Abstract: We designed a randomized controlled study to identify and compare the liver tissue responses in systemic hypoxia and resuscitation with 21% and 100% oxygen using an animal model of neonatal hypoxia and reoxygenation. Twenty-seven piglets (1-3 days old, weight 1.5-2.0 kg) were acutely instrumented and mechanically ventilated. The animals underwent 2 h of normocapnic alveolar hypoxia (10-15% oxygen) then reoxygenation with 21% or 100% oxygen for 1 h, then 1 h with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. After 2 h of reoxygenation liver tissue samples were immediately processed for histological and biochemical analyses of markers of oxidative stress and tissue injury. Two hours of hypoxia caused a significant reduction in mean arterial pressure with cardiogenic shock and metabolic acidemia, with similar recovery upon resuscitation with 21% and 100% oxygen. After 2 h of reoxygenation, the hepatic GSSG:total glutathione ratio and matrix metalloproteninase-9 activity, which correlated with the portal venous oxygenation at 15 min of reoxygenation, were greater in the 100% group and hepatic lactate level was higher in the 21% group than the controls (all P<0.05). Both hypoxic-reoxygenated groups had similarly elevated hepatic Bcl-2 levels. Apart from more non-distinct mitochondria identified in the 100% group, hepatic tissue adenylate energy charge and plasma transaminases levels did not differ among groups. We concluded that in this acute model of neonatal hypoxia and reoxygenation, resuscitation using 21% oxygen avoids the excess oxidative stress and elevated matrix metalloproteninase-9 activity in the liver when 100% oxygen was used. The study supports the conservative use of oxygen in optimizing post-hypoxic hepatic recovery.

Abstract: BACKGROUND: Neonatal hypoxia-ischemia (HI) is a common complication of pregnancy and delivery. Conventional clinical practice is to resuscitate neonates with 100% O2, and evidence is building to suggest resuscitation with lower O2 concentrations is safer. Significant neurochemical changes are associated with HI injury and persistent changes in amino acids are related to cell death, therefore we used a swine survival model of neonatal HI-reoxygenation (HI/R) to investigate the effects of resuscitation with 100%, 21% or 18% O2 on amino acid neurotransmitters. METHODS: In a blinded randomized fashion, following permanent ligation of the left common carotid artery, newborn pigs (1-4 d, 1.7-2.5 kg) received alveolar normocapnic hypoxia (FiO2=0.15, 2h) and were reoxygenated with 18%, 21% or 100% O2. After a 4-day survival period, brain regions were processed for amino acid levels using high-performance liquid chromatography (HPLC). RESULTS: Results showed that resuscitation with different O2 concentrations caused hemispheric and regional changes in all amino acids investigated including glutamate, alanine, gamma-amino butyric acid, glycine and aspartate, 4 days post-HI. Resuscitation with 100% O2 significantly increased glutamate and glycine in the dorsal cortex contralateral to the ligated common carotid artery, compared to piglets resuscitated with 21% O2. Additionally, piglets resuscitated with 21% O2 had significantly lower alanine levels than those resuscitated with 18% O2. CONCLUSION: Significant resuscitation-dependent changes in amino acid neurotransmitters are still evident 4 days post-HI in the newborn piglet. These data suggest that persistent changes in neurochemistry occur 4 days after HI/R and further studies are warranted to elucidate the consequences of this on neonatal brain development.

Abstract: OBJECTIVES: The increase in oxidative stress following neonatal hypoxia-reoxygenation can be related to subsequent cardiovascular deficits. We compared the acute systemic, pulmonary and regional hemodynamic recovery in hypoxic newborn pigs reoxygenated by low (18%) or high (100%) concentration of oxygen with that by 21% oxygen. STUDY DESIGN: Pigs (1-3 days, 1.5-2.5 kg) were acutely instrumented to continuously measure pulmonary artery flow (surrogate for cardiac index), mean and pulmonary artery pressures, common carotid, superior mesenteric and renal artery flow indices. After 1h of normocapnic alveolar hypoxia (8-10% oxygen), animals were randomized to receive 18%, 21% or 100% oxygen for 1h then 21% oxygen for 3 h (n=7 per group). Sham-operated pigs (n=6) had no hypoxia-reoxygenation. RESULTS: Severe hypoxia caused significant compromises in systemic and regional hemodynamics and oxygen delivery (vs. shams). Despite reoxygenation, mean arterial pressure remained significantly lower than that of shams with no difference among hypoxic-reoxygenated groups. There was an oxygen-dependent recovery of pulmonary artery pressure. Cardiac index improved with reoxygenation but deteriorated over time in the 100% group. Both 18% and 100% groups had lower systemic oxygen delivery. Regional flows and oxygen delivery in all hypoxic-reoxygenated piglets were similarly reduced in all groups. CONCLUSIONS: In this swine model of neonatal hypoxia-reoxygenation, resuscitation with 18% and 100% oxygen results in differential compromises in systemic and pulmonary circulations when compared with 21% oxygen.

Abstract: OBJECTIVE: Reactive oxygen species have been implicated in the pathogenesis of hypoxia-reoxygenation injury. However, little information is known regarding the temporal profile of cerebral hydrogen peroxide (HPO) production and its response to N-acetylcysteine (an antioxidant) administration during neonatal hypoxia-reoxygenation. Using an acute swine model of neonatal hypoxia-reoxygenation, we examined the short-term neuroprotective effects of N-acetylcysteine on cerebral HPO production and oxidative stress in the brain. DESIGN: Controlled, block-randomized animal study. SETTING: University animal research laboratory. SUBJECTS: Newborn piglets (1-3 days, 1.7-2.1 kg). INTERVENTIONS: At 5 min after reoxygenation, piglets were given either saline or N-acetylcysteine (20 or 100 mg/kg/h) in a blinded, randomized fashion. MEASUREMENTS AND RESULTS: Newborn piglets were block-randomized into a sham-operated group (without hypoxia-reoxygenation, n = 5) and three hypoxic-reoxygenated groups (2 h of normocapnic alveolar hypoxia followed by 2h of reoxygenation, n = 7/group). Heart rate, mean arterial pressure, cortical HPO concentration, amino acid levels in cerebral microdialysate, and cerebral tissue glutathione and lipid hydroperoxide levels were examined. Hypoxic piglets were hypotensive and acidotic, and they recovered similarly in all hypoxic-reoxygenated groups. In hypoxic-reoxygenated control piglets, the cortical HPO concentration gradually increased during reoxygenation. Both doses of N-acetylcysteine abolished the increased HPO concentration and oxidized glutathione levels and tended to reduce the glutathione ratio and lipid hydroperoxide levels in the cerebral cortex (p = 0.08 and p = 0.1 vs. controls, respectively). N-acetylcysteine at 100mg/kg/h also increased the cerebral extracellular taurine levels. CONCLUSION: In newborn piglets with hypoxia-reoxygenation, postresuscitation administration of N-acetylcysteine reduces cerebral HPO production and oxidative stress, probably through a taurine-related mechanism.

Abstract: Dobutamine, a beta-adrenoceptor agonist that is often used to treat myocardial dysfunction in asphyxiated neonates, may act on the adrenoceptors of platelets resulting in activation. Little information is available on the effect and mechanistic pathway of dobutamine on the platelet aggregatory function in neonatal asphyxia. Newborn piglets were acutely instrumented and exposed to hypoxia for 2 h and reoxygenation for 4 h. Piglets were randomized to receive dobutamine infusion (5, 10, or 20 microg/kg per min) or saline (hypoxic-control) at 2 to 4 h of reoxygenation (n = 8 each), and sham-operated animals were not exposed to hypoxia and reoxygenation (n = 6). Platelet number, collagen-stimulated whole blood aggregation, and plasma concentrations of thromboxane B2 were studied. The effects of alpha- and beta-adrenoceptor antagonists (phentolamine and propranolol, respectively) on platelet aggregation to in vitro administration of dobutamine (3microM) were also examined. Shock and metabolic acidosis developed similarly in all hypoxia-reoxygenated groups. At 4 h of reoxygenation, platelet numbers in all groups decreased, with no differences among groups. Platelet aggregation deteriorated significantly with a rightward shift of concentration-response curve in piglets receiving 10 and 20 microg/kg per min of dobutamine. The group that received 20 microg/kg per min of dobutamine had increased plasma thromboxane B2 concentrations from baseline (P < 0.05). The platelet aggregatory response induced by 3 microM of dobutamine was improved by the coadministration of the beta-butnot the alpha-adrenoceptor antagonist. We observed platelet aggregatory dysfunction in hypoxic-reoxygenated newborn piglets treated with high-dose dobutamine. Further investigation is needed to examine the differential effects of dobutamine and hypoxia-reoxygenation in platelet aggregation in newborns.

Abstract: OBJECTIVES: We examined the effects of 18%, 21% or 100% oxygen on the recovery of the heart and kidneys in a short-term survival model of neonatal hypoxia-reoxygenation (HR). DESIGN: Controlled, block-randomized animal study. SETTING: University animal research laboratory. SUBJECT: Large white piglets (1-3 days, 1.7-2.5[Symbol: see text]kg). INTERVENTIONS: Piglets received normocapnic hypoxia (15% oxygen) (2[Symbol: see text]h) and were reoxygenated with 18%, 21% or 100% oxygen (1[Symbol: see text]h) (n[Symbol: see text]=[Symbol: see text]7 per group) then 21% oxygen (2[Symbol: see text]h). Sham-operated pigs (n[Symbol: see text]=[Symbol: see text]7) had no HR. MEASUREMENTS AND RESULTS: Seventeen of 21 HR piglets recovered from moderate hypoxemia (mean PaO(2) 27-33[Symbol: see text]mmHg and pH 7.20-7.22, associated with tachycardia and hypotension). Systemic arterial pressure, heart rate, left renal arterial flow, oxygen transport, plasma troponin-I and creatinine levels were monitored and recovered with no differences among HR groups over 4 days after resuscitation. The 100% group had increased myocardial oxidative stress (oxidized glutathione levels) and the most cardiac HR-induced injury. There were no differences in renal oxidative stress and HR-induced injury among groups. Early oxygenation at 1[Symbol: see text]h after resuscitation correlated with the plasma troponin-I level at 6[Symbol: see text]h (r[Symbol: see text]=[Symbol: see text]-0.51 and 0.64 for SaO(2) and systemic oxygen extraction ratio, p[Symbol: see text]<[Symbol: see text]0.05, respectively) and renal HR-induced injury at 4 days (r[Symbol: see text]=[Symbol: see text]0.61 for renal oxygen delivery, p[Symbol: see text]<[Symbol: see text]0.05). CONCLUSIONS: In hypoxic piglets, 18%, 21% and 100% reoxygenation caused similar systemic and renal hemodynamic and functional recovery. The indicators of oxidative stress and HR injury in myocardial and renal tissues suggest that the reoxygenation with 100% oxygen appears sub-optimal and the use of 18% oxygen offers no further benefit, when compared with 21% oxygen.

Abstract: OBJECTIVE: Neonatal asphyxia causes cardiogenic shock and pulmonary hypertension with decreased brain perfusion. We examined the dose-response of milrinone on systemic, pulmonary, and carotid circulations in a model of neonatal hypoxia-reoxygenation. DESIGN AND SETTING: Controlled, block-randomized study in a university research laboratory. SUBJECTS: Mixed breed piglets (1-3[Symbol: see text]days, 1.5-2.3[Symbol: see text]kg). INTERVENTIONS: In acutely instrumented piglets normocapnic alveolar hypoxia (10-15% oxygen) was induced for 2[Symbol: see text]h followed by reoxygenation with 100% oxygen (1[Symbol: see text]h) then 21% oxygen (3[Symbol: see text]h). At 2[Symbol: see text]h of reoxygenation after a volume loading (10[Symbol: see text]ml/kg) either saline or milrinone (bolus and infusion at 0.25, 0.5, or 0.75[Symbol: see text]mug/kg per minute) was given for 2[Symbol: see text]h in a blinded-randomized fashion (n[Symbol: see text]=[Symbol: see text]7/group). MEASUREMENTS AND RESULTS: All milrinone-treated groups had higher cardiac output and stroke volume than those of saline-treated hypoxic controls, which showed progressive decline in these measurements. At 2[Symbol: see text]h of infusion plasma milrinone levels were significantly correlated with cardiac output (r[Symbol: see text]=[Symbol: see text]0.6), which increased from pretreatment value in the group receiving 0.75[Symbol: see text]mug/kg per minute. Milrinone maintained mean arterial pressure; heart rate and pulmonary arterial pressure did not differ between groups. Milrinone prevented continued increases in systemic and pulmonary vascular resistances after hypoxia-reoxygenation. Milrinone infusion at higher doses increased common carotid flow. Milrinone-treated piglets had increased systemic and carotid oxygen delivery, with no difference in plasma and myocardial lactate levels among groups. CONCLUSIONS: When used to treat shock in newborn piglets with hypoxia-reoxygenation, milrinone improved cardiac output and carotid flow while maintaining systemic blood pressure. Pulmonary hypertension was not aggravated. Further studies are needed to confirm these findings in asphyxiated neonates.

