP is an important mediator of the hypoxic hyperventilation in the neonate. We speculate that the administration of exogenous L-ASP modifies the balance of central nervous system neurotransmitters during hypoxia, resulting in predominance of excitatory neurotransmission.

Depressed ventilatory response to hypoxia in hypothermic newborn piglets: role of glutamate.

To evaluate whether changes in extracellular glutamate (Glu) levels in the central nervous system could explain the depressed hypoxic ventilatory response in hypothermic neonates, 12 anesthetized, paralyzed, and mechanically ventilated piglets <7 days old were studied. The Glu levels in the nucleus tractus solitarius obtained by microdialysis, minute phrenic output (MPO), O2 consumption, arterial blood pressure, heart rate, and arterial blood gases were measured in room air and during 15 min of isocapnic hypoxia (inspired O2 fraction = 0.10) at brain temperatures of 39.0 +/- 0.5 degrees C [normothermia (NT)] and 35.0 +/- 0.5 degrees C [hypothermia (HT)]. During NT, MPO increased significantly during hypoxia and remained above baseline. However, during HT, there was a marked decrease in MPO during hypoxia (NT vs. HT, P < 0.03). Glu levels increased significantly in hypoxia during NT; however, this increase was eliminated during HT (P < 0.02). A significant linear correlation was observed between the changes in MPO and Glu levels during hypoxia (r = 0.61, P < 0.0001). Changes in pH, arterial PO2, O2 consumption, arterial blood pressure, and heart rate during hypoxia were not different between the NT and HT groups. These results suggest that the depressed ventilatory response to hypoxia observed during HT is centrally mediated and in part related to a decrease in Glu concentration in the nucleus tractus solitarius.

Effect of N-methyl-D-aspartate-receptor blockade on hypoxic ventilatory response in unanesthetized piglets.

The central excitatory amino acid (EAA) neurotransmitter glutamate has been shown to mediate the ventilatory response to hypoxia through N-methyl-D-aspartate (NMDA) receptors in anesthetized adult animals. To determine the role of the EAA glutamate in the neonatal ventilatory response to hypoxia, 19 unanesthetized chronically instrumented piglets were studied. Minute ventilation (VE), oxygen consumption (VO2), arterial blood pressure (ABP), heart rate (HR), and blood gases were measured in room air (RA) and after 1, 5, and 10 min of hypoxia (inspired oxygen fraction = 0.10) before and after an infusion of saline or CGS-19755, a competitive NMDA-receptor blocker (10 mg/kg i.v.). Nine control piglets [age 6 +/- 1 (SD) days; weight 2.02 +/- 0.40 kg] and 10 CGS-19755-treated animals (age 6 +/- 1 days; weight 1.90 +/- 0.66 kg) were studied during quiet sleep and in a thermoneutral environment. There was a marked decrease in the VE response to hypoxia after the administration of CGS-19755. The ventilatory response to hypoxia was not modified by saline infusion. Changes in ABP and arterial PO2 during hypoxia were similar between groups, whereas the decrease in arterial PCO2 was significantly less after CGS-19755 administration. The increase in HR with hypoxia was eliminated by the NMDA-receptor blocker administration. VO2 decreased with hypoxia in both groups, but this decrease was more marked after the NMDA-receptor blockade. These results suggest that the central EAA glutamate mediates, at least in part, the hypoxic hyperventilation in unanesthetized newborn piglets.

Decreased ventilatory response to hypoxia in sedated newborn piglets prenatally exposed to cocaine.

OBJECTIVE: Infants exposed to cocaine in utero have been reported to have a higher incidence of apnea and altered ventilatory response to carbon dioxide and hypoxia. We investigated whether in utero cocaine exposure results in greater ventilatory depression during hypoxia in piglets. METHODS: Cocaine hydrochloride, 1.0 or 2.0 mg/kg given intramuscularly, or saline solution was administered daily to pair-fed pregnant sows during the last month of gestation. Thirteen cocaine-exposed piglets (mean +/- SD: age, 4.4 +/- 1.3 days; weight, 2.10 +/- 0.10 kg) and 15 saline solution-exposed piglets (age, 4.6 +/- 1.1 days; weight, 2.32 +/- 0.42 kg) were studied under chloral hydrate sedation. Minute ventilation (VE), arterial blood pressure (BP), heart rate (HR), oxygen consumption (VO2), and arterial blood gases were measured in room air. During hypoxia (fraction of inspired oxygen = 0.10), the values for VE, BP, and HR were obtained at 1, 5, and 10 minutes, VO2 was calculated during the last 5 minutes, and arterial blood gas samples taken after 10 minutes. RESULTS: Basal VE did not differ between saline solution- and cocaine-exposed animals. The increase in VE at 1 minute of hypoxia was also similar. However, at 5 and 10 minutes of hypoxia, VE was significantly lower in the cocaine group than in the saline group (6% +/- 9% and 4% +/- 10% vs 15% +/- 13% and 21% +/- 14%; p < 0.02). Mean baseline BP and the initial increase in BP during hypoxia were not different between groups. However, BP remained increased throughout hypoxia only in the saline solution-exposed animals (p < 0.05). Changes in HR, VO2, arterial oxygen tension, and base excess during hypoxia were similar between groups. CONCLUSIONS: These results show a decrease in the ventilatory response to hypoxia in newborn piglets prenatally exposed to cocaine. This change is most likely to be centrally mediated because the initial hypoxic hyperventilation was not modified by the intrauterine cocaine exposure. This decrease in ventilation cannot be explained by changes in metabolic rate or in cardiovascular or acid-base status.

Effects of chloral hydrate on the cardiorespiratory response to hypoxia in newborn piglets.

To assess the effects of chloral hydrate (CH) on the cardiorespiratory response to hypoxia in the neonate, 17 newborn piglets were chronically instrumented 48-72 h before study and randomly assigned to a CH group (100 mg/kg, i.p.) or saline group. The animals were intubated and studied under quiet sleep which was determined by behavioral states, and continuous electro-oculographic and electroencephalographic monitoring. Minute ventilation (VE), tidal volume, respiratory rate, arterial blood gases (ABG), oxygen consumption (VO2), arterial blood pressure (ABP) and heart rate (HR) were measured before and after CH or saline administration during room air and after 10 min of hypoxia (fraction of inspired oxygen concentration = 0.10). Cardiorespiratory response to hypoxia was similar before and after saline infusion. Basal VE and the ventilatory response to hypoxia were similar before and after CH administration. In contrast, the basal ABP decreased significantly (p < 0.05) after CH administration, but the ABP response to hypoxia was similar before and after CH. A significant increase in both basal HR and HR with hypoxia was observed after CH administration. In addition, VO2 and ABG were not modified by CH treatment during normoxia and hypoxia. These data demonstrate that a sedative dose of CH does not significantly modify the ventilatory response to hypoxia in newborn piglets. However, CH produced some changes in the cardiovascular system which should be considered when using it in infants with hemodynamic derangements.

Effects of epinephrine on the cardiorespiratory response to hypoxia in sedated newborn piglets with intact and denervated carotid bodies.

In order to evaluate the effects of epinephrine on the cardiorespiratory response to hypoxia in the neonate, 35 sedated, spontaneously breathing newborn piglets (mean +/- SD, age 5 +/- 0.8 days; weight 1.6 +/- 0.3 kg) with intact (ICB) or denervated (DCB) carotid bodies were studied before and during an infusion of saline or epinephrine (2.2 +/- 1.0 microgram/kg/min, i.v.). Cardiorespiratory measurements were performed while the animals breathed room air and after 10 min of hypoxia (FiO2 0.10) during saline or epinephrine infusion. During epinephrine infusion, the ICB animals had a sustained increase in minute ventilation during hypoxia while the control group showed a biphasic ventilatory response with depression during sustained hypoxia. After the chemodenervation, the ventilatory response to hypoxia was completely blunted in saline and epinephrine animals. In the ICB and DCB animals, the arterial blood pressure decreased significantly with hypoxia during epinephrine infusion, while cardiac output increased significantly in all ICB and DCB saline animals. The oxygen consumption (VO2) decreased significantly after 10 min of hypoxia in all groups except in the ICB epinephrine animals, in whom the VO2 did not change with hypoxia. In conclusion, the administration of epinephrine to newborn piglets reverses the depressed ventilatory response to hypoxia and this effect requires the activity of the peripheral chemoreceptors.

Effects of GABA receptor blockage on the respiratory response to hypoxia in sedated newborn piglets.

