Xiang-Qing Yu

Effects of hypoxemia and reoxygenation with 21% or 100% oxygen in newborn piglets: extracellular hypoxanthine in cerebral cortex and femoral muscle.

OBJECTIVE To determine whether reoxygenation with an FIO2 of 0.21 (21% oxygen) is preferable to an FIO2 of 1.0 (100% oxygen) in normalizing brain and muscle hypoxia in the newborn. DESIGN Prospective, randomized, animal study. SETTING Hospital surgical research laboratory. SUBJECTS Twenty-six anesthetized, mechanically ventilated, domestic piglets, 2 to 5 days of age. INTERVENTIONS The piglets were randomized to control or hypoxemia groups. Hypoxemia was induced by ventilating the piglets with 8% oxygen in nitrogen, which was continued until mean arterial pressure decreased to <20 mm Hg. After hypoxemia, the piglets were further randomized to receive reoxygenation with an FIO2 of 0.21 (21% oxygen group, n = 9) or an FIO2 of 1.0 for 30 mins followed by an FIO2 of 0.21 (100% oxygen group, n = 9), and followed for 5 hrs. The piglets in the control group were mechanically ventilated with 21% oxygen (n = 8). MEASUREMENTS AND MAIN RESULTS We measured extracellular concentrations of hypoxanthine in the cerebral cortex and femoral muscle (in vivo microdialysis), plasma hypoxanthine concentrations, cerebral arterial-venous differences for hypoxanthine, acid base balances, arterial and venous (sagittal sinus) blood gases, and mean arterial pressures. The lowest pH values of 6.91 +/- 0.11 (21% oxygen group, mean +/- SD) and 6.90 +/- 0.07 (100% oxygen group) were reached at the end of hypoxemia and then normalized during the reoxygenation period. Plasma hypoxanthine increased during hypoxemia from 28.1 +/- 9.3 to 119.1 +/- 31.9 micromol/L in the 21% oxygen group (p < .001) and from 32.6 +/0- 14.5 to 135.0 +/- 31.4 micromol/L in the 100% oxygen group (p <.001). Plasma hypoxanthine concentrations then normalized over the next 2 hrs in both groups. In the cerebral cortex, extracellular concentrations of hypoxanthine increased during hypoxemia from 3.9 +/- 2.8 to 20.2 +/- 7.4 micromol/L in the 21% oxygen group (p < .001) and from 5.9 +/- 5.0 to 25.1 +/- 7.1 micromol/L in the 100% oxygen group (p < .001). In contrast to plasma hypoxanthine, extracellular hypoxanthine in the cerebral cortex increased significantly further during early reoxygenation, and, within the first 30 mins, reached maximum values of 24.9 +/- 6.3 micromol/L in the 21% oxygen group (p < .01) and 34.8 +/- 10.9 micromol/L in the 100% oxygen group (p < .001). This increase was significantly larger in the 100% oxygen group than in the 21% oxygen group (9.7 +/- 4.7 vs. 4.7 +/- 2.6 micromol/L, p < .05). There were no significant differences between the two reoxygenated groups in duration of hypoxemia, hypoxanthine concentrations in femoral muscle, plasma hypoxanthine concentrations, pH, or mean arterial pressure. The cerebral arterial-venous difference for hypoxanthine was positive both at baseline, at the end of hypoxemia, and after 30 mins and 300 mins of reoxygenation, and no differences were found between the two reoxygenated groups. CONCLUSIONS Significantly higher extracellular concentrations of hypoxanthine were found in the cerebral cortex during the initial period of reoxygenation with 100% oxygen compared with 21% oxygen. Hypoxanthine is a marker of hypoxia, and reflects the intracellular energy status. These results therefore suggest a possibly more severe impairment of energy metabolism in the cerebral cortex or an increased blood-brain barrier damage during reoxygenation with 100% oxygen compared with 21% oxygen in this newborn piglet hypoxia model.