Abstract:

Abstract: Hydrogen peroxide (H2O2) and nitric oxide (NO) contribute to the pathogenesis of cerebral hypoxic-ischemic injury. We evaluated the neuroprotective effect of N-acetyl-L-cysteine (NAC, a free radical scavenger) against oxidative stress and perfusion in a model of neonatal hypoxia-reoxygenation (H-R). Piglets (1-3d, 1.6-2.3kg) were randomized into a sham-operated group (without H-R)(n=5) and 2 H-R experimental groups (2h normocapnic alveolar hypoxia followed by 4h reoxygenation)(n=7/group). At 5min after reoxygenation, piglets were given either i.v. saline (H-R controls) or NAC (30 mg/kg bolus then 20 mg/kg/h infusion) in a blinded-randomized fashion. Heart rate, mean arterial pressure, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 and NO production (electrochemical sensor), cerebral tissue glutathione and nitrotyrosine levels (ELISA) were examined. Hypoxic piglets were acidotic (pH 6.88-6.90), which recovered similarly in the H-R groups (p>0.05 vs. shams). Post-resuscitation NAC treatment significantly attenuated the increase in cortical H2O2, but not NO, concentration during reoxygenation, with lower cerebral oxidized glutathione levels. NAC-treated piglets had significantly higher carotid oxygen delivery and lower cerebral lactate levels than that of H-R controls with corresponding changes in carotid arterial flow and vascular resistance. In newborn piglets with H-R, post-resuscitation administration of NAC reduced cerebral oxidative stress and improved cerebral perfusion.

Abstract: Hypoxia/reoxygenation (H/R) creates an energetic deficiency in the heart, which may contribute to myocardial dysfunction. We hypothesized that H/R-induced impairment of cardioenergetic enzymes occurs in asphyxiated newborn animals. After hypoxia for 2 h (10-15% oxygen), newborn piglets were resuscitated with 100% oxygen for 1 h, followed by 21% oxygen for 3 h. Sham-operated control piglets had no H/R. Hemodynamic parameters in the piglets were continuously measured. At the end of experiment, hearts were isolated for proteomic analysis. In asphyxiated hearts, the level of isocitrate dehydrogenase and malate dehydrogenase was reduced compared to controls. Inverse correlations between the level of myocardial malate dehydrogenase and cardiac function were observed in the control, but not the H/R hearts. We conclude that reoxygenation of asphyxiated newborn piglets reduces the level of myocardial isocitrate dehydrogenase and malate dehydrogenase. While the cause is not clear, it may be related to the impaired tricarboxylic acid cycle pathway and energy production in the heart.

Abstract: Shock and tissue hypoperfusion are common after asphyxia. We compared systemic and regional hemodynamic effects of epinephrine and dopamine in the treatment of shock and hypotension in asphyxiated newborn piglets resuscitated with 100% oxygen. Twenty-four piglets (1-3 days old; weight, 1.4-2.6 kg) were acutely instrumented to measure cardiac index (CI), carotid, mesenteric and renal arterial blood flows, and mean systemic (SAPs) and pulmonary arterial pressures (PAPs). Piglets had normocapnic alveolar hypoxia (F(IO2)=0.08-0.10) for 50 min and reoxygenated with F(IO2)=1.0 for 1 h then F(IO2)=0.21 for 3.5 h. After 2 h reoxygenation, either dopamine (2 microg kg(-1) min(-1)) or epinephrine (0.2 microg kg(-1) min(-1)) was given for 30 min in a blinded randomized manner, which was then increased to maintain SAP (within 10% of baseline, pressure-driven dose) for 2 h. Hypoxia caused hypotension (SAP, 44%+/-3% of baseline), cardiogenic shock (CI, 41%+/-4%), and metabolic acidosis (mean pH, 7.04-7.09). Upon reoxygenation, hemodynamic parameters immediately recovered but gradually deteriorated during 2 h with SAP at 45+/-1 mmHg, CI at 74+/-9% of baseline, and pH 7.32+/-0.03. Low doses of either drug had no significant systemic and renal hemodynamic response. Epinephrine (0.3-1.5 microg kg(-1) min(-1)) for 2 h increased SAP and CI (with higher stroke volume) and decreased pulmonary vascular resistance (with reduced PAP-SAP ratio), whereas the responses with dopamine (10-25 microg kg(-1) min(-1)) were modest. Low-dose epinephrine improved mesenteric and carotid arterial flows, whereas the pressure-driven doses of epinephrine and dopamine increased carotid and mesenteric arterial flows, respectively. To treat shock in asphyxiated newborn piglets resuscitated with 100% oxygen, epinephrine exhibits an inotropic action compared with dopamine, whereas both catecholamines can increase carotid and mesenteric perfusion.

Abstract: Asphyxiated neonates usually have myocardial stunning and hypotension and require inotropic support. A randomized controlled study was designed to examine the dose-response effect of dobutamine (5-20 microg x kg(-1) x min(-1)) on systemic and regional circulations and oxygen metabolism in a neonatal swine model of hypoxia/reoxygenation. Thirty-eight anesthetized newborn piglets were acutely instrumented for continuous monitoring of heart rate, systemic and pulmonary arterial pressures, and pulmonary (surrogate for cardiac index), right common carotid, and superior mesenteric and left renal arterial flows. After stabilization, they were exposed to normocapnic alveolar hypoxia (10%-15% oxygen) for 2 h followed by reoxygenation with 100% oxygen for 1 h, then 21% for 3 h. Piglets were block randomized to receive dobutamine infusion (5, 10, or 20 microg x kg(-1) x min(-1)) or saline (control) at 2 to 4 h of reoxygenation (n = 8 each). A nonasphyxiated, sham-operated group was included (n = 6). Blood samples were collected for blood gas analysis, arterial and venous co-oximetry, and plasma lactate concentration determination. At 2-h reoxygenation after hypoxia, there was hypotension (systemic arterial pressure, 27 to 36 mmHg) and myocardial dysfunction (cardiac index from 178-209 to 134-156 mL x kg(-1) x min(-1)). Cardiac index improved significantly with 20 microg x kg(-1) x min(-1) of dobutamine (P < 0.05) and modestly in the treatment groups of 5 and 10 microg x kg(-1) x min(-1) (P < 0.1) (at 120 min, 172 +/- 35, 160 +/- 30, and 158 +/- 56 mL x kg(-1) x min(-1) vs. 119 +/- 33 mL x kg(-1) x min(-1) of controls, respectively), with corresponding increases in stroke volume. Pulmonary vascular resistance was lower in all dobutamine-treated groups (vs. controls, P < 0.05) There were no differences in heart rate, systemic and pulmonary arterial pressures, systemic vascular resistance, and regional flows between groups. The group of 20 mug.kg.min of dobutamine also had higher systemic oxygen delivery (at 120 min, 18 +/- 5 vs. 11 +/- 3 O(2) mL x kg(-1) x min(-1) of controls, P < 0.05) with no significant differences in systemic oxygen consumption and regional oxygen delivery between groups. After the reoxygenation of newborn piglets with severe hypoxia, high dose of dobutamine is effective to treat myocardial stunning and low cardiac output with no significant effect on blood pressure or regional circulation. Further clinical studies are needed to confirm these findings in the human neonate.

Abstract: The differential effects of the use of high or low oxygen levels during resuscitation on the neonatal liver are unknown. We compared the hepatic hemodynamics and oxygen metabolism in hypoxic newborn piglets resuscitated with 21% or 100% oxygen. Twenty-seven piglets (age, 1-3 days; weight, 1.5-2.0 kg) were acutely instrumented to measure cardiac output, hepatic artery, and portal venous blood flows (hepatic artery flow index [HAFI] and portal venous flow index [PVFI], respectively). The animals underwent 2 h of hypoxia (fraction of inspired oxygen, 0.10-0.15), then reoxygenation with 21% (n = 9) or 100% (n = 9) oxygen for 1 h, then 1 h with 21% oxygen. The controls (n = 9) were sham-operated without hypoxia-reoxygenation. Oxygen transport and plasma lactate concentrations were studied. Hypoxic animals had hypotension and decreased cardiac index with metabolic acidosis (mean pH, 7.00-7.02; P < 0.05 vs. controls). The PVFI and the total hepatic blood flow (THFI = PVFI + HAFI), despite the absence of significant change in HAFI, decreased to 16 +/- 2 mL/min/kg and 19 +/- 3 mL/min/kg, respectively (versus 24 +/- 2 mL/min/kg and 28 +/- 2 mL/min/kg of controls; P < 0.05). Fifteen minutes after reoxygenation, the cardiac index improved, PVFI recovered, HAFI was maintained, and THFI was not different between the groups. The hepatic oxygen consumption decreased (59%; P < 0.05) and the extraction increased (89%; P < 0.001) during hypoxia. Similarly, on reoxygenation, the hepatic oxygen consumption improved; however, extraction decreased versus controls on 100% but not on 21% oxygen (P < 0.05). The plasma lactate concentrations increased in both groups with hypoxia and were not different during reoxygenation between the group administered with 21% oxygen and the group administered with 100% oxygen. The hypoxic neonatal liver has reduced hepatic blood flow but has relatively preserved HAFI, and oxygen consumption recovered similarly on reoxygenation with 21% and 100% oxygen. The increased oxygen extraction during hypoxia normalized in 21% but reduced in 100% reoxygenation, with no differences in plasma lactate concentrations.

Abstract: Thromboembolic and bleeding complications are common after asphyxia. We studied the temporal effects of different oxygen concentrations used in resuscitating hypoxic newborn piglets on platelet aggregatory function. Alveolar normocapnic hypoxia (fractional inspired oxygen concentration = 0.15) was induced in piglets (1-4 d, 1.7-2.5 kg) for 2 h, followed by reoxygenation with 18%, 21%, or 100% oxygen for 1 h and then 21% for 2 h (n = 8-9 per group). Control piglets underwent surgery with no hypoxia-reoxygenation (n = 5). Platelet counts and collagen-stimulated (2-10 microg/mL) whole blood aggregation were studied at normoxic baseline and at 3 h, 2 d, and 4 d of recovery. Platelet activation markers including plasma thromboxane B2 and matrix metalloproteinase 2 and 9 levels were measured. At 2 h hypoxia (mean PaO2 30-35 mmHg), all piglets were hypotensive and acidotic (mean pH 7.19-7.24). In 100% reoxygenation piglets, the concentration-response curves of collagen-stimulated platelet aggregation were significantly shifted upward at 3 h and 2 d of recovery with no differences in the collagen concentration required to induce 50% of maximum aggregation, and this normalized to baseline on 4 d. In the 18% and 21% reoxygenated groups, there were no changes in platelet aggregation during the experiment. Platelet counts were not different between groups and over time. Hypoxic-reoxygenated piglets had increased plasma thromboxane B2 (100% group) and matrix metalloproteinase-2 levels (21% and 100% groups) (versus respective baseline, P < 0.05), with no difference between experimental groups. These findings suggest transient platelet activation in hypoxic newborn piglets resuscitated with 100% but not with 18% and 21% oxygen, of which the clinical significance requires further investigation.

Abstract: Shock and poor regional perfusion are common in asphyxiated neonates. We compared the systemic and regional hemodynamic effects of high-dose epinephrine (E) with those of dopamine combined with low-dose epinephrine (DE) infusions in a neonatal model of hypoxia-reoxygenation. Neonatal piglets (1-3 days, 1.5-2.5 kg) were acutely instrumented to continuously monitor systemic arterial pressure (SAP), pulmonary artery pressure, cardiac index (CI), and blood flows at the left common carotid, superior mesenteric, and renal arteries. Either epinephrine (1 microg.kg(-1).min(-1)) or dopamine (10 microg.kg(-1).min(-1)) and epinephrine (0.2 microg.kg(-1).min(-1)) were given for 2 h in hypoxic piglets resuscitated with 100% oxygen (n = 8 per group) in a randomized blinded fashion. Control piglets received hypoxia and reoxygenation but no catecholamine infusion (n = 7). Alveolar hypoxia (PaO2, 33-37 mmHg) caused reduced CI (89-92 vs. 171-186 mL.kg(-1).min(-1) of baseline, P < 0.05), hypotension (SAP, 28-32 mmHg) with pH 7.05 to 7.10, and decreased regional flows. Upon reoxygenation, CI and SAP improved but gradually deteriorated to 131 to 136 mL.kg(-1).min(-1) and 41 to 49 mmHg at 2 h of reoxygenation, respectively. E and DE administration similarly improved CI (167 +/- 60 and 166 +/- 55 vs. 121 +/- 35 mL.kg(-1).min(-1) of controls) and SAP (53 +/- 7 and 56 +/- 10 vs. 39 +/- 8 mmHg of controls), respectively, and the pulmonary vascular resistance (vs. controls, all P < 0.05). Heart rate and pulmonary artery pressure were not different between groups. Systemic oxygen delivery and consumption were increased in E- and DE-treated groups with no difference in extraction ratio between groups. There were no differences in regional blood flows and oxygen delivery between groups. After hyperlactatemia with hypoxia, plasma lactate levels decreased with no difference between groups. Epinephrine given as the sole agent is as effective as dopamine and low-dose epinephrine combined in treating shock and hypotension that follow the resuscitation of hypoxic neonatal piglets, with no reduction in regional perfusion.

