Inhaled nitric oxide and inhibition of platelet aggregation in critically ill neonates.
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Administration, Inhalation↗
Biomedical subjects
P Y Cheung
Publications and source records attributed to P Y Cheung.
Thiols protect the inhibition of myocardial aconitase by peroxynitrite.
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-.
Aconitate Hydratase↗
Temporal effects of prolonged hypoxaemia and reoxygenation on systemic, pulmonary and mesenteric perfusions in newborn piglets.
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.
Animals↗
The outcome of very low birth weight neonates (</=1500 g) rescued by inhaled nitric oxide: neurodevelopment in early childhood.
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.
Administration, Inhalation↗
Comparative study of mortality and morbidity in premature infants (birth weight, < 1,250 g) with candidemia or candidal meningitis.
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.
Candida↗
Effects of a continuous epinephrine infusion on regional blood flow in awake newborn piglets.
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.
Animals↗
High prevalence of sensorineural hearing loss among survivors of neonatal congenital diaphragmatic hernia. Western Canadian ECMO Follow-up Group.
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.
Audiometry↗
Carotid artery reconstruction in neonates receiving extracorporeal membrane oxygenation: a 4-year follow-up study. Western Canadian ECMO Follow-Up Group.
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.
Anastomosis, Surgical↗
Nitric oxide and platelet function: implications for neonatology.
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.
Blood Platelets↗
The role of tyrosine phosphorylation in lipopolysaccharide- and zymosan-induced procoagulant activity and tissue factor expression in macrophages.
The expression of surface procoagulants by exudative macrophages represents an important mechanism underlying local fibrin deposition at sites of extravascular inflammation. The present studies investigated the contribution of tyrosine phosphorylation to the generation of macrophage procoagulant activity (PCA) and tissue factor expression in response to proinflammatory stimuli. Both lipopolysaccharide (LPS) and zymosan rapidly stimulated tyrosine phosphorylation in elicited murine peritoneal macrophages. This effect was prevented by the tyrosine kinase inhibitors genistein and herbimycin and augmented by the addition of the phosphotyrosine phosphatase inhibitor vanadate. The vanadate-mediated rise in phosphotyrosine accumulation was abrogated by the use of diphenylene iodonium, an inhibitor of the respiratory burst oxidase, suggesting a role for peroxides of vanadate as contributors to the tyrosine phosphorylation. This notion was supported by the finding that vanadyl hydroperoxide markedly increased the accumulation of phosphotyrosine residues. To define the role of tyrosine phosphorylation in the induction of macrophage PCA by LPS, the effects of tyrosine kinase inhibition by genistein and herbimycin were investigated. Both agents inhibited the expression of macrophage PCA. Further, Northern blot analysis with the cDNA probe for murine tissue factor indicated that the inhibition occurred at the mRNA level or earlier. Since vanadate augmented phosphotyrosine accumulation, it was hypothesized that it might enhance generation of macrophage products. However, vanadate reduced induction of PCA in response to LPS. By contrast, vanadate augmented basal prostaglandin E2 (PGE2) release and stimulated PGE2 release by macrophages. Indomethacin prevented the increase in PGE2 but only partially restored normal levels of PCA. The effect of vanadate on tissue factor expression appeared to be posttranscriptional. These studies thus demonstrate, by functional Western blotting and Northern blotting techniques, that tyrosine phosphorylation plays a role in the regulation of macrophage PCA and tissue factor expression in response to proinflammatory stimuli.
Animals↗
Glutathione causes coronary vasodilation via a nitric oxide- and soluble guanylate cyclase-dependent mechanism.
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.
Analysis of Variance↗
Rescue high frequency oscillatory ventilation for preterm infants: neurodevelopmental outcome and its prediction.
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.
Cohort Studies↗
Systemic, pulmonary and mesenteric perfusion and oxygenation effects of dopamine and epinephrine.
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.
Animals↗
Sensorineural hearing loss in survivors of neonatal extracorporeal membrane oxygenation.
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.
Evoked Potentials, Auditory, Brain Stem↗
Neurodevelopmental outcome in extracorporeal membrane oxygenation survivors.
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Child Development↗
Dopaminergic receptor-mediated effects in the mesenteric vasculature and renal vasculature of the chronically instrumented newborn piglet.
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.
Animals↗
Hyperlactatemia associated with hypocarbic hyperventilation.
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Animals↗
Plasma lactate as a predictor of early childhood neurodevelopmental outcome of neonates with severe hypoxaemia requiring extracorporeal membrane oxygenation.
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.
Biomarkers↗