Pulmonary Hemodynamics and Plasma Endothelin-1 during Hypoxemia and Reoxygenation with Room Air or 100% Oxygen in a Piglet Model

The immediate effect on the pulmonary circulation of reoxygenation with either room air or 100% O2 was studied in newborn piglets. Hypoxemia was induced by ventilation with 8% O2 until base excess was <-20 mmol/L or mean arterial blood pressure was <20 mm Hg. Reoxygenation was performed with either room air (n = 9) or 100% O2 (n = 9). Mean pulmonary artery pressure increased during hypoxemia (p = 0.012). After 5 min of reoxygenation, pulmonary artery pressure increased further from 24 ± 2 mm Hg at the end of hypoxemia to 35 ± 3 mm Hg (p = 0.0077 versus baseline) in the room air group and from 27 ± 3 mm Hg at the end of hypoxemia to 30 ± 2 mm Hg (p = 0.011 versus baseline) in the O2 group (NS between groups). Pulmonary vascular resistance index increased (p = 0.0005) during hypoxemia. During early reoxygenation pulmonary vascular resistance index decreased rapidly to values comparable to baseline within 5 min of reoxygenation in both groups (NS between groups). Plasma endothelin-1 (ET-1) decreased during hypoxemia from 1.5 ± 0.1 ng/L at baseline to 1.2 ± 0.1 ng/L at the end of hypoxemia (p = 0.003). After 30 min of reoxygenation plasma ET-1 increased to 1.8 ± 0.3 and 1.5 ± 0.2 ng/L in the room air and O2 groups, respectively (p = 0.0077 in each group versus end hypoxemia; NS between groups). We conclude that hypoxemic pulmonary hypertension and plasma ET-1 normalizes as quickly when reoxygenation is performed with room air as with 100% O2 in this hypoxia model with newborn piglets.

Nitric Oxide Contributes to Surfactant-Induced Vasodilatation in Surfactant-Depleted Newborn Piglets

To investigate whether nitric oxide (NO) is involved in surfactant-induced systemic and pulmonary vasodilatation in newborn piglets with surfactant deficiency, 2-6-d-old piglets were subjected to repeated saline lung lavages. They were then randomly assigned to one of two groups (seven in each group): the Nω-nitro-L-arginine methyl ester (L-NAME) group received 3 mg/kg L-NAME i.v. 45 min before endotracheal instillation of 200 mg/kg porcine surfactant; the saline group received saline i.v. at the same time point, and instillation of 200 mg/kg surfactant. Mean arterial blood pressure, systemic vascular resistance, pulmonary arterial pressure, and pulmonary vascular resistance increased significantly after injection of L-NAME (all p < 0.01), whereas the cardiac index decreased significantly (p < 0.05). Saline injection did not change any variable. Significant decreases in mean arterial blood pressure (from a mean± SD of 66 ± 10 to 53 ± 9 mm Hg, p < 0.01), pulmonary arterial pressure (from 29 ± 6 to 23 ± 6 mm Hg,p < 0.01), and systemic vascular resistance (from 0.40 ± 0.13 to 0.33 ± 0.12 mm Hg/mL/min/kg, p < 0.05) were observed only in the saline group after surfactant instillation, whereas the decrease in pulmonary vascular resistance was not significant after surfactant instillation (p = 0.06). In contrast to the saline group, these variables were not modified in the L-NAME group after surfactant instillation. We conclude that the vasodilatory effect of porcine surfactant instillation in newborn piglets with surfactant deficiency is associated with activation of NO synthase.

Acute Effects on Systemic and Pulmonary Hemodynamics of Intratracheal Instillation of Porcine Surfactant or Saline in Surfactant-Depleted Newborn Piglets

Surfactant instillation may affect systemic and pulmonary hemodynamics. The aim of this study was to investigate whether this effect is specific to surfactant or if it can be triggered by instillation of the same volume of saline. Piglets 3-5-d-old were subjected to repeated lung lavage using 20 mL/kg 0.9% saline until the partial pressure of arterial O2 was <10 kPa and partial pressure of arterial CO2 was between 4.0 and 6.0 kPa with fraction of inspired oxygen (Fio2) 1.0 and peak inspiratory pressure 25 cm H2O. Porcine surfactant 200 mg/kg (80 mg/mL) or the same volume of 0.9% saline was instilled into the lungs through a feeding catheter entered through the endotracheal tube. Mean arterial blood pressure, pulmonary artery pressure, and cardiac output were measured continuously. There was a significant decrease in mean arterial blood pressure from 67 (±13) mm Hg to 52 (±18) mm Hg (p < 0.05) 210 s after instillation of surfactant. Systemic vascular resistance decreased from 0.42 (±0.18) to 0.34 (±0.18) mm Hg × mL-1 × min × kg(p < 0.05) from 0 min to 180 s after instillation of surfactant. In the group receiving saline instillations there were no significant changes in mean arterial blood pressure or systemic vascular resistance. A transient but significant increase in mean pulmonary artery pressure was seen 120 s after instillation in both groups with a return to presurfactant level 240 s after instillation. Pulmonary vascular resistance increased transiently and significantly only in the group receiving surfactant. We conclude that porcine surfactant causes a decrease in systemic vascular resistance, resulting in a decrease in mean arterial blood pressure in newborn lung-lavaged piglets not seen after instillation of the same volume of saline.

