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Biomedical subjects

John P Kinsella

Publications and source records attributed to John P Kinsella.

At least 19 recordsLinked to original sources
PubMed2006

Early inhaled nitric oxide therapy in premature newborns with respiratory failure.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

Administration, Inhalation↗
PubMed2006

Bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is a chronic lung disease that affects premature babies and contributes to their morbidity and mortality. Improved survival of very immature infants has led to increased numbers of infants with this disorder. This increase puts a heavy burden on health resources since these infants need frequent re-admission to hospital in the first 2 years after birth and, even as adolescents, have lung-function abnormalities and persistent respiratory symptoms. Unlike the original description of the disease in 1967, premature infants can develop chronic oxygen dependency without severe, acute respiratory distress; this "new bronchopulmonary dysplasia" could be the result of impaired postnatal lung growth. Whether such infants subsequently have catch-up lung growth, especially if given corticosteroids postnatally, is unknown. No safe and effective preventive therapy has been identified, but promising new treatments directed either at reducing lung injury or improving lung growth are under study.

Antioxidants↗
PubMed2006

Neonatal extracorporeal life support: impact of new therapies on survival.

OBJECTIVE: To evaluate the effects of pre-extracorporeal life support (ECLS) management with nitric oxide (NO), high frequency ventilation (HFV), and surfactant on mortality among neonates supported with ECLS. STUDY DESIGN: Extracorporeal Life Support Organization (ELSO) data on 7017 neonates cannulated for respiratory reasons between 1996 and 2003 were analyzed using chi2, analysis of variance, and logistic regression. RESULTS: The use of ECLS declined by 26.6% over the study period with no significant change in mortality. Unadjusted ECLS mortality for NO-treated patients was lower than for infants not treated with NO (25.1% vs 28.6%, P = .0012) and for infants treated with surfactant than for infants not treated with surfactant (18.7% vs 30.3%, p <.0001.) Unadjusted mortality for HFV-treated patients was no different than for non-HFV-treated patients (26.0% vs 26.6%, P = .56). After adjusting for confounders (primary diagnosis, age at cannulation, ECMO year 1996-1999 vs 2000-2003), surfactant use was associated with decreased mortality. NO-treated neonates were less likely to have a pre-ECLS cardiopulmonary arrest than infants not treated with NO. NO, HFV, and surfactant were not associated with prolongation of ECLS or mechanical ventilation. CONCLUSIONS: NO, HFV, and surfactant were not associated with increased mortality in neonates who require ECLS for hypoxic respiratory failure.

Bronchodilator Agents↗
PubMed2006

Inhaled nitric oxide therapy in premature newborns.

PURPOSE OF REVIEW: Inhaled nitric oxide therapy reduces the need for extracorporeal membrane oxygenation in near-term and term newborns with hypoxemic respiratory failure and persistent pulmonary hypertension, and is now a standard of care for this population. There is also considerable interest, however, in the potential role of inhaled nitric oxide in premature newborns with hypoxemic respiratory failure. The purpose of this review is to summarize the results of clinical trials of inhaled nitric oxide in premature newborns, with particular emphasis on studies published in the last 12 months. RECENT FINDINGS: Several trials of inhaled nitric oxide in premature newborns with respiratory failure have been published in the last year. Interpretation of the findings is complicated by differences in the severity of illness of the study populations, the trial designs, and relevant outcome measures recorded. SUMMARY: Trials of inhaled nitric oxide in premature newborns have yielded conflicting results to date, and the role of inhaled nitric oxide therapy in this population remains controversial. The largest trials of inhaled nitric oxide therapy in premature newborns have completed enrollment but have yet to be published. The results of these ongoing trials will help clarify the potential risks and benefits of inhaled nitric oxide therapy in the premature newborn.

Administration, Inhalation↗
PubMed2005

Superoxide dismutase improves gas exchange and pulmonary hemodynamics in premature lambs.