Abstract: We compared the responses towards oxidative stress in the liver, lung, brain, heart, kidney and small intestine of hypoxic newborn animals resuscitated with 21% or 100% oxygen. After stabilization, piglets (1-3 days, 1.6-2.0 kg, n=8/group) were randomized to receive 2 h of alveolar hypoxia (FiO(2)=0.10-0.14) followed by reoxygenation with 21% or 100% oxygen for 1 h and then another hour with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. At the end of the experiment, tissues from liver, lung, brain, heart, kidney and small intestine were collected and tested for GSH, GSSG and lipid peroxidation levels and histological examination. In normoxic controls, liver had the highest GSH level, followed by brain, heart, lung, small intestine and kidney which had the highest level of oxidative stress markers (GSSG level and GSSG:GSH ratio). Hypoxic-reoxygenated piglets had the highest GSSG levels and GSSG:GSH ratio in the kidney. Hypoxic piglets resuscitated with 100% oxygen had higher GSSG:GSH ratios in the lung and liver, but not in the kidney, brain, heart and small intestine, than controls, which were not different from the 21% group. No significant differences in peroxidation and histological tissue damage were found between groups in the liver and lung. We concluded that although hypoxic piglets resuscitated with 100% oxygen have higher oxidative stress in the liver and lung than with 21% oxygen, there are no significant differences in peroxidation and histological tissue damage acutely.

Abstract: Neonatal asphyxia may lead to cardiac and renal complications perhaps mediated by oxygen free radicals. Using a model of neonatal hypoxia-reoxygenation, we tested the hypothesis that N-acetylcysteine (NAC) would improve cardiac function and renal blood flow. Eighteen piglets (aged 1-4 days old, weighing 1.4-2.2 kg) were anesthetized and acutely instrumented for continuous monitoring of pulmonary and renal artery flow (cardiac index [CI] and renal artery flow index [RAFI], respectively) and mean blood pressure. Alveolar hypoxia was induced for 2 h, followed by resuscitation with 100% oxygen for 1 h and 21% oxygen for 3 h. Animals were randomized to sham-operated, hypoxic control, and NAC treatment (i.v. bolus of 150 mg/kg given at 10 min of reoxygenation followed by 100 mg/kg per h infusion) groups. Myocardial and renal tissue glutathione content and lipid hydroperoxide levels were assayed, and histology was examined. After 2 h of hypoxia, all animals were acidotic (pH 6.96 +/- 0.04) and in cardiogenic shock with depressed renal blood flow. Upon reoxygenation, CI and RAFI increased but gradually deteriorated later. The NAC treatment prevented the decreased CI, stroke volume, mean blood pressure, systemic oxygen delivery, RAFI, and renal oxygen delivery at 2 to 4 h of reoxygenation observed in hypoxic controls (versus shams, all P < 0.05). The myocardial and renal tissue glutathione content was significantly higher in the NAC treatment group (versus controls). The CI and RAFI at 4 h of reoxygenation correlated with the tissue glutathione redox ratio (r = 0.5 and 0.6, respectively, P < 0.05). There were no significant differences in heart rate, pulmonary artery pressure, systemic oxygen uptake, and tissue lipid hydroperoxide levels between groups. No histologic injury was found in the heart or kidney. In this porcine model of neonatal hypoxia and 100% reoxygenation, NAC improved cardiac function and renal perfusion, with improved tissue glutathione content.

Abstract: Hypoxia is a potent stimulus of angiogenic factors and angiostatin can inhibit angiogenesis. Little is known about the expression of angiostatin and its related factors in hypoxic newborns. Using a swine model of neonatal hypoxia, we hypothesized that hypoxia would decrease plasma levels of angiostatin in a time-dependent fashion. In this study newborn piglets underwent hypoxia (15-18% oxygen) for 3 hr, were allowed to recover in 21% oxygen and were then observed for 96 hr. Sham-operated piglets did not experience hypoxia. Plasma levels of angiostatin, plasminogen/plasmin, MMP-2 and -9, and VEGF were determined at normoxic baseline; at the end of hypoxia; at 5 hr; and at 96 hr post-hypoxia. Plasma levels of angiostatin, but not plasminogen/plasmin, decreased significantly at the end of hypoxia and 5 hr after hypoxia compared with the sham-operated group (P < 0.05). Plasma MMP-2 levels at the end of hypoxia were lower in the hypoxic group than in sham animals (P < 0.005). In the hypoxic but not sham-operated group, plasma levels of angiostatin and MMP-2 were positively correlated (r = 0.69; P < 0.001). Plasma MMP-9 and VEGF levels were not different between sham-operated and hypoxic groups and did not correlate with plasma angiostatin levels. In conclusion, hypoxia showed a transient suppressive effect on the expression of plasma angiostatin in newborn piglets. This may imply an inhibitory role of hypoxia on MMP-2 and the proteolytic cleavage of plasminogen to angiostatin.

Abstract: Platelet activation and dysfunction occurs upon hypoxia and reoxygenation and is associated with oxygen free radical generation and matrix metalloproteinase (MMP) -2 and -9 activation. The effect of NAC on platelet function in newborn piglets after asphyxia was studied along with plasma MMP-2 and MMP-9 activities. Piglets (1-4 day, 1.4-2.2 kg) were acutely instrumented for the induction of normocapnic hypoxia (10-15% O2) for 2hr followed by reoxygenation for 1hr with 100% O2 and then 3hr with 21% O2. Animals were randomized to 3 groups (n = 6 each); sham, control and treatment with NAC upon reoxygenation (150 mg/kg i.v. bolus and 100 mg/kg/hr i.v. infusion). Platelet count and collagen (2, 5 and 10 microg/mL)-stimulated whole blood aggregation were studied at baseline and after 4hr reoxygenation. Plasma MMP -2 and -9 activities were analyzed by gelatin zymography. Piglets had severe hypoxia (PaO2 32 +/- 2 vs. 65 +/- 2 mmHg sham; p < 0.05) and metabolic acidosis (pH 6.96 +/- 0.04 vs. 7.33 +/- 0.01 sham; p < 0.05). At 4hr of reoxygenation, platelet counts decreased similarly in all experimental groups, and no animal had a platelet count < 100 x 10(9)/L. Platelet aggregation was significantly reduced with a rightward shift of concentration-response curve. NAC treatment improved platelet aggregatory function at 4hr of reoxygenation (p < 0.05). Plasma MMP-9, but not MMP-2, activities were increased with NAC treatment (147 +/- 19 vs. 51 +/- 20 and 42 +/- 11 AU of control and sham, respectively, p < 0.001). In a newborn piglet model of asphyxia and reoxygenation, NAC treatment effectively improves platelet aggregation when given upon resuscitation.

Abstract: Little is known about angiostatin and its related factors in the hypoxia-reoxygenation of neonates. In this study we compared the effect of 21% and 100% reoxygenation on temporal changes in the plasma level of these factors in newborn piglets subjected to hypoxia. Newborn piglets were subjected to 2 h hypoxia followed by 1 h of reoxygenation with either 21% or 100% oxygen and observed for 4 days. On day 4 of recovery in 100% hypoxic-reoxygenated group, there were increases in total angiostatin, plasminogen/plasmin and MMP-2 levels, and decreases in VEGF levels (vs. respective baseline levels, all P <0.001), whereas no significant temporal changes were found in the 21% hypoxic-reoxygenated and sham-operated groups. Angiostatin levels correlated positively with the levels of MMP-2 and HIF-1alpha and negatively with VEGF levels in 100% hypoxic-reoxygenated group (all P <0.05). In comparison to 21% oxygen, neonatal resuscitation with 100% oxygen was found to increase the levels anti-angiogenic factors.

Abstract: Shock and tissue hypoperfusion are common after asphyxia. We compared systemic and regional hemodynamic effects of epinephrine and dopamine in the treatment of shock and hypotension in asphyxiated newborn piglets resuscitated with 100% oxygen. Twenty-four piglets (1-3 days old; weight, 1.4-2.6 kg) were acutely instrumented to measure cardiac index (CI), carotid, mesenteric and renal arterial blood flows, and mean systemic (SAPs) and pulmonary arterial pressures (PAPs). Piglets had normocapnic alveolar hypoxia (Fio2 = 0.08-0.10) for 50 min and reoxygenated with Fio2= 1.0 for 1 h then Fio2 = 0.21 for 3.5 h. After 2 h reoxygenation, either dopamine (2 mug kg min) or epinephrine (0.2mug kg min) was given for 30 min in a blinded randomized manner, which was then increased to maintain SAP (within 10% of baseline, pressure-driven dose) for 2 h. Hypoxia caused hypotension (SAP, 44% +/- 3% of baseline), cardiogenic shock (CI, 41% +/- 4%), and metabolic acidosis (mean pH, 7.04-7.09). Upon reoxygenation, hemodynamic parameters immediately recovered but gradually deteriorated during 2 h with SAP at 45 +/- 1 mmHg, CI at 74 +/- 9% of baseline, and pH 7.32 +/- 0.03. Low doses of either drug had no significant systemic and renal hemodynamic response. Epinephrine (0.3-1.5 mug kg min) for 2 h increased SAP and CI (with higher stroke volume) and decreased pulmonary vascular resistance (with reduced PAP-SAP ratio), whereas the responses with dopamine (10-25 mug kg min) were modest. Low-dose epinephrine improved mesenteric and carotid arterial flows, whereas the pressure-driven doses of epinephrine and dopamine increased carotid and mesenteric arterial flows, respectively. To treat shock in asphyxiated newborn piglets resuscitated with 100% oxygen, epinephrine exhibits an inotropic action compared with dopamine, whereas both catecholamines can increase carotid and mesenteric perfusion.

Abstract: OBJECTIVE: To study systemic and pulmonary effects of low-dose sildenafil with surfactant in newborn piglets with pulmonary hypertension (PHT) induced by thromboxane A(2) analog (U46619). DESIGN/METHODS: Piglets (1-3 days, 1.7-2.5 kg) were mechanically ventilated and prepared for the continuous measurement of mean systemic and pulmonary arterial pressures (MAP and PAP, respectively), heart rate and pulmonary artery flow (as cardiac output). Following stabilization, PHT was induced by intravenous U46619 infusion (0.2-0.8 microg/kg/min) for 120 min. Piglets were randomized for intratracheal administration of surfactant (BLES, 4 ml/kg) with saline (n=6) or sildenafil (0.05 mg/kg, n=6) given after 60 min of U46619 treatment. Temporal changes of hemodynamic measurements were analyzed by two-way ANOVA. RESULTS: There was progressive PHT induced by U46619 (161% of baseline), with increased PAP and pulmonary vascular resistance and decreased cardiac output. Surfactant and sildenafil combined improved PAP along with reduced pulmonary vascular resistance. Cardiac output was higher with surfactant and sildenafil combined than surfactant alone. No significant changes in heart rate, stroke volume, MAP and systemic vascular resistance were observed. Ratio of PAP:MAP was lowered with surfactant and sildenafil combined. Systemic oxygen consumption was not different between groups but the oxygen extraction ratio was higher than baseline in surfactant alone (P<0.05). CONCLUSIONS: Adding low-dose sildenafil to surfactant is effective in alleviating the progressive PHT developed in newborn piglets induced by thromboxane A(2). Intratracheal sildenafil may be a useful therapeutic adjunct to critically ill neonates with PHT.

Abstract: AIM: To determine relationships between ototoxic drugs and 4-y sensorineural hearing loss (SNHL) in near-term and term survivors of severe neonatal respiratory failure. METHODS: All 81 survivors of the Canadian arm of the Neonatal Inhaled Nitric Oxide Study (mortality 32, loss to follow-up 9) received loop diuretics, aminoglycosides, and neuromuscular blockers (NMB), and 50 received vancomycin as neonates. Prospective, longitudinal secondary outcome using audiological tests diagnosed late-onset, progressive SNHL in 43 (53%); not flat (sloping) in 29, flat (severe to profound) in 14. Risk for SNHL was determined. RESULTS: A combination of duration of diuretic use of >14 d and average NMB dose of >0.96 mg/kg/d contributed to SNHL among survivors (odds ratio 5.2; 95% CI 1.6, 16.7). Markers of illness severity did not contribute. Dosage or duration of aminoglycosides use did not relate to SNHL. Cumulative dosages and duration of use of diuretics; NMB; use of vancomycin; and overlap of diuretics with NMB, aminoglycosides, and vancomycin individually linked to SNHL (p<0.001). CONCLUSION: Overuse of loop diuretics and/or NMB contributes to SNHL after neonatal respiratory failure; markers of illness severity or the appropriate administration of aminoglycosides do not.

Abstract: PURPOSE: It is controversial to choose an appropriate oxygen concentration to resuscitate asphyxiated newborns regarding the clinical and biochemical oxidative effects. We examined the vasomotor response to reoxygenation with graded reoxygenation and the effects on matrix metalloproteinases and amino acids of the immature brain. METHODS: Thirty-two piglets (1-3 days, 1.5-2.1 kg) were instrumented for continuous monitoring of left common carotid and pulmonary arterial flows (Transonic). Piglets were randomized to a sham-operated control group (without hypoxia/reoxygenation) or 2 h hypoxia induced by decreasing the inspired oxygen concentration to 10-15%, followed by reoxygenation with 21, 50 or 100% oxygen for 1 h and then 21% oxygen for 3 h (n=8 each). The brains were then flash frozen and analyzed for matrix metalloproteinases and amino acid levels by zymography and HPLC, respectively. RESULTS: After 2 h oxygen deprivation, the absolute carotid flow remained similar but accounted for 38% of cardiac output (increased from 17% at baseline, p=0.001). During early reoxygenation, the flow rose in the piglets resuscitated with air (p<0.05), but not in those with supplemental oxygen. Carotid vascular resistance correlated significantly with the arterial partial pressure of oxygen (r=0.7). There was an oxygen-dependent increase in global cerebral activity of matrix metalloproteinase-2 with specific increases in the basal ganglia of all hypoxic-reoxygenated brains. There were no significant differences in glutamate and other amino acids in any brain regions. CONCLUSIONS: Although using high oxygen concentration to resuscitate asphyxiated newborn piglets increased carotid vascular resistance and cerebral matrix metalloproteinase-2 activity, there is no detrimental effect observed in this acute model of hypoxia-reoxygenation.

Abstract: Hemostatic disturbances are common in asphyxiated newborns after resuscitation. We compared platelet function in hypoxic newborn piglets reoxygenated with 21% or 100% oxygen. Piglets (1-3 d, 1.5-2.1 kg) were anesthetized and acutely instrumented for hemodynamic monitoring. After stabilization, normocapnic hypoxia was induced with an inspired oxygen concentration of 10-15% for 2 h. Piglets were then resuscitated for 1 h with 21% or 100% oxygen, followed by 3 h with 21% oxygen. Platelet counts and collagen (2, 5, and 10 microg/mL)-stimulated whole blood aggregation were studied before hypoxia and at 4 h of post-hypoxia/reoxygenation. Platelet function was studied using transmission electron microscopy and by measuring plasma thromboxane B2 (TxB2) and matrix metalloproteinase (MMP)-2 and -9 levels. Control piglets were sham-operated without hypoxia/reoxygenation. The hypoxemic (PaO2 33 mm Hg) piglets developed hypotension with metabolic acidosis (pH 7.02-7.05). Upon reoxygenation, piglets recovered and blood gases gradually normalized. At 4 h reoxygenation, platelet aggregation ex vivo was impaired as evidenced by a rightward-downward shifting of the concentration-response curves. Electron microscopy showed features of platelet activation. Plasma MMP-9 but not MMP-2 activity significantly increased. Resuscitation with 100% but not 21% oxygen increased plasma TxB2 levels. Platelet counts decreased after hypoxia/reoxygenation but were not different between groups during the experiment. Resuscitation of hypoxic newborn piglets caused platelet activation with significant deterioration of platelet aggregation ex vivo and increased plasma MMP-9 levels. High oxygen concentrations may aggravate the activation of prostaglandin-thromboxane mechanistic pathway.

Abstract: In neonates with acute pulmonary hypertension (PHT), the dose-response effect of sildenafil citrate, a selective phosphodiesterase-5 inhibitor that can alleviate PHT, has not been detailedly examined. We tested the hypothesis that the treatment of hypoxia-induced acute PHT with sildenafil would dose-dependently reduce the elevated pulmonary and systemic arterial pressures (PAP and SAP, respectively) with no effect on the oxygenation in newborn animals. We also examined the regional hemodynamic responses. Using a randomized controlled design, piglets (age range, 1-3 days; weight range, 1.5-2.1 kg) were anesthetized and acutely instrumented to measure cardiac index, left common carotid, superior mesenteric and left renal arterial flow indexes, SAP, and PAP. After stabilization, hypoxia was induced with fractional inspired oxygen concentration at 0.15 and, subsequently, piglets were randomized to receive i.v. sildenafil at 0.06, 0.2, or 2.0 mg/kg per hour or normal saline (controls) for 90 min (n = 6 each). Within 30 min of hypoxia (PaO2, 31 +/- 5 mmHg), the piglets developed PHT (PAP, 33 +/- 5 vs. 26 +/- 4 mmHg at baseline; P < 0.05. Sildenafil dose-dependently reduced the hypoxia-induced PHT (PAP at 90 min: 33 +/- 6, 29 +/- 6, and 26 +/- 6 mmHg of 0.06, 0.2, and 2.0 mg/kg per hour, respectively, vs. 44 +/- 8 mmHg of controls; P < 0.05. Sildenafil at 2.0 mg/kg per hour had the greatest decrease in SAP (P < 0.05) with no significant change at 0.06 and 0.2 mg/kg per hour. Pulmonary selectivity (PAP:SAP ratio) was best in the group treated with 0.2 mg/kg per hour dosage of sildenafil (P < 0.05). There were no differences in cardiac index and regional flow indexes between groups. Although hypoxia decreased oxygen delivery and increased oxygen extraction with no significant effect on oxygen consumption, the administration of sildenafil did not affect the oxygen metabolism (vs. controls). In neonatal piglets, i.v. sildenafil dose-dependently alleviates the hypoxia-induced acute PHT, with the best pulmonary selectivity at 0.2 mg/kg per hour, and shows no significant effect on regional circulation and oxygen metabolism.

Abstract: AIM: To study the effect of WeiJia on chronic liver injury using carbon tetrachloride (CCl(4)) induced liver injury animal model. METHODS:Wistar rats weighing 180-220g were randomly divided into three groups: normal control group (Group A), CCl(4) induced liver injury control group (Group B) and CCl(4) induction with WeiJia treatment group (Group C). Each group consisted of 14 rats. Liver damage and fibrosis was induced by subcutaneous injection with 40% CCl(4) in olive oil at 3 mL/kg body weight twice a week for eight weeks for Groups B and C rats whereas olive oil was used for Group A rats. Starting from the third week, Group C rats also received daily intraperitoneal injection of WeiJia at a dose of 1.25 microg/kg body weight. Animals were sacrificed at the fifth week (4 male, 3 female), and eighth week (4 male, 3 female) respectively. Degree of fibrosis were measured and serological markers for liver fibrosis and function including hyaluronic acid (HA), type IV collagen (CIV), gamma-glutamyl transferase (gamma-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Alpha smooth muscle actin (alpha-SMA) and proliferating cell nuclear antigen (PCNA) immunohistochemistry were also performed. RESULTS: CCl(4) induction led to the damage of liver and development of fibrosis in Group B and Group C rats when compared to Group A rats. The treatment of WeiJia in Group C rats could reduce the fibrosis condition significantly compared to Group B rats. The effect could be observed after three weeks of treatment and was more obvious after eight weeks of treatment. Serum HA, CIV, ALT, AST and gamma-GT levels after eight weeks of treatment for Group C rats were 58+/-22 microg/L (P<0.01), 57+/-21 microg/L (P<0.01), 47+/-10 U/L (P<0.01), 139+/-13 U/L (P<0.05) and 52+/-21 U/L (P>0.05) respectively, similar to normal control group (Group A), but significantly different from CCl(4) induced liver injury control group (Group B). An increase in PCNA and decrease in alpha-SMA expression level was also observed. CONCLUSION: WeiJia could improve liver function and reduce liver fibrosis which might be through the inhibition of stellate cell activity.

Abstract: The inhibitory effect of different sulfur compounds and antioxidants at the activity level of matrix metalloproteinase (MMP)-2 and -9 during neonatal hypoxia-reoxygenation is unknown. The tissue activity of MMP-2 and -9 was first determined by gelatin zymography in different tissues of 6 newborn piglets that underwent alveolar hypoxia and reoxygenation. The in vitro inhibitory effects of sulfur compounds and antioxidants with or without the thiol group were compared at the highest concentrations of MMP-2 and -9 found. These compounds included: amino acids containing sulfur [cysteine, DL-homocysteine, L-methionine] and not containing sulfur [L-histidine], antioxidants containing sulfur [L-glutathione and N-acetyl-cysteine] and not containing sulfur [ascorbic acid], and oxidized glutathione. Lung had the highest activity of MMP-2 and -9 among the tissues studied. The compounds showed differential effects on the activity of MMP-2 and -9. The order of the potency of inhibition of these compounds for MMP-2 was cysteine> or =histidine> or =ascorbic acid> or =glutathione> or =oxidized glutathione> or =homocysteine> or =N-acetyl-cysteine>methionine, whereas for MMP-9, it was cysteine> or =ascorbic acid> or =histidine>glutathione>homocysteine>N-acetyl-cysteine>oxidized glutathione>methionine. The IC50 values of these compounds on MMP-2 were significantly lower than the corresponding IC50 values on MMP-9. In conclusions, at the activity level of MMP-2 and -9 measured after neonatal hypoxia-reoxygenation, cysteine showed the highest potency of inhibition. The compounds showed different potencies of inhibition, regardless of the presence or absence of the thiol group or the antioxidant property of the compound.

Abstract: Neonatal hypoxia-ischemia (HI) is a major contributor to many perinatal neurologic disorders and, thus, the search for therapies and effective treatments for the associated brain damage has become increasingly important. The tetracycline derivative, doxycycline (DOXY), has been reported to be neuroprotective in adult animal models of cerebral ischemia. To investigate the putative neuroprotective effects of DOXY in an animal model of neonatal HI, a time-course study was run such that pups received either DOXY (10 mg/kg) or VEH immediately before hypoxia, 1, 2, or 3 hours after HI (n=6). At 7 days after injury, the pups were euthanized, and the brains were removed and processed for immunohistochemical and Western blot analyses using antibodies against specific markers for neurons, apoptotic markers, microglia, oligodendrocytes, and astrocytes. Results showed that in vulnerable brain regions including the hippocampal formation, thalamus, striatum, cerebral cortex and white matter tracts, DOXY significantly decreased caspase-3 immunoreactivity (a marker of apoptosis), promoted neuronal survival, inhibited microglial activation and reduced reactive astrocytosis compared with VEH-treated HI pups. These effects were found to occur in a time-dependent manner. Taken together, these results strongly suggest that doxycycline has potential as a pharmacological treatment for mild HI in neonates.

Abstract: OBJECTIVES: An observational cohort study was conducted in infants less than 6 weeks of age undergoing intracardiac surgery to examine the predictive value of serial postoperative lactate determination on survival and early childhood neurodevelopment. METHODS: A total of 85 infants with congenital heart disease underwent intracardiac surgery between 1996 and 1999. Differences in serial lactate concentrations after surgery among 3 outcome groups were compared. The predictive value of plasma lactate concentration on outcome (1) at discharge from initial hospitalization and (2) 18 to 24 months postnatal age was examined. RESULTS: Compared with survivors, the nonsurvivors had higher lactate concentrations on admission to the pediatric intensive care unit at day 1 peak and area under the curve of the lactate profile than those of adverse and intact survivors (all P < .001, analysis of variance). Significant differences in the time for lactate concentrations to return to 2 mmol/L or less during the first postoperative day were observed among the groups: nonsurvivors > adverse survivors > intact survivors. Lactate concentrations of less than 7 mmol/L on admission or less than 8 mmol/L at day 1 peak predicted survival with 82% sensitivity and 83% specificity, and positive and negative predictive values of 97% and 43%, respectively (P < .001, chi2). Plasma lactate concentrations were associated with adverse outcome but had lower predictive values compared with that for nonsurvival. CONCLUSIONS: Serial lactate determination accurately predicts survival and may help differentiate survivors with adverse outcome from those with intact neurodevelopment in early childhood.

Abstract: After asphyxia, it is standard to resuscitate the newborn with 100% oxygen, which may create a hypoxia-reoxygenation process that may contribute to subsequent myocardial dysfunction. We examined the effects of graded reoxygenation on cardiac function, myocardial glutathione levels, and matrix metalloproteinase (MMP)-2 activity during recovery. Thirty-two piglets (1-3 days old, weighing 1.5-2.1 kg) were anesthetized and instrumented for continuous monitoring of cardiac index, and systemic and pulmonary arterial pressures. After 2 h of hypoxia, piglets were randomized to receive reoxygenation for 1 h with 21%, 50%, or 100% oxygen (n = 8 each), followed by 3 h at 21% oxygen. At 2 h of hypoxemia (PaO2 32-34 mmHg), the animals had hypotension, decreased cardiac index, and elevated pulmonary arterial pressure (P < 0.001 vs. controls). Upon reoxygenation, cardiac function recovered in all groups with higher cardiac index and lower systemic vascular resistance in the 21% group at 30 min of reoxygenation (P < 0.05 vs. controls). Pulmonary artery pressure normalized in an oxygen-dependent fashion (100% = 50% > 21%), despite an immediate recovery of pulmonary vascular resistance in all groups. The hypoxia-reoxygenated (21%-100%) hearts had similarly increased MMP-2 activity and decreased glutathione levels (P < 0.05, 100% vs. controls), which correlated significantly with cardiac index and stroke volume during reoxygenation, and similar features of early myocardial necrosis. In neonatal resuscitation, if used with caution because of a slower resolution of pulmonary hypertension, 21% reoxygenation results in similar cardiac function and early myocardial injury as 50% or 100%. The significance of higher oxidative stress with high oxygen concentration is unknown, at least in the acute recovery period.

Abstract: OBJECTIVE: To compare mesenteric blood flow, oxidative stress, and mucosal injury in piglet small intestine during hypoxemia and reoxygenation with 21%, 50%, or 100% oxygen. SUMMARY BACKGROUND DATA: Necrotizing enterocolitis is a disease whose pathogenesis likely involves hypoxia-reoxygenation and the generation of oxygen-free radicals, which are known to cause intestinal injury. Resuscitation of asphyxiated newborns with 100% oxygen has been shown to increase oxidative stress, as measured by the glutathione redox ratio, and thus may predispose to free radical-mediated tissue injury. METHODS: Newborn piglets subjected to severe hypoxemia for 2 hours were resuscitated with 21%, 50%, or 100% oxygen while superior mesenteric artery (SMA) flow and hemodynamic parameters were continuously measured. Small intestinal tissue samples were analyzed for histologic injury and levels of oxidized and reduced glutathione. RESULTS: SMA blood flow decreased to 34% and mesenteric oxygen delivery decreased to 9% in hypoxemic piglets compared with sham-operated controls. With reoxygenation, SMA blood flow increased to 177%, 157%, and 145% of baseline values in piglets resuscitated with 21%, 50%, and 100% oxygen, respectively. Mesenteric oxygen delivery increased to more than 150% of baseline values in piglets resuscitated with 50% or 100% oxygen, and this correlated significantly with the degree of oxidative stress, as measured by the oxidized-to-reduced glutathione ratio. Two of eight piglets resuscitated with 100% oxygen developed gross and microscopic evidence of pneumatosis intestinalis and severe mucosal injury, while all other piglets were grossly normal. CONCLUSIONS: Resuscitation of hypoxemic newborn piglets with 100% oxygen is associated with an increase in oxygen delivery and oxidative stress, and may be associated with the development of small intestinal hypoxia-reoxygenation injury. Resuscitation of asphyxiated newborns with lower oxygen concentrations may help to decrease the risk of necrotizing enterocolitis.

Abstract: Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in a variety of physiologic growth and development and pathophysiologic inflammatory conditions. We hypothesized that 1) MMP-2 and -9 plasma activities and TIMP-1 and -2 plasma concentrations in preterm and term neonates were dependent on the gestational and postnatal age; and 2) the respective MMP and their inhibitors were deranged in the development of bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) in preterm neonates. From 1998 to 1999, blood samples were collected from preterm neonates (25-36 wk gestation) with or without BPD and/or IVH as well as from healthy term (37-40 wk gestation) neonates during the first 28 d of life. MMP-2 and MMP-9 plasma activities were measured by zymography; TIMP-1 and TIMP-2 plasma concentrations were determined by ELISA. In neonates without BPD or IVH (n = 50), MMP-2 and MMP-9 plasma activities both appeared to be gestational age dependent, with the highest levels observed in neonates of 33-36 wk gestation. TIMP-1 plasma concentration was highest in term neonates but no gestational difference was found in TIMP-2. Only MMP-9 showed a 50% decrease after d 1 in the first postnatal month. Twelve preterm infants with BPD and/or IVH had significantly lower MMP-2 but higher MMP-9 activity and higher TIMP-1 concentration than those of corresponding neonates without BPD or IVH. These findings show the gestational age-dependent expression of plasma MMP activities and their inhibitors. MMP and TIMP may be involved in the feto-neonatal development and may contribute to the pathogenesis of BPD and/or IVH in critically ill preterm neonates.

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Abstract: During lung development, the extracellular matrix undergoes dynamic remodeling. Matrix metalloproteinases (MMPs), and tissue inhibitors of matrix metalloproteinases (TIMPs), are important enzymes that participate in regulating tissue remodeling. There is an abnormal balance of the synthesis and degradation of collagen and elastin in perinatal lung associated with congenital diaphragmatic hernia (CDH). This study was designed to (1) determine the expression and gelatinolytic activity patterns of MMPs 2 and 9 and TIMPs 1 and 2 in rat lungs during the perinatal period, and (2) to test the hypothesis that they are abnormal in nitrofen-induced CDH. Measurements were made using reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and zymography. The mRNA expression and activity of MMP 2 did not change significantly from embryonic day 16 to postnatal day 14. The most striking feature found was the rapid increase in the expression of MMP 9 soon after birth. Measurements were repeated on lung tissue isolated from embryonic rats with nitrofen-induced CDH. The expression and activity of MMPs and TIMPs were similar to control values and thus we conclude that these proteins appear not to be responsible for the altered extracellular matrix and morphological abnormalities noted in CDH lungs at birth.

Abstract: BACKGROUND/PURPOSE: In neonates receiving extracorporeal membrane oxygenation (ECMO), platelet activation and dysfunction occur with the release of matrix metalloproteinase (MMP)-2, which stimulates platelet aggregation. Because inhaled nitric oxide (NO) reduces pulmonary hypertension and inhibits platelet aggregation, the authors examined the effects of inhaled NO on platelet activation induced by ECMO. METHODS: Ten adult white New Zealand rabbits were instrumented for ECMO and assigned randomly to receive either inhaled NO at 40 ppm or 30% oxygen for 1 hour before ECMO and continued for 4 hours after starting ECMO. Platelet counts, collagen-induced platelet aggregation ex vivo, plasma MMP-2, and MMP-9 activities were measured. RESULTS: (1) ECMO caused thrombocytopenia, decreased platelet aggregation, and increased plasma MMP-2 and MMP-9 activities in controls. (2) Inhaled NO inhibited platelet aggregation before ECMO but did not affect the ECMO-induced thrombocytopenia and platelet activation. (3) Inhaled NO significantly abolished the ECMO-induced increase in plasma MMP-2 but not MMP-9 activities. CONCLUSIONS: Although inhaled NO did not inhibit the platelet activation during ECMO in adult rabbits, it attenuated the increase in plasma MMP-2 activity that may be important for neonates treated with ECMO.

Abstract: OBJECTIVES: To determine the prevalence of sensorineural hearing loss (SNHL) at the age of 4 years among survivors of severe neonatal respiratory failure with and without congenital diaphragmatic hernia and to document the occurrence of late-onset or progressive SNHL among the survivors. DESIGN: Prospective, longitudinal secondary outcome study. SETTING: Multicenter Canadian study in 9 tertiary referral centers. PATIENTS: Eighty-one (89%) of ninety 4-year-old survivors born from 1994 to 1996 of > or =34 weeks gestation at birth with severe neonatal respiratory failure (2 oxygenation indices > or =25 at least 15 minutes apart). MAIN OUTCOME MEASURES: Repeated audiologic measurements from birth to the age of 4 years with documentation of the entire cohort at 2 and 4 years of age. RESULTS: Forty-three (53%) of 81 tested 4-year-old survivors had SNHL; 28 (42%) of 66 without congenital diaphragmatic hernia and 15 (100%) of 15 with congenital diaphragmatic hernia. High-frequency SNHL occurred in 65% of the patients. Of the 43 children with SNHL at 4 years, 30 (70%) had loss at 2 years, and 18 (60%) of these 30 had progressive loss between 2 and 4 years of age. For 13 children with SNHL onset after 2 years of age, the loss was less severe with lesser involvement of the lower frequencies. CONCLUSION: Survivors of severe neonatal respiratory failure frequently develop late-onset SNHL that may be progressive. Urgent investigation is required to enable further understanding and prevention of this problem. Severe neonatal respiratory failure should be an indication for long-term audiologic surveillance.

Abstract: OBJECTIVE: To examine the use of plasma lactate levels to predict mortality and neurodevelopmental outcome of neonates treated with extracorporeal membrane oxygenation. DESIGN: Prospective cohort study. SETTING: Two level III neonatal intensive care units in Canada and the United States. PATIENTS: Seventy-four neonates requiring extracorporeal membrane oxygenation in two neonatal intensive care units from 1994 to 1996. INTERVENTIONS: Differences in clinical and biochemical measurements, including serial lactate levels between three outcome groups (early deaths, adverse survivors, and normal survivors) were compared using analysis of variance. We also examined the predictive relationship between plasma lactate levels and the outcome at neonatal intensive care unit discharge and at 18-24 months postnatal age by backward, stepwise regression and Fisher's exact test. MEASUREMENTS AND MAIN RESULTS: Fifteen (20%) neonates died before neonatal intensive care unit discharge (early deaths), with seven additional deaths before follow-up, which are included in the adverse survivors group. Among 49 early childhood survivors (22 +/- 7 months), 27 were disabled or delayed with Mental and Performance Developmental Indices of 70 +/- 21 and 72 +/- 22, respectively. Early deaths had higher plasma lactate levels and were more acidemic than adverse and normal survivors, who were not different from each other (p <.05). Plasma lactate and the lowest arterial pH independently predicted 42% of the variance of the outcome ( p<.001). A peak lactate level of >or=25 mM predicted early mortality (sensitivity, 47%; specificity, 100%; positive and negative predictive values, 100% and 88%, respectively; p<.001), whereas a level of >or=15 mM predicted adverse outcome (sensitivity, 35%; specificity, 91%; positive and negative predictive values, 89% and 38%, respectively; p<.05). The predictability of plasma lactate was significantly improved in 45 neonates without congenital diaphragmatic hernia or lethal anomalies (sensitivity of 100% for early mortality, negative predictive value of 63% for adverse outcome).CONCLUSIONS In addition to assessing tissue oxygenation, plasma lactate may facilitate the decision-making process by providing early predictive information about the outcome of neonates treated with extracorporeal membrane oxygenation.

Abstract: BACKGROUND: The most appropriate inotropic agent for use in the newborn is uncertain. Dopamine and epinephrine are commonly used, but have unknown effects during hypoxia and pulmonary hypertension; the effects on the splanchnic circulation, in particular, are unclear. METHODS: The effects on the systemic, pulmonary, hepatic, and mesenteric circulations of infusions of dopamine and epinephrine (adrenaline) were compared in 17 newborn piglets. Three groups [control (n = 5), dopamine (n = 6) and epinephrine (n = 6)] of fentanyl anesthetized newborn piglets were instrumented to measure cardiac index (CI), hepatic arterial and portal venous blood flow, mean systemic arterial pressure (SAP), mean pulmonary arterial pressure (PAP), and arterial, portal and mixed venous oxygen saturations. Systemic, pulmonary, and mesenteric vascular resistance indices [systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), mesenteric vascular resistance index (MVRI)], and systemic and splanchnic oxygen extraction and consumption were calculated. Alveolar hypoxia was induced, with arterial oxygen saturation being maintained at 55-65%. After 1 h of stabilization during hypoxia, each animal received either dopamine or epinephrine; randomly administered doses of 2, 10, and 32 microg kg-1 min-1 and 0.2, 1.0, and 3.2 microg kg-1 min-1 respectively were infused for 1 h at each dose. Results were compared with the 1 h hypoxia values by two-way analysis of variance. RESULTS: Epinephrine increased CI at all doses, with no significant effects on SAP and SVRI. Although epinephrine increased PAP at 3.2 microg kg-1min-1, it had no effect on PVRI. Dopamine had no effect on CI, SAP, and SVRI, but increased PAP at all doses and PVRI at 32 microg kg-1min-1. The SAP/PAP ratio was decreased with 32 microg kg-1min-1 dopamine, whereas epinephrine did not affect the ratio. In the mesenteric circulation, dopamine at 32 microg kg-1 min-1 increased portal venous flow and total hepatic blood flow and oxygen delivery, and decreased MVRI; epinephrine had no effect on these variables. Epinephrine increased hepatic arterial flow at 0.2 microg kg-1 min-1; dopamine had no effect on hepatic arterial flow at any dose. Despite these hemodynamic changes, there were no differences in systemic or splanchnic oxygen extraction or consumption at any dose of dopamine or epinephrine. CONCLUSIONS: Epinephrine is more effective than dopamine at increasing cardiac output during hypoxia in this model. Although epinephrine preserves the SAP/PAP ratio, dopamine shows preferential pulmonary vasoconstriction, which might be detrimental if it also occurs during the management of infants with persistent fetal circulation. Dopamine, but not epinephrine, increases portal flow and total hepatic flow during hypoxia.

Abstract: There are differences in the temporal expression of MMP-2 and TIMP-4 in human milk from Day 1 to 30 postpartum in healthy mothers of term pregnancies: (i) MMP-2 activity peaked at Day 1 (colostrum) then exponentially decreased afterwards; and (ii) The expression of TIMP-4 was maximal at Day 7 and persisted thereafter. From our preliminary findings, the differential expression of MMP and the tissue inhibitor in human milk may be related to the protective action of human milk.

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Abstract: OBJECTIVE: To determine the effects of therapy with inhaled nitric oxide (NO) gas and partial or complete blockade of endogenous NO synthesis with N(omega)nitro-L-arginine (L-NA) on the hemodynamic responses to group B streptococci infusion in newborn piglets. DESIGN: Randomized, acute intervention study. SETTING: Animal research laboratory. SUBJECTS: Twenty-five anesthetized piglets younger than 3 days of age divided into five groups. INTERVENTIONS: Heat-killed group B streptococci (GBS) were infused systemically until a 50% increase in pulmonary artery pressure (PAP) was obtained, and the infusion was continued for another 2 hrs. The five groups were designed as follows: group 1, sepsis control: continuous GBS infusion, with two brief trials (10 mins) of inhaled NO given after the initial development of pulmonary hypertension and again 2 hrs later; group 2, continuous inhaled NO: NO was given at 40 ppm for 2 hrs during GBS infusion; group 3, high-dose L-NA pretreatment: 10 mg/kg L-NA bolus followed by 1 mg/kg/min before, and continuing throughout, GBS infusion; group 4, high-dose L-NA: same dose as in group 3, but given after the start of the GBS infusion with continuous inhaled NO at 40 ppm; and group 5, low-dose L-NA: 3 mg/kg bolus given after start of GBS infusion with continuous inhaled NO at 40 ppm. MEASUREMENTS AND MAIN RESULTS: The sepsis controls, group 1, had an increase in PAP, which took 15-45 mins to develop, from a mean of 3.4 (SD 0.7) to 5.9 (1.9) kPa (p < .05), at which time the cardiac index had decreased from 169 (28) to 146 (46) mL/kg/min (p < .05). Brief inhaled NO during the early phase decreased PAP to normal. Two hours later, PAP had increased to 6.1 (0.2) kPa and cardiac index had decreased to 88 (31) mL/kg/min. Inhaled NO after 2 hrs decreased PAP to 3.2 (0.5) kPa and increased cardiac index to 106 (44) ml/kg/min (p < .05). Continuous inhaled NO (group 2) ameliorated the deterioration in cardiac index, which at 2 hrs was 140 (30) mL/kg/min (significantly greater than in the sepsis controls) (p < .05). The L-NA-pretreated animals (group 3) had a greater increase in PAP and pulmonary vascular resistance index when GBS infusion was started. PAP increased from 3.0 (0.7) to 7.3 (1.5) kPa within 15 mins, and cardiac index simultaneously decreased to 68 (20) mL/kg/min. Cardiac index subsequently rapidly deteriorated to 48 (21) mL/kg/min, and only one of five animals survived for 2 hrs. Group 4 animals also developed a rapid deterioration in cardiac output, and only two of five survived for 2 hrs. Group 5 animals had results indistinguishable from group 2 animals. CONCLUSION: Pulmonary hypertension and shock resulting from GBS infusion in newborn piglets are much worse if endogenous NO production is completely inhibited. Continuous inhaled NO with or without low-dose L-NA inhibits the decrease in cardiac output.

Abstract: BACKGROUND: Matrix metalloproteinases (MMPs) contribute to collagen degradation and remodeling of the extracellular matrix after myocardial infarction; however, their role in myocardial dysfunction immediately after ischemia and reperfusion is unknown. METHODS AND RESULTS: We measured the release of MMPs into the coronary effluent of isolated, perfused rat hearts during aerobic perfusion and reperfusion after ischemia. Aerobically perfused control hearts expressed pro-MMP-2 and MMP-2, as well as an unidentified 75-kDa gelatinase. These enzymes were also detected in the coronary effluent. After 20 minutes of global no-flow ischemia, there was a marked increase in pro-MMP-2 in the coronary effluent that peaked within the first minute of reperfusion. The release of pro-MMP-2 into the coronary effluent during reperfusion was enhanced with increasing duration of ischemia and correlated negatively with the recovery of mechanical function during reperfusion (r(2)=0.99). MMP-2 antibody (1.5 to 15 microg/mL) and the inhibitors of MMPs doxycycline (10 to 100 micromol/L) and o-phenanthroline (3 to 100 micromol/L) improved whereas MMP-2 worsened the recovery of mechanical function during reperfusion. CONCLUSIONS: These results show that acute release of MMP-2 during reperfusion after ischemia contributes to cardiac mechanical dysfunction. The inhibition of MMPs may be a novel pharmacological strategy for the treatment of ischemia-reperfusion injury.

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Abstract: PURPOSE: The aim of this study was to determine whether recirculation could be quantified by a thermodilution technique during venovenous (VV) extracorporeal membrane oxygenation (ECMO) in a rabbit model. METHODS: Five New Zealand white rabbits, mean weight, 4.5 (range, 3.7 to 5.7) kg, were anesthetized, instrumented, cannulated with a double-lumen catheter, and placed on VV ECMO. Serial injections of ice-cold saline were performed at the arterial arm of the circuit, and the resultant temperature change at various pump flows was measured at the venous arm of the circuit using a thermistor-tipped catheter and a cardiac output computer. Results were compared with the respective 100% recirculation measured with all the circuit flow passing through the bridge. RESULTS: Using linear regression, recirculation percentage could be calculated as: 19 + 0.1 x pump flow (R2 = 0.81, P < .005). Recirculation correlated positively with pump flow. Variability between results at each flow was less than 10%. CONCLUSIONS: Recirculation can be quantified during VV ECMO by measuring the change in temperature in the venous arm using a cardiac output computer after injection of a known quantity of ice-cold saline in the arterial side of the circuit. The effect of interventions to reduce recirculation can be assessed conveniently and reliably.

Abstract: Peroxynitrite (ONOO(-)) formation during acute reperfusion of the ischemic heart contributes to the poor recovery of mechanical function. As glutathione (GSH) detoxifies ONOO(-), we studied whether it could protect isolated rat hearts subjected to exogenous ONOO(-)or to ischemia-reperfusion. We showed that GSH (300 microm, n=5) abolished the detrimental effect of ONOO(-)(80 microm, n=5) on mechanical function of aerobically perfused hearts. Hearts were subjected to 25 min aerobic perfusion, 20 min global, no-flow ischemia and 30 min reperfusion. GSH (3-300 microm, n=7-12) or saline vehicle (control, n=22) were infused for 10 min prior to ischemia and throughout reperfusion. During reperfusion, GSH caused a concentration-dependent improvement in the recovery of mechanical function, which was not associated with significant changes in the intracellular concentration of GSH. The concentration of dityrosine (a marker of ONOO(-) formation) in the coronary effluent during reperfusion was significantly reduced in GSH-treated hearts. The concentration of myocardial cGMP was significantly elevated by GSH during ischemia and early reperfusion. GSH improves the recovery of myocardial mechanical function after ischemia-reperfusion, an effect which may be related to the detoxification of ONOO(-)by GSH and the stimulation of soluble guanylate cyclase.

Abstract: OBJECTIVE: Although bleeding associated with thrombocytopenia often complicates extracorporeal membrane oxygenation (ECMO), the mechanisms of platelet dysfunction during ECMO remain poorly understood. We investigated the role of matrix metalloproteinase (MMP)-2, which recently has been shown to mediate a novel pathway of platelet aggregation, in the platelet dysfunction induced by ECMO. DESIGN: Prospective longitudinal case study. SETTING: Level III neonatal intensive care unit. PATIENTS: Ten neonates treated with ECMO. INTERVENTION: ECMO procedure. MEASUREMENTS: Platelet counts and collagen-induced platelet aggregation ex vivo; plasma markers of platelet (soluble P-selectin) and endothelial (soluble E-selectin and total nitrite/nitrate) activation; plasma MMP-2 and MMP-9 activities; and concentrations of tissue inhibitors of MMPs. MAIN RESULTS: During ECMO, time-dependent platelet activation, as evidenced by thrombocytopenia, decreased platelet aggregation, and increased plasma soluble P-selectin concentrations were found in the absence of endothelial activation, as shown by normal plasma concentrations of soluble E-selectin and nitric oxide metabolites (nitrite/nitrate). There was a time-dependent increase in plasma MMP-2 but not MMP-9 activity; tissue inhibitors of MMPs were not detected. Plasma soluble P-selectin concentrations significantly correlated with simultaneous plasma MMP-2 (r2 = .37, p < .0001) but not with MMP-9 activities. Platelet dysfunction persisted despite repeated platelet transfusions to maintain platelet counts >100 x 10(9)/L. CONCLUSIONS: ECMO resulted in the activation of platelets but not endothelial cells. During ECMO, platelet dysfunction persisted despite platelet transfusions. MMP-2 may play a role in the development of platelet dysfunction caused by ECMO.

Abstract: Apnea commonly occurs in preterm infants and may persist beyond term. We prospectively investigated the relationship between apnea that persisted beyond 35 weeks post-conceptional age and subsequent neurodevelopment in early childhood. Between January, 1990-November, 1993, we performed predischarge respiratory recordings, using 24-hr, 4-channel pneumography, at 35 weeks or more of postconceptional age in 164 infants (birth weight, <1,250 g; gestational age, < or = 32 weeks), who subsequently underwent multidisciplinary neurodevelopmental assessment at 15-64 (median 24) months of adjusted age. The duration of initial artificial ventilation for respiratory distress syndrome and the grade of intraventricular hemorrhage were independent predictors of neurodevelopmental outcome. Mean oximetry desaturation and frequency of predischarge apnea correlated with mental and motor developmental scores. Mean oximetry desaturation during apnea was an independent predictor for motor score in the total population, and for both mental and motor scores in 50 infants with grade 3 or 4 intraventricular hemorrhage, but not in 114 infants without grade 3 or 4 intraventricular hemorrhage. Despite its limited predictability for early childhood neurodevelopment, predischarge respiratory recordings may be useful in predicting subsequent neurodevelopment of high-risk preterm infants, especially those with severe intraventricular hemorrhage.

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Abstract: OBJECTIVE: To determine the systemic, pulmonary, mesenteric, and renal hemodynamic effects of short and prolonged infusions of dobutamine. DESIGN: Prospective randomized unblinded study. SETTING: University research laboratory. SUBJECTS: Thirteen newborn (1-3 days old) piglets. INTERVENTIONS: Piglets were instrumented and studied 48 hrs later. Fifteen-minute infusions of dobutamine at 5, 10, 20 and 50 microg/ kg x min were randomly given with 15-min rests between the doses. After a 1-hr hiatus, a dose of 10 microg/kg x min was continuously administered for 2 hrs. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary arterial pressures, cardiac index (thermodilution), and superior mesenteric and renal artery flows were measured. Vascular resistance values were calculated. MAIN RESULTS: Fifteen-minute infusions: Dobutamine dose-dependently increased cardiac index with tachycardia but not stroke volume (from 187 +/- 43 to 238 +/- 51 mL/kg x min at baseline and 50 microg/ kg x min, respectively, p < .05; values expressed as mean +/- SD). Systemic, but not pulmonary, vascular resistance decreased, resulting in a significant decrease in systemic to pulmonary arterial pressure ratio (from 3.8 +/- 0.8 at baseline to 3.2 +/- 1.0 at 50 microg/ kg x min). Superior mesenteric and renal flows were not affected. Two-hour infusion at 10 microg/kg x min: Cardiac index progressively increased from 173 +/- 34 to 240 +/- 58 mL/kg x min at baseline and 120 mins, respectively, (p < .05). The initial tachycardia was transient, and stroke volume was significantly increased at 60 mins and thereafter. Although systemic and pulmonary vascular resistance values fell simultaneously, systemic to pulmonary arterial pressure ratio decreased significantly to 3.4 +/- 0.9 at 120 mins from 3.9 +/- 0.7 at baseline. Superior mesenteric and renal artery flows increased significantly with vasodilation after 60 mins. CONCLUSIONS: Short infusions of dobutamine dose-dependently increase cardiac output due to tachycardia, without significant effect on mesenteric and renal blood flows. Prolonged infusion of dobutamine at 10 microg/kg x min progressively increases cardiac output and stroke volume with transient tachycardia, and increases mesenteric and renal blood flows. Caution is required in the treatment of critically ill neonates with dobutamine, which could also reduce systemic to pulmonary arterial pressure ratio.