Acute effects on systemic circulation after intratracheal instillation of Curosurf or Survanta in surfactant-depleted newborn piglets

Systemic vasodilatation in surfactant‐depleted newborn piglets is induced by 200 mg/kg of modified porcine lung surfactant (Curosurf™). The aim of this investigation was to study whether this effect is dependent on dose and could further be induced by instillation of a bovine surfactant preparation (Survanta™). Twenty‐two 3–5‐d old piglets were subjected to repeated saline lung lavage and then randomized to one of three groups. Instillation of either Curosurf 100 mg/kg (n= 8), Survanta 100 mg/kg (n= 7) or Curosurf 200 mg/kg (n= 7) was performed through the endotracheal tube. Systemic vascular resistance decreased 7 (± 4)%, 15 (± 12)% and 18 (± 6)% in the three groups, respectively (p < 0:05 in all three groups). A significant difference between the high and low dose Curosurf groups was found (p < 0:05), whereas no significant difference was seen between the Curosurf 100 mg group and the Survanta group. The decrease in vascular resistance was compensated by an increase in cardiac output, resulting in a stable mean arterial blood pressure. In conclusion, both Curosurf and Survanta induce a significant decrease in systemic vascular resistance in surfactant‐depleted newborn piglets. A more pronounced effect was observed after 200 mg/kg than after 100 mg/kg of Curosurf.

Nebulization of sodium nitroprusside in lung-lavaged newborn piglets.

The aim of the present study was to test the hypothesis that nebulization of the nitric oxide donor sodium nitroprusside may selectively reduce pulmonary vascular resistance and improve oxygenation in lung-lavaged newborn piglets. Thirteen anesthetized piglets (1-3 d old) were subjected to repeated lung lavages and then randomly assigned to one of the following two groups: 1) an SNP group, which received SNP nebulization, and 2) a saline group, which received saline nebulization. Pulmonary arterial pressure and pulmonary vascular resistance increased significantly after lung lavage, whereas cardiac output decreased significantly in both groups. After SNP nebulization, pulmonary arterial pressure decreased from 32 ± 1 to 17 ± 1 mm Hg (p < 0.01) and PVR decreased from 255 ± 20 to 172 ± 15 mm Hg L-1 min-1 kg-1 (p < 0.01). The arterial tension of oxygen concomitantly increased from 9.4 ± 4.0 to 17.0 ± 3.0 kPa (p < 0.01), and the arterial/alveolar ratio of oxygen tension increased from 0.11 ± 0.01 to 0.22 ± 0.03 (p < 0.01). Systemic hemodynamics were not modified significantly during nebulization of SNP. On the other hand, all variables were stable during nebulization of saline. These data suggest that SNP nebulization produces a selective pulmonary vasodilatation and improves oxygenation in lung-lavaged newborn piglets.

Pulmonary Circulation and Plasma-Endothelin-1 (P-Et-1) During Hypoxia and Reoxygenation With 21% and 100% O2 in Piglets

Background: We tested the hypothesis that room air normalises pulmonary arterial pressure (PAP) and pulmonary vascular resistance index(PVRI) during reoxygenation as efficient as 100% O2 in hypoxic piglets .Subjects: Eighteen 1-3 d old piglets. Intervention: Hypoxia was induced by ventilation with 8% O2. When mean arterial blood pressure fell below 20 mm Hg or base excess was reduced to <-20 mmol/L a 2-hour reoxygenation-period was started, the piglets were randomly divided into 2 groups; 21% O2 (group 1, n=9) and 100% O2 (group 2, n=9).Results: P-ET-1 decreased during hypoxia from 1.53 ±0.51 ng/L(mean±SD) to 1.17 ±0.55 ng/L (p=0.011) in both groups. At 2 h reoxygenation P-ET-1 increased to 1.92 ±0.90 ng/L (p=0.017) in group 1, and to 1.67 ±0.61 ng/L (p=0.002) in group 2. PAP increased from 24±6 mm Hg at start to 35 ±9 mm Hg at 5 min. reoxygenation in group 1 (p=0.01), and from 27 ±8 mmHg to 31 ±6 (N.S.) in group 2. PVRI decreased from the start of reoxygenation from 0.42 ±0.25 to to 0.15 ±0.11 (p=0.011) and from 0.54 ±0.50 to 0.23 ±0.13(N.S) at 20 min reoxygenation in group 1 and 2, respectively .Conclusion: During reoxygenation PVRI is reduced just as efficient with 21% as 100% O2, an the changes in P-ET-1 are comparable to the changes PVRI, suggesting that changes in PVRI may be mediated by P-ET-1.