RATIONALE: Oxidant stress may increase the severity of respiratory distress syndrome (RDS) after premature birth by altering vasoreactivity and increasing lung edema, but the acute effects of superoxide dismutase (SOD) treatment on gas exchange, lung compliance (CL), and pulmonary vascular resistance in premature animals with RDS are unknown. OBJECTIVE: We studied the effects of intratracheal recombinant human SOD treatment (rhSOD) on gas exchange, CL, and pulmonary hemodynamics in 46 premature lambs with RDS. METHODS: After C-section delivery, lambs were randomly assigned to treatment with SOD (2.5-10 mg/kg) with or without inhaled nitric oxide (iNO, 5 ppm), and mechanically ventilated for 4 hours. At the end of the study, pressure-volume curves and wet-dry lung weights were measured to assess CL and edema, respectively. MAIN RESULTS: Despite an initial rise in Pa(O(2)), Pa(O(2)) in control animals progressively declined over the 4-hour treatment period (Pa(O(2)) = 25.0 +/- 7.5 mm Hg at 4 hours). In comparison with control animals, early treatment with SOD at 5 and 10 mg/kg improved Pa(O(2)) at 4 hours (167 +/- 44 and 269 +/- 33 mm Hg, respectively; p < 0.05 vs. control), but did not decrease lung edema or improve CL. In contrast, late treatment with SOD did not improve Pa(O(2)). Treatment with iNO increased Pa(O(2)) (196 +/- 22 vs. 25 +/- 8 mm Hg, control animals; p < 0.01), but the response to iNO was not augmented by combined therapy (SOD + iNO). After 4 hours of ventilation with FI(O(2)) = 1.00, rhSOD treatment lowered pulmonary vascular resistance compared with control animals. CONCLUSIONS: Early intratracheal rhSOD treatment improves oxygenation in premature lambs with RDS and prevents the development of pulmonary hypertension.

Administration, Inhalation↗
PubMed2005

Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats.

Exposure of newborn rats to hyperoxia impairs alveolarization and vessel growth, causing abnormal lung structure that persists during infancy. Recent studies have shown that impaired angiogenesis due to inhibition of vascular endothelial growth factor (VEGF) signaling decreases alveolar and vessel growth in the developing lung, and that nitric oxide (NO) mediates VEGF-dependent angiogenesis. The purpose of this study was to determine whether hyperoxia causes sustained reduction of lung VEGF, VEGF receptor, or endothelial NO synthase (eNOS) expression during recovery, and whether inhaled NO improves lung structure in infant rats after neonatal exposure to hyperoxia. Newborn rat pups were randomized to hyperoxia [fraction of inspired oxygen (Fio(2)), 1.00] or room air exposure for 6 d, and then placed in room air with or without inhaled NO (10 ppm) for 2 wk. Rats were then killed for studies, which included measurements of body weight, lung weight, right ventricular hypertrophy (RVH), morphometric analysis of alveolarization (by mean linear intercept (MLI), radial alveolar counts (RAC), and vascular volume (Vv), and immunostaining and Western blot analysis. In comparison with controls, neonatal hyperoxia reduced body weight, increased MLI, and reduced RAC in infant rats. Lung VEGF, VEGFR-2, and eNOS protein expression were reduced after hyperoxia. Inhaled NO treatment after hyperoxia increased body weight and improved distal lung growth, as demonstrated by increased RAC and Vv and decreased MLI. We conclude that neonatal hyperoxia reduced lung VEGF expression, which persisted during recovery in room air, and that inhaled NO restored distal lung growth in infant rats after neonatal hyperoxia.

Animals↗
PubMed2005

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation.

Mechanisms that maintain high pulmonary vascular resistance (PVR) and oppose vasodilation in the fetal lung are poorly understood. In fetal lambs, increased pulmonary artery pressure evokes a potent vasoconstriction, suggesting that a myogenic response contributes to high PVR in the fetus. In adult systemic circulations, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been shown to modulate the myogenic response, but its role in the fetal lung is unknown. We hypothesized that acute increases in pulmonary artery pressure release 20-HETE, which causes vasoconstriction, or a myogenic response, in the fetal lung. To address this hypothesis, we studied the hemodynamic effects of N-methylsufonyl-12,12-dibromododec-11-enamide (DDMS), a specific inhibitor of 20-HETE production, on the pulmonary vasoconstriction caused by acute compression of the ductus arteriosus (DA) in chronically prepared fetal sheep. An inflatable vascular occluder around the DA was used to increase pulmonary artery pressure under three study conditions: control, after pretreatment with nitro-L-arginine (L-NA; to inhibit shear-stress vasodilation), and after combined treatment with both L-NA and a specific 20-HETE inhibitor, DDMS. We found that DA compression after L-NA treatment increased PVR by 44 +/- 12%. Although intrapulmonary DDMS infusion did not affect basal PVR, DDMS completely abolished the vasoconstrictor response to DA compression in the presence of L-NA (44 +/- 12% vs. 2 +/- 4% change in PVR, L-NA vs. L-NA + DDMS, P < 0.05). We conclude that 20-HETE mediates the myogenic response in the fetal pulmonary circulation and speculate that pharmacological inhibition of 20-HETE might have a therapeutic role in neonatal conditions characterized by pulmonary hypertension.

Amides↗
PubMed2005

Inhaled nitric oxide therapy in children.

Inhaled nitric oxide therapy improves oxygenation and reduces the need for treatment with extracorporeal membrane oxygenation in term newborns with hypoxaemic respiratory failure and persistent pulmonary hypertension. In this review, we summarise the current status of iNO therapy in the newborn and the potential role of iNO in other paediatric populations.

Child↗
PubMed2005

Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension.

Pulmonary hypertension complicates the course of many newborns with congenital diaphragmatic hernia. In the most severe cases, the fetal condition of markedly elevated pulmonary vascular resistance persists after birth and is associated with hypoxemic respiratory failure and severe disturbances in cardiac performance. Late pulmonary hypertension (weeks to months after birth) is increasingly recognized in this population, and chronic pulmonary vascular abnormalities (months to years after birth) are now being discovered. In this review, we will discuss the pathophysiology of acute, late, and chronic pulmonary hypertension in patients with congenital diaphragmatic hernia. We will also review the role of currently available pulmonary vasoactive drugs in the management of pulmonary hypertension in this population.

Acute Disease↗
PubMed2005

High-frequency oscillatory ventilation: lessons from the neonatal/pediatric experience.

Efforts to minimize ventilator-induced lung injury in adults with hypoxemic respiratory failure have recently focused on the potential role of high-frequency oscillatory ventilation (HFOV). However, HFOV has been studied in newborns with hypoxemic respiratory failure for nearly 3 decades. In this brief review, we attempt to summarize key physiological principles learned from this cumulative neonatal/pediatric experience with HFOV.

Child↗
PubMed2004

Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor.

VEGF plays a critical role during lung development and is decreased in human infants with bronchopulmonary dysplasia. Inhibition of VEGF receptors in the newborn rat decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). Nitric oxide (NO) is a downstream mediator of VEGF, but whether the effects of impaired VEGF signaling are due to decreased NO production is unknown. Therefore, we sought to determine whether impaired VEGF signaling downregulates endothelial NO synthase (eNOS) expression in the developing lung and whether inhaled NO (iNO) decreases PH and improves lung growth after VEGF inhibition. Newborn rats received a single dose of SU-5416 (a VEGF receptor inhibitor) or vehicle by subcutaneous injection and were killed up to 3 wk of age for assessments of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), lung eNOS protein, and NOx production in isolated perfused lungs (IPL). Neonatal treatment with SU-5416 increased RVH in infant rats and reduced RAC. Compared with controls, SU-5416 reduced lung eNOS protein expression by 89% at 5 days (P < 0.01). IPL studies from day 14 rats demonstrated increased baseline pulmonary artery pressure and lower perfusate NOx concentration after SU-5416 treatment. Importantly, iNO treatment prevented the increase in RVH and improved RAC after SU-5416 treatment. We conclude that treatment of neonatal rats with SU-5416 downregulates lung eNOS expression and that iNO therapy decreases PH and improves lung growth after SU-5416 treatment. We speculate that decreased NO production contributes to PH and decreases distal lung growth caused by impaired VEGF signaling.

Administration, Inhalation↗
PubMed2003

Acute hemodynamic effects and home therapy using a novel pulsed nasal nitric oxide delivery system in children and young adults with pulmonary hypertension.

In 26 patients, we evaluated a novel pulsed nasal delivery system for nitric oxide (NO) that, in the short term, was as effective as continuous delivery for decreasing pulmonary artery pressure and pulmonary vascular resistance. In 2 patients, NO delivered in the home using this pulsing system was well tolerated for up to 2 years. The long-term safety, efficacy, and acceptability of NO delivered in the home remains to be studied.

Administration, Inhalation↗
PubