Atle Moen

Hypoxemia and reoxygenation with 21% or 100% oxygen in newborn pigs : changes in blood pressure, base deficit, and hypoxanthine and brain morphology

ABSTRACT: To study whether room air is as effective as 100% O2 in resuscitation after hypoxia, hypoxemia (Pao2 2.3–4.3 kPa) was induced in newborn pigs (2–5 d old) by ventilation with 8% O2 in nitrogen. When systolic blood pressure had fallen to 20 mm Hg, animals were randomly reoxygenated with either 21% O2 (group 1, n = 9) or 100% O2 (group 2, n = 11) for 20 min followed by 21% O2 in both groups. Controls (group 3, n = 5) were ventilated with 21% O2 throughout the experiment. Base deficit peaked at 31 ± 5 mmol/L (mean ± SD) for both hypoxic groups at 5 min of reoxygenation and then normalized over the following 3 h. There were no statistically significant differences between the two groups during reoxygenation concerning blood pressure, heart rate, base deficit, or plasma hypoxanthine. Hypoxanthine peaked at 165 ± 40 and 143 ± 42 μmol/L in group 1 and 2 (NS), respectively, and was eliminated monoexponentially in both groups with an initial half-life for excess hypoxanthine of 48 ± 21 and 51 ± 27 min (NS), respectively. Blinded pathologic examination of cerebral cortex, cerebellum, and hippocampus after 4 d showed no statistically significant differences with regard to brain damage. We conclude that 21% O2 is as effective as 100% O2 for normalizing blood pressure, heart rate, base deficit, and plasma hypoxanthine after severe neonatal hypoxemia in piglets and that the extent of the hypoxic brain damage is similar in the two groups.

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.

Hemodynamics and tissue blood flow after porcine surfactant replacement in surfactant-depleted newborn piglets

In 22 newborn piglets we studied the effect of hypovolemia or hypoxemia on hemodynamics and regional blood flow after instillation of porcine surfactant. Surfactant deficiency was obtained by repeated lung lavage, and blood flow measurements were carried out using radioactive microspheres. Three groups of piglets were studied, controls (n = 8), hypovolemia (n = 7), and hypoxemia (n = 7). Three to five minutes after instillation of surfactant, mean arterial blood pressure decreased significantly in all three groups with a mean decrease (±SD) of 31(±12), 33(±9), and 29(±9) mm Hg, respectively (p < 0.01 in all three groups). Systemic vascular resistance decreased significantly in all three groups immediately after surfactant instillation (p < 0.01) and returned to presurfactant level after 60 min. Blood flow did not change after surfactant instillation in any of the three groups, in neither skin, muscle, pancreas, brain, nor retina. In liver, kidney, intestine, and choroidea there was a decrease in blood flow immediately after instillation with return to presurfactant levels within 60 min. Hypoxemia or hypovolemia before surfactant instillation did not increase the hemodynamic instability. The decrease in mean arterial blood pressure was caused by a vasodilation and not by a reduced cardiac output.

Release of xanthine oxidase to the systemic circulation during resuscitation from severe hypoxemia in newborn pigs

Xanthine oxidase may contribute to oxygen free radical formation during reoxygenation after hypoxia, but in humans the enzyme is present in substantial amounts only in the liver and intestine. We developed a sensitive assay for xanthine oxidase using 14C–xanthine as substrate and investigated whether xanthine oxidase was released into the systemic circulation when 19 newborn pigs were resuscitated after severe hypoxemia. In five piglets plasma xanthine oxidase concentrations increased from undetectable levels to a median value of 8 (range 4–18) μU/ml after 30 min of reoxygenation. In these pigs serum aspartate aminotransferase increased from 45 to 148 U/l, while alanine aminotransferase was unchanged (28–31 U/l). The release of xanthine oxidase did not seem to correlate with the severity of the histological brain damage after 4 days. We conclude that only low levels of xanthine oxidase are released to the systemic circulation after severe hypoxemia in newborn pigs.

162 Acute Blood Pressure Effects of Surfactant Replacement in Newborn Piglets

As part of a study on cerebral blood flow and hemodynamics after replacement therapy with a natural porcine surfactant, we present preUminary data on acute changes in blood pressure. Three groups of piglets, age 3-6 days chosen to secure closed ductus arteriosus, underwent lung lavage with 0.9% saline. Group 1 was normovolemic and normoxic before surfactant was given. Group 2 was normoxic and made hypovolemic by bleeding 20% of estimated blood volume. Group 3 was normovolemic and hypoxic. Mean blood pressure (MBP) was measured continuously and is given as mean ±SD. ΔMBP is the difference between MBP immediately before surfactant and at lowest MBP after surfactantBlood pressure decreased significantly in all three groups reaching a minimum value at 4 minutes ±1.5 after surfactant instillation. The blood pressure decreased significantly more in group 2 and 3 than in group 1. MBP was restored to pre-surfactant values within 22 min ±13 min. a/APo2-ratio decreased significantly in group 2. Later a/APo2 ratio increased beyond pre-surfactant value in all three groups. We conclude that in normovolemic, normoxic piglets MBP decreased significantly less than in hypovolemic and hypoxic piglets treated with natural porcine surfactant. The change in MBP was independent of changes in pO2 and not related to a persistent ductus arteriosus.

Oxygen delivery and consumption in surfactant-depleted newborn piglets

Objective: To study the relationship between oxygen (O2) delivery (DO2) and O2 consumption (VO2) in surfactant-depleted newborn piglets.Design: Prospective animal study.Setting: Hospital surgical research laboratory.Subjects: Twenty-six anesthetized and ventilated newborn piglets.Interventions: Twenty of the animals were subjected to repeated saline lung lavages, and then assigned to either the saline group or the L-NAME group. The other six animals without lavage were studied as the control group. Piglets in the L-NAME group and the control group received 3 mg/kg of Nω-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase) i.v.; and those in the saline group received the same volume of saline i. v.Measurements and results: Cardiac output (CO) was measured and arterial and mixed venous blood gases were analyzed. DO2, O2 extraction ratio (O2ER) and VO2 were calculated. Plasma hypoxanthine was analyzed. In the lung lavaged groups, cardiac index, DO2 and VO2 decreased significantly after L-NAME i. v. but not after saline i. v. Further, the decrease in VO2 in the L-NAME group correlated with the decrease in DO2 (r=0.83, p < 0.001). In the control group, cardiac index and DO2, but not VO2, decreased significantly after L-NAME i.v. Simultaneously, O2ER increased significantly. Plasma hypoxanthine was not modified by lung lavage but increased after L-NAME i. v. in both the L-NAME and control groups.Conclusion: These data suggest that O2 supply dependency is present in surfactant-depleted newborn piglets.

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.

Acute Hemodynamic Effects of Porcine and Bovine Surfactant Replacement in Surfactant Depleted Newborn Piglets

Background: We have previously shown that instillation of 200mg/kg of porcine surfactant (Curosurf™) induces a systemic vasodilation in surfactant depleted newborn piglets. In the present work we wanted to study if this effect is dependent on dose and further could be induced also by instillation of a bovine surfactant preparation(Survanta™).