Brain gamma-aminobutyric acid (GABA) levels increase during hypoxia, which may modulate the ventilatory response to hypoxia. To test the possibility that the depressed neonatal ventilatory response to hypoxia may be related to increased central nervous system GABA activity, 26 sedated spontaneously breathing newborn piglets (age 5 +/- 1 day, wt 1.7 +/- 0.4 kg) were studied. Minute ventilation (VE), oxygen consumption, heart rate, arterial blood pressure, and arterial blood gases were measured in room air and after 1, 5, and 10 min of hypoxia (inspired O2 fraction 0.10) before drug intervention. Immediately after these measurements, an infusion of saline or the GABA alpha-receptor blocker (bicuculline, 0.3 mg/kg iv) or beta-receptor blocker (CGP-35348, 100-300 mg/kg iv) was administered while animals were hypoxic. All measurements were repeated at 1, 5, and 10 min after initiation of the drug infusion. Basal VE was similar among groups. During hypoxia, VE increased significantly in the animals that received either a GABA alpha- or beta-receptor blocker but not in those receiving saline. Changes in arterial Po2, oxygen consumption, heart rate, and arterial blood pressure were similar among groups before and after saline or GABA antagonist infusion. These results suggest that the decrease in ventilation during the biphasic ventilatory response to hypoxia in the neonatal piglet is in part mediated through the depressant effect of GABA on the central nervous system.

Effect of dopamine on hypoxic ventilatory response of sedated piglets with intact and denervated carotid bodies.

To determine whether the neonatal hypoxic ventilatory depression is in part produced by an increased endogenous dopamine release that can depress the activity of central and peripheral chemoreceptors, 31 sedated and spontaneously breathing newborn piglets [age 5 +/- 1 (SD) days; weight 1.7 +/- 0.4 kg] were randomly assigned to an intact carotid body or a chemodenervated group. Minute ventilation (VE), arterial blood pressure, and cardiac output (CO) were measured in room air before infusion of saline or the dopamine antagonist flupentixol (0.2 mg/kg i.v.) and 15 min after drug infusion and were repeated after 10 min of hypoxia (inspiratory O2 fraction = 0.10). VE increased significantly after 10 min of hypoxia in the piglets that received flupentixol independent of whether the carotid bodies were intact or denervated. However, the increase in VE was largest and sustained throughout the 10 min of hypoxia only in the intact carotid body flupentixol group. As expected, the initial increase in VE with hypoxia was abolished by carotid body denervation. Changes in arterial blood gases, CO, and mean arterial blood pressure with hypoxia were not different among groups. These results demonstrate that flupentixol reverses the late hypoxic decrease in VE, acting through peripheral and central dopamine receptors. This effect is not related to changes in cardiovascular function or acid-base status.

Changes in ventilation and oxygen consumption during acute hypoxia in sedated newborn piglets.

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 VO2 was 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 VO2 values did not differ between groups during normoxia, and a similar decrease in VO2 occurred in both groups after 10 min of hypoxia. Furthermore, no correlation was observed between changes in VE and VO2 during hypoxia either in absolute values or in the percent change from room air baseline. Arterial PO2 decreased similarly in both groups, but PACO2 decreased 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 VO2 that occurs during hypoxia.

Effect of amino acid infusion on the ventilatory response to hypoxia in protein-deprived neonatal piglets.

Several amino acids (AA) act as neurotransmitters 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 AA 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.

Effect of cyclooxygenase inhibition on retinal and choroidal blood flow during hypercarbia in newborn piglets.

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 CO2 pressure 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 less than 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 arachidonic acid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of alpha adrenergic blockade on brain blood flow and ventilation during hypoxia in newborn piglets.

The influence of cardiovascular changes on ventilation has been demonstrated in adult animals and humans (Jones, French, Weissman & Wasserman, 1981; Wasserman, Whipp & Castagna 1974). It has been suggested that neonatal hypoxic ventilatory depression may be related to some of the hemodynamic changes that occur during hypoxia (Brown & Lawson, 1988; Darnall, 1985; Suguihara, Bancalari, Bancalari, Hehre & Gerhardt, 1986). To test the possible relationship between the cardiovascular and ventilatory response to hypoxia in the newborn, eleven sedated spontaneously breathing piglets (age: 5.9 +/- 1.6 days; weight: 1795 +/- 317 g; SD) were studied before and after alpha adrenergic blockade with phenoxybenzamine. Minute ventilation (VE) was measured with a pneumotachograph, cardiac output (CO) by thermodilution and total and regional brain blood flow (BBF) with radiolabeled microspheres. Measurements were performed while the animals were breathing room air and after 10 min of hypoxia induced by breathing 10% O2. Hypoxia was again induced one hour after infusion of phenoxybenzamine (6 mg/kg over 30 min). After 10 min of hypoxia, in the absence of phenoxybenzamine, the animals responded with marked increases in VE (P less than 0.001), CO (P less than 0.001), BBF, and brain stem blood flow (BSBF) (P less than 0.02). However, the normal hemodynamic response to hypoxia was eliminated after alpha adrenergic blockade. There were significant decreases in systemic arterial blood pressure, CO, and BBF during hypoxia after phenoxybenzamine infusion; nevertheless, VE increased significantly (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of conventional and high frequency oscillatory ventilation in normal and septic piglets.