Abstract: Sensorineural hearing loss (SNHL) is a significant neurologic morbidity in survivors of neonatal congenital diaphragmatic hernia (CDH), with a reported incidence of up to 60%. In a historical cohort study of 37 neonates with CDH, we investigated the use of pancuronium bromide (PB) and common ototoxic drugs during the neonatal period and their relationship to SNHL in childhood survivors. Survivors with SNHL (n = 23) had significantly higher cumulative dose of PB administered during the neonatal illness than survivors without SNHL (n = 14). The cumulative dose and duration of PB use significantly correlated (r = 0.66-0.81) and independently predicted (adjusted r (2) = 0.42-0.64) the greatest intensity (in decibels) and the widest band (lowest frequency in hertz) loss of SNHL. No differences were identified between survivors with and without SNHL regarding demographic and neonatal characteristics (including oxygenation and ventilation variables and the cumulative dose and duration of therapy with aminoglycosides, vancomycin, and furosemide), although survivors with SNHL had received a modestly higher cumulative dose of ethacrynic acid than survivors without SNHL. Although we show that prolonged administration of PB during the neonatal period is associated with SNHL in childhood survivors of CDH, further multicenter studies are required to investigate the possible etiologies of SNHL in this high-risk population.

Abstract: AIM: To determine the correlation between gastric intramucosal pH and superior mesenteric artery (SMA) flow in newborn piglets. METHODS: Fourteen newborn piglets were randomly assigned to either a control or to an epinephrine group which received 0,1,2,4,0 microg/kg/min of epinephrine for 60 minutes, each dose. Gastric tonometry was performed, SMA flow was measured, and intramucosal pH and the ratio of tonometer pCO(2) over arterial pCO(2) (rCO(2)) were calculated. RESULTS: Intramucosal pH decreased over time in both groups, but tended to be lower in the epinephrine group. With increasing dose of epinephrine, SMA flow decreased; this in turn increased rCO(2) (p = 0.04) with a tendency to decrease intramucosal pH (p = 0.06). CONCLUSIONS: Gastric tonometry may be useful in human neonates to evaluate gut ischaemia.

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Abstract: Peroxynitrite (ONOO-) is a potent inhibitor of myocardial aconitase. Because ONOO- reacts with sulfhydryl moieties, we investigated whether thiols protect against ONOO(-)-mediated inhibition of aconitase. Aconitase activity was examined in ventricular homogenates prepared from freshly isolated rat hearts. Peroxynitrite, but not the nitric oxide donor S-nitroso-N-acetyl-d,l-penicillamine (0.03-300 microM), inhibited aconitase activity (IC50 = 47 +/- 6 microM). L-Cysteine (0.03-3 mM), glutathione (0.03-3 mM), and N-(2-mercaptoproprionyl)-glycine (MPG, 0.1-3 mM) protected against the inhibitory effect of ONOO- (100 microM) with the rank order of potency of MPG > glutathione > L-cysteine. D-Cysteine (3 mM) had a protective effect similar to L-cysteine, but L-cystine, the oxidized form of L-cysteine, offered no protection. Ferrous ammonium sulfate (1 mM) markedly enhanced the protection provided by L-cysteine, but not by glutathione or MPG. Thiols protect myocardial aconitase against inhibition by ONOO- in a manner which is sulfhydryl group dependent and not stereospecific. The protection is related to the maintenance of the redox state of the iron-sulfur cubane cluster and cysteine residues at the active site of the enzyme. Both naturally occurring thiols and thiol-based drugs may be useful to protect the heart during ischemia-reperfusion injury where there is an excessive production of ONOO-.

Abstract: OBJECTIVE: To determine the effects of a continuous epinephrine infusion on renal and mesenteric blood flow in both healthy newborn piglets and animals subjected to hemorrhagic shock. METHODS: Superior mesenteric artery (SMA) and left renal artery ultrasonic flow probes were implanted into 16 1- to 3-day-old piglets. Two days later, the effects of epinephrine on SMA and renal blood flow, mean arterial pressure (MAP) and central venous pressure were measured in conscious, non-sedated normovolemic piglets. Epinephrine doses of 0.2, 0.4, 0.8, 1.6 and 3.2 microg/kg.min were used in random order. Piglets were subsequently hemorrhaged (20 ml/kg) to mild hypotension and again received epinephrine infusion in the same doses. RESULTS: Doses of epinephrine less than 3.2 microg/kg.min had no significant effects on renal or mesenteric arterial flow. At 3.2 microg/kg.min of epinephrine during normovolemia, there was a significant decrease in SMA blood flow (34% [SD 42], p < 0.05) and increase in SMA vascular resistance (147% [SD 114], p < 0.05). Similar results were shown during hypovolemia, SMA flow decreased by 32% (SD 33), and SMA vascular resistance increased by 220.3% (SD 177). At 3.2 microg/kg.min renal artery flow decreased by 43% (SD 21) during normovolemia and a similar decrease occurred during hypovolemia, 37% (SD 31). Renal vascular resistance increased by about 200% at this dose (normovolemia 211% [SD 185], hypovolemia 186% [SD 150], p < 0.01). Low-to-moderate dose epinephrine caused no significant change in SMA or renal blood flow. During hypovolemia low dose epinephrine infusion was associated with a trend to increased SMA blood flow. CONCLUSION: Low-dose epinephrine does not cause vasoconstriction in the renal or mesenteric circulations during normovolemia or hypovolemia. High doses of epinephrine above 1.6 microg/kg.min may cause renal or mesenteric ischemia, in either the normovolemic or hypovolemic neonate.

Abstract: Little information is available on long-term neurodevelopment of premature neonates with invasive candidal infections. We retrospectively studied the outcomes for 25 premature neonates (birth weight, < 1,250 g) with candidemia or candidal meningitis (cases) and compared them with 25 neonates matched for birth weight (+/- 100 g) and gestational age (+/- 1 week) (controls). Durations of antibiotic therapy, artificial ventilation, invasive catheterizations, and hyperalimentation were longer for cases than for controls. Cases had a higher final grade of intraventricular hemorrhage than did controls (median: 3.0 vs. 2.5, respectively; P < .05). Forty-four percent (11 of 25) of cases and 16% (4 of 25) of controls died (P > .05), and 29% (4 of 14) of surviving cases and 14% (3 of 21) of controls were disabled (P > .05). More cases had combined mortality and neurodevelopmental disabilities than did controls (60% vs. 28%, respectively; P < .05). Use of invasive therapies should be minimized for premature neonates at risk for invasive candidal infection that is associated with adverse outcomes.

Abstract: Although inhaled nitric oxide (INO) improves oxygenation in critically ill neonates, the neurodevelopmental outcome of premature neonates with severe hypoxemic respiratory failure treated with INO has not been reported. Mortality and prospective neurodevelopmental assessment in early childhood were studied in a cohort of 24 very low birth weight neonates (</=1500 g) consecutively admitted from 1993 to 1997 and rescued with INO because of severe hypoxemic respiratory failure (oxygenation index 28 to 52) unresponsive to aggressive conventional treatment. Significant improvements in arterial oxygen tension and oxygenation index with lower inspired oxygen concentration and less ventilator support after initiating INO were observed (P <.05, analysis of variance). Despite the dramatic improvement in systemic oxygenation, the mortality rate was high (14 of 24, 58%). Only 6 of 23 had normal cranial ultrasonographies. At 13 to 40 (22 +/- 10) months of adjusted age, 10 survivors had Bayley Scales mental and psychomotor developmental indexes of 81 +/- 21 and 64 +/- 22, respectively. Of the 10 children, 5 (50%) were disabled, 2 (20%) were developmentally delayed, and 3 (30%) had normal development. In view of the poor outcome in very low-birth-weight neonates rescued by INO, randomized controlled trials are required to examine the role of INO in premature neonates. Before, during, and after INO therapy, cranial ultrasonography is recommended.

Abstract: OBJECTIVE: This study aimed to determine the prevalence of sensorineural hearing loss (SNHL) in 2-5-year-old survivors with neonatal respiratory failure due to congenital diaphragmatic hernia (CDH) with or without the need for extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: The study design was a prospective, multicenter, longitudinal outcome study of consecutively surviving neonates admitted to a single tertiary intensive care unit. SETTING: The study was conducted at four audiologic departments affiliated with tertiary-level intensive care follow-up programs. PATIENTS: Thirty-seven surviving children receiving neonatal intensive care from February 1989 through January 1995 for neonatal respiratory failure due to CDH were studied. Excluded were 15 children with early death and I child lost to follow-up. INTERVENTION: The initial treatment depended on the severity of neonatal respiratory failure: ECMO-treated (n=31, 20 survivors) (death before ECMO initiation, 2) and non-ECMO treated (n=20, 17 survivors, another survivor lost to follow-up). MAIN OUTCOME MEASURE: Early childhood audiologic test results were measured. RESULTS: Sensorineural hearing loss was found in almost 60% of subjects: ECMO-treated, 12 (60%) of 20; non-ECMO-treated, 10 (59%) of 17. Of the 22 children with SNHL, 16 had mild- to-moderate low-frequency sloping to moderate-to-severe high-frequency loss. Of the remaining, six had severe-to-profound loss at 500 Hz and above. Seventeen children had normal responses to sound as newborns or in infancy. Five children were not tested. Documented progression was found in nine children. Twenty children currently are using amplification, and 2 have had cochlear implantation. CONCLUSIONS: Of children with CDH in this area presenting early with severe neonatal respiratory failure, SNHL developed in 60% by 2-5 years of life. Ongoing monitoring of the hearing status of children with CDH is imperative.

Abstract: OBJECTIVE: Temporal effects of prolonged hypoxaemia and reoxygenation, on the systemic pulmonary and mesenteric circulations in newborn piglets, were investigated. METHODS: Two groups [control (n = 5), hypoxaemic (n = 7)] of 1-3 day old anaesthetised piglets were instrumented with ultrasound flow probes placed to measure cardiac, hepatic arterial flow and portal venous flow indices, and catheters inserted for measurements of systemic and pulmonary arterial pressures. Hypoxaemia with arterial oxygen saturation 40-50% was maintained for 3 h, followed by reoxygenation with 100% inspired oxygen. RESULTS: Cardiac index was transiently elevated at 30-60 min of hypoxaemia (23% increase from baseline 158 +/- 39 ml/kg/min), along with increases in stroke volume but not heart rate. A significant decrease in systemic vascular resistance after 30 min of hypoxaemia was followed by hypotension at 180 min of hypoxaemia. Progressive pulmonary hypertension with significant vasoconstriction was found after 30 min of hypoxaemia. The hypoxaemic mesenteric vasoconstriction was transient with a 37% decrease in portal venous flow index at 15 min of hypoxaemia (29 +/- 12 vs. 46 +/- 18 ml/kg/min of baseline, p < 0.05). The hepatic arterial to total hepatic oxygen delivery ratio increased significantly during hypoxaemia. In contrast to the significant increase in systemic oxygen extraction throughout hypoxaemia, elevation in mesenteric oxygen extraction decreased after 30 min of hypoxaemia associated with modest decreases in oxygen consumption. Following reoxygenation, the pulmonary hypertension was partially reversed. Cardiac index decreased further (130 +/- 39 ml/kg/min) with reduced stroke volume, persistent systemic hypotension and decreased systemic oxygen delivery. CONCLUSIONS: We demonstrated differential temporal changes in systemic, pulmonary and mesenteric circulatory responses during prolonged hypoxaemia. Cautions need to be taken upon reoxygenation because the neonates are at risk of developing myocardial stunning, persistent pulmonary hypertension and necrotising enterocolitis.

Abstract: The response of the systemic, pulmonary, hepatic and portal circulations to infusion of dopamine and epinephrine was studied in newborn piglets 1 to 3 d of age. Anesthetized animals were instrumented to measure cardiac index (CI), hepatic arterial flow, and portal venous blood flow. Catheters were inserted for measurement of systemic arterial pressure (SAP), pulmonary arterial pressure (PAP), and for sampling of arterial, portal venous, and mixed venous oxygen saturations and plasma lactate levels. Systemic, pulmonary and mesenteric vascular resistance indices (SVRI, PVRI, MVRI), and systemic and mesenteric oxygen extraction were calculated. Dopamine and epinephrine were infused in doses of 2, 10, 32 microg/kg/min and 0.2, 1.0, 3.2 microg/kg/min respectively, given in random order. Significant increases in SAP, PAP, and CI were demonstrated with 32 microg/kg/min of dopamine and the two higher doses (1.0 and 3.2 microg/kg/min) of epinephrine. There were no significant changes in SVRI and PVRI with dopamine infusions. Epinephrine at 3.2 microg/kg/min significantly elevated SVRI and PVRI. The SAP/PAP ratio was decreased with 32 microg/kg/min of dopamine whereas epinephrine did not affect the ratio. Dopamine had no significant effect on hepatic arterial flow, portal venous flow, or mesenteric vascular resistance. Epinephrine infusion at 3.2 microg/kg/min decreased portal venous blood flow, total hepatic blood flow, and hepatic oxygen delivery with an increase in calculated mesenteric vascular resistance. Systemic and mesenteric oxygen extraction were not affected by dopamine or epinephrine infusions. Plasma lactate levels were significantly elevated with epinephrine infusion 3.2 microg/kg/min. The differential responses of dopamine and epinephrine on pulmonary and mesenteric circulations may be significant in the pathophysiology and management of persistent fetal circulation and necrotizing enterocolitis.

Abstract: The role of rescue high-frequency oscillatory ventilation (HFO) in treating very-low-birth-weight neonates with severe respiratory failure in relation to neurodevelopmental outcome has not been evaluated. We performed a retrospective cohort study on 21 patients (out of 52 consecutively admitted preterm neonates with gestational age < or = 30 weeks and birth weight < or = 1.250 g; mortality rate 60%) rescued with HFO between October 1988 and August 1993. Neurodevelopment, including Bayley Scales in Infant Development, was assessed at 12-61 (mean 28.5) months adjusted age. Thirteen normal (scores better than 2 SD below mean, and no sensory or motor disability) (62%) and neurodevelopmentally disabled children (38%) survived more than 1 year for developmental assessment. The mental and performance developmental indices were 94 (78-117) and 89 (68-110), and 63 (49-102) and 49 for the 13 normal and 8 disabled children, respectively (both p < 0.05). The incidence of bronchopulmonary dysplasia, intraventricular hemorrhage (IVH; grade 3 or 4), growth retardation, developmental scores and disabilities of these 21 HFO survivors were not significantly different from that of a birth-weight- and gestational-age-matched comparison group. While all HFO survivors had significant improvement in oxygenation 12 and 24 h after starting HFO, FiO2 and the alveolar-arterial oxygen gradient (A-aDO2) decreased significantly 1 h after starting HFO in survivors with normal neurodevelopmental outcome. The lack of initial response to HFO (20% decrease in A-aDO2 1 h after starting HFO) and the presence of grade 3 or 4 IVH predicted neurodevelopmental disability with a sensitivity of 63%, a specificity of 100%, and positive and negative predictive values of 100 and 81%, respectively. We concluded that HFO could be used as a rescue treatment in sick preterm neonates. The lack of early improvement in oxygenation and the presence of grade 3 or 4 IVH can predict adverse early childhood neurodevelopment in such neonates.

Abstract: Although venoarterial extracorporeal membrane oxygenation (ECMO) is an accepted form of cardiopulmonary support for critically ill neonates, carotid artery reconstruction (CAR) after decannulation remains controversial. Long-term follow-up information regarding the natural progression of the anastomosis is unavailable. From January 1990 through December 1990, 13 venoarterial neonatal ECMO survivors had CAR performed and were enrolled into this prospective study based on sonographic follow-up of CAR. A total of 34 carotid artery sonographic studies were performed (13 within 1 week after reconstruction, 8 at 6 to 9 months, and 13 at 4 years of age). A high patency rate during the neonatal period was observed (12 of 13, 92%). Among 12 children with normal neonatal sonographic studies, 5 had completely normal studies during 4 years of follow-up. Narrowing at the anastomotic site (defined as structural narrowing with velocity ratio of peak systolic velocity at the anastomosis to peak systolic velocity proximal to the anastomosis > 1.0 but < or =2.0) by 4 years of age developed in 7 children. Two of these 7 children had hemodynamically significant stenotic anastomosis (defined as structural narrowing with velocity ratio >2.0) by 4 years of age. One neonate had a narrowed anastomosis that resolved completely by the age of 4 years. The incidence of normal studies decreased from 92% to 75% to 46% during the neonatal period, at 6 to 9 months, and at 4 years follow-up, respectively (Chi-square test for trend, P < .01). Long-term follow-up information on the natural progression of carotid reanastomosis is required.

Abstract: Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.

Abstract: The actions of thiols on coronary vascular tone in the intact heart are unknown. Glutathione (GSH), glutathione disulfide (GSSG), and L-cysteine (10-1,000 microM each) and GSH ethyl ester (3-300 microM) were infused into isolated rat hearts perfused with Krebs buffer at a constant pressure by the Langendorff method. GSH, GSSG, and GSH ethyl ester, but not L-cysteine, caused a concentration-dependent increase in coronary flow with the following order of potency: GSH ethyl ester > GSH = GSSG. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (300 microM), prevented the increase in coronary flow with GSH and attenuated that with GSSG (300 microM each). The vasodilation with GSH or GSSG and the associated increase in myocardial guanosine 3',5'-cyclic monophosphate were abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (a specific inhibitor of soluble guanylate cyclase) at 1 and 3 microM, respectively. The vasodilator action of GSH was abolished by superoxide dismutase (50 U/ml). Inhibition of GSH reductase abolished GSSG-induced vasodilation. Neither glibenclamide (1 microM) nor indomethacin (4 microM) affected the vasodilator action of GSH and GSSG. We conclude that GSH and GSSG cause coronary vasodilation that is mediated by a nitric oxide- and guanylate cyclase-dependent mechanism, possibly mediated by the reaction between GSH and peroxynitrite to form S-nitrosoglutathione, a nitric oxide donor.

Abstract: The follow-up information of sensorineural hearing loss (SNHL) in neonatal extracorporeal membrane oxygenation (ECMO) survivors was reviewed by Medline search (1985-1996) using indexing terms; ECMO, follow-up outcome. Only seven reports (from six different centres) provide information on the results of audiologic assessment in 371 ECMO survivors with follow-up duration of 1-10 years. SNHL is a significant neurologic morbidity in neonatal ECMO survivors with a reported frequency of 3-21% (average 7.5%, 28 of 371). From three of the seven reports that provide information of clinical features in the survivors with SNHL, SNHL is often an isolated disability (16 of 19, 84%) and the loss is usually bilateral involving high frequencies. SNHL can be late-onset (7 of 19, 37% diagnosed after infancy) and progressive. Multicentre prospective studies with regular comprehensive audiologic assessment until bilateral thresholds can be obtained are urgently required to define the course of SNHL. Basic research is needed to evaluate the role of various factors (e.g., peroxynitrite and free radicals) in the pathogenesis of SNHL. The information generated will help to develop preventive measures and cost-effective management of these ECMO survivors.

Abstract: Dopamine is important for renal perfusion, natriuresis, and the control of blood pressure. Modulation of the activities of adenylyl cyclase, phospholipase C and protein kinases is involved in the signal transduction pathway of dopamine. Peripheral dopamine receptors are classified as the DA1 and DA2 subtypes on the basis of synaptic localization and their pharmacological profiles. In the kidney, DA1 receptors are localized in the medial layer of the renal vasculature and along the nephron; DA2 receptors are found in the glomerulus and the nerves surrounding renal blood vessels. While DA1 receptor stimulation results in renal vasodilatation and natriuresis, DA2 receptors may play a synergistic role in the DA1 modulated natriuresis. There is increasing evidence that these effects of dopamine are attenuated in younger than in older animals. Future studies should be directed to identify the ontogenic differences in vascular and tubular dopamine receptors (density and affinity) and their coupling mechanisms, in order to evaluate the role of dopamine which is frequently used in the management of shock in newborns.

Abstract: Although plasma lactate concentration has been widely used as an indicator of tissue hypoxia, no clinical study has been conducted to relate these values to the neurological outcome of sick neonates. Seventeen consecutively cared for and surviving neonates with severe hypoxaemia requiring extracorporeal membrane oxygenation (ECMO) were evaluated at a mean age of 19.6 months. The serial plasma lactate concentrations were significantly correlated with the scores of the Bayley Scales of Infant Development. Admission and peak plasma lactate of < or = 15 mmol/l predicted favourable outcome (MDI and PDI > 70 and no disability): sensitivity 100%, specificity 88%, positive predictive value 90%, and negative predictive value 100%. Plasma lactate values could help predict neurodevelopmental outcome in these sick neonates.

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Abstract: OBJECTIVE: To determine the effects of stimulation of vascular dopaminergic receptor subtype 1 (dopamine-1) receptors in the renal and mesenteric vascular beds of a neonatal model. DESIGN: Prospective, unblinded, dose-response evaluation in an awake animal. SETTING: University research laboratory. SUBJECTS: Thirty newborn piglets, obtained and instrumented at 1 to 3 days of age and studied 48 hrs later. INTERVENTIONS: Animals were chronically instrumented with transit time ultrasound flow probes around the left renal and superior mesenteric arteries. They were then intravenously infused with either dopamine (2 to 32 micrograms/kg/min) or fenoldopam (1 to 100 micrograms/kg/min), which is a selective agonist of the dopamine-1 receptor. MEASUREMENTS AND MAIN RESULTS: Blood pressure was only significantly increased by the highest infusion rate of dopamine (32 micrograms/kg/min), from a mean of 78 mm Hg at baseline to 87 mm Hg. Mesenteric and renal vascular resistances were unchanged by dopamine at any dose. Dopamine at 32 micrograms/kg/min decreased renal blood flow by 16.6 +/- 19.6 (SD) % and increased renal vascular resistance by 39.6 +/- 41.1% (p < .05). Mesenteric blood flow increased by 15% at 32 micrograms/kg/min (p < .05) but mesenteric vascular resistance was not affected by dopamine. Fenoldopam reduced blood pressure at infusion rates of 5, 10, and 100 micrograms/kg/min. Fenoldopam had no effect on renal vascular resistance at any dose. Fenoldopam reduced mesenteric vascular resistance at 5 micrograms/kg/min and at all higher doses. CONCLUSIONS: These data demonstrate the absence of dopaminergic receptor-mediated vasodilation in the porcine neonatal renal vascular bed. In the mesenteric artery, dopamine-1 receptor-mediated vasodilation may be obtained. Dopamine itself, probably because of stimulation of other receptors, causes renal artery vasoconstriction and does not increase superior mesenteric artery blood flow.

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Abstract: From February 1989 to January 1994, nine of 63 (14.3%) survivors of neonatal extracorporeal membrane oxygenation developed bilateral sensorineural hearing loss. Seven of nine children were tested and passed initial or repeat clinical auditory brainstem response evaluation completed before discharge from neonatal intensive care. Hearing loss was suspected and confirmed between 6-36 and 10-48 months of age, respectively. We recommend regular audiologic follow-up for these high-risk infants until bilateral thresholds for hearing can be obtained.

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Abstract: Plasma lactate concentrations have been used as an indicator of tissue hypoxia and as a predictor of the outcome of critical illness in adults. We evaluated the value of plasma lactate levels in predicting death in neonates with severe hypoxemia requiring extracorporeal membrane oxygenation (ECMO). We retrospectively reviewed the medical records in regard to plasma lactate levels and other clinical and biochemical measurements in 28 consecutive neonates requiring ECMO from July 1992 to December 1993. Seven infants died (mortality rate, 25%); 21 infants were short-term survivors and 20 infants were discharged from the unit. The plasma lactate values for survivors and nonsurvivors, respectively, were 10.0 +/- 6.35 mmol/L vs 24.9 +/- 9.90 mmol/L on admission, and 13.7 +/- 6.32 mmol/L vs 38.4 +/- 9.20 mmol/L at peak (both p < 0.00001). The survivors had a significant decrease in plasma lactate levels 12 hours after the start of ECMO: the nonsurvivors had persistent, severe hyperlactatemia. Apart from being less acidotic, the survivors did not differ from the nonsurvivors in other clinical and biochemical measurements. An admission plasma lactate concentration of < 25 mmol/L predicted survival with a sensitivity 100%, a specificity 71.4%, and positive and negative predictive values of 91.3% and 100%, respectively. We conclude that plasma lactate levels could be useful in predicting death in neonates with severe hypoxemia requiring ECMO. Further prospective evaluations of the predictive value of plasma lactate levels in sick neonates are required to confirm these initial observations.