Sodium Nitroprusside Prevents Oxygen-Free-Radical-Induced Pulmonary Vasoconstriction in Newborn Piglets

The aim of the present study was to test whether hypoxanthine-xanthine oxidase (XO) induced a pulmonary vasoconstriction in newborn piglets, and whether this vasoconstriction could be attenuated or abolished by pretreatment of nitric oxide (NO) donor sodium nitroprusside (SNP). Twenty-five anesthetized newborn piglets (1–3 days old) were randomly assigned to the following four groups: the control group received saline intravenously only; the XO group received 0.1 mmol/kg of hypoxanthine subsequent with XO (1.5 U/kg); the SNP group received the same dosages of hypoxanthine/ XO together with SNP intravenously, allopurinol (ALP) group received ALP intravenously prior to hypoxanthine and XO injection. After giving XO, the pulmonary arterial pressure (PAP) and vascular resistance (PVR) increased, while the cardiac index decreased significantly in the XO group. By contrast, these variables were not significantly modified by XO injection in the SNP and ALP groups. The data suggest that oxygen free radicals induce a pulmonary vasoconstriction in newborn piglets, and this vasoconstriction can be prevented by infusion of the NO donor SNP.

EFFECTS OF HYPOXIA AND RESUSCITATION WITH 21% and 100% O 2 IN NEWBORN PIGLETS: EXTRACELLULAR HYPOXANTHINE (HX) IN BRAIN CORTEX AND FEMORAL MUSCLE. • 1232

EFFECTS OF HYPOXIA AND RESUSCITATION WITH 21% and 100% O 2 IN NEWBORN PIGLETS: EXTRACELLULAR HYPOXANTHINE (HX) IN BRAIN CORTEX AND FEMORAL MUSCLE. • 1232

EFFECT OF NITRIC OXIDE (NO) SYNTHASE INHIBITION ON PLASMA HYPOXANTHINE (Hx) IN NEWBORN PIGLETS WITH SURFACTANT DEFICIENCY: A POSSIBLE RELATIONSHIP BETWEEN PLASMA Hx AND PULMONARY HYPERTENSION |[dagger]| 1627

The Hx-xanthine oxidase system is an important generator of free radical which are reported to induce pulmonary hypertension. In vitro studies have shown that NO is an important free radical scavenger, and inhibition of NO synthase enhances production of superoxide anion in adult rats. The purpose of this study was to investigate the effect of NO synthase inhibition on plasma Hx in newborn piglets with surfactant deficiency, and to study a possible relationship between plasma Hx and pulmonary arterial pressure (Ppa). Methods: Nineteen anesthetized and instrumented newborn piglets were subjected to repeated lung lavages, and then randomly assigned to two groups: the L-NAME group (n = 12) received 3 mg/kg of L-NAME i.v; and the control group (n = 7) received same volume of saline i.v. Ppa was continuously recorded. Plasma Hx was analyzed with HPLC. Results: Plasma Hx was not modified by the repeated lung lavages, but increased significantly 45 minutes after L-NAME i.v. (p < 0.01)(fig). Saline injection, however, did not modify plasma Hx. Furthermore, the differences in Δ-plasma Hx between the two groups after L-NAME and saline i.v. were also significant (p < 0.05). Ppa was not changed after saline i.v., but increased significantly after L-NAME i.v. The change in Ppa after L-NAME i.v. was significantly correlated to plasma Hx (n = 24, r = 0.43, p < 0.05). Conclusion: These data show that inhibition of NO synthase may augments plasma Hx. We speculate that inhibition of NO synthase may potentiate production of free radicals during reperfusion which may contribute to pulmonary hypertension.