The cardiovascular effects of high frequency oscillation (HFO) and conventional ventilation (CMV) were evaluated in 10 piglets prior to and during an infusion of group B streptococci (GBS). Animals were randomized to begin ventilation with either HFO or CMV. Arterial blood gases, cardiac output (CO), and pulmonary artery (Ppa), pulmonary wedge (Ppw) and arterial blood pressures were measured. These values were recorded at a mean airway pressure (MAP) of 2 cm H2O for both modes of ventilation after which a continuous infusion of GBS (4 X 10(7) CFU/kg/min) was begun. MAP was increased in both ventilators in the following sequence: 4, 8 and 12 cm H2O. Prior to GBS infusion, HFO was associated with small but significant changes in hemodynamic parameters when compared to CMV for the following: Ppa (15 +/- 4 vs. 13 +/- 4.0 mm Hg; p less than 0.03), Ppw (3 +/- 1 vs. 2 +/- 1 mm Hg; p less than 0.02), and CO (0.24 +/- 0.08 vs. 0.25 +/- 0.09 l/min/kg; p less than 0.05). Similar statistically significant increases in Ppa (p less than 0.005) and Ppw (p less than 0.0001), and decrease in CO (p less than 0.007) were present during GBS infusion when animals were ventilated with HFO, irrespective of the MAP used. Our results suggest that the use of HFO in both normal piglets and those receiving an infusion of GBS results in mild but consistent impairment in cardiovascular function compared to CMV. In summary, these data demonstrate that HFO has no beneficial effect compared to CMV at similar MAP in the management of the septic piglet model and may in fact further compromise the animal's hemodynamic status.

Brain blood flow and ventilatory response to hypoxia in sedated newborn piglets.

To evaluate the relationship between brain blood flow and ventilatory response to hypoxia, seventeen sedated, spontaneously breathing newborn piglets were studied. Minute ventilation (VE) 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 increased VE during the 1st min of hypoxia, but nine (mean +/- SD; age 5 +/- 1.3 d; wt 1828 +/- 437 g) sustained increased VE after 10 min of hypoxia (increases VE group). The remaining eight animals (age 5 +/- 1.2 d; wt 1751 +/- 168 g) had decreased VE at 10 min of hypoxia to values less than their room air baseline (decreases VE group). The decrease in PaO2 during hypoxia was similar in both groups, however the PaCO2 decreased significantly only in the increases VE group. Although cardiac output increased significantly during hypoxia in both groups, the values during normoxia and hypoxia were lower in the decreases VE group (p less than 0.001). Arterial blood pressure increased significantly during hypoxia only in the increases VE group. 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.

Effect of distal endotracheal bias flow on PaCO2 during high frequency oscillatory ventilation.

In order to evaluate the effect of distal endotracheal bias flow during HFOV on PaCO2 we studied adult rabbits with normal lungs and those who had meconium-induced lung dysfunction. Animals were studied while 1.0, 1.4 and 1.8 ml/kg tidal volumes (VT) were delivered by a high frequency oscillator. In animals with normal lungs and a 1.0 liter/min distal bias flow, the PaCO2 decreased significantly (p less than 0.01) with all VT used. In animals with meconium instillation the decrease in PaCO2 was also significant (p less than 0.05) at all combinations of VT and distal bias flow. The higher the distal bias flow the more pronounced was the lowering effect on PaCO2. We conclude that during HFOV it is possible to improve CO2 elimination using small additional bias flow delivered near the tip of the endotracheal tube in animals with normal abnormal lung function. This may allow adequate alveolar ventilation with even smaller VT, thus reducing the risk of barotrauma.

Effect of cyclooxygenase and lipoxygenase products on pulmonary function in group B streptococcal 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 less than 0.001), pulmonary artery wedge pressure (7.5 +/- 1.3 to 2.2 +/- 0.4 mm Hg, p less than 0.001) and thromboxane B2 (6.51 +/- 1.56 to 1.01 +/- 0.27 ng/ml, p less than 0.01) and an increase in dynamic lung compliance (1.10 +/- 0.10 to 1.28 +/- 0.14 ml/cm H2O/kg, p less than 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 less than 0.02) only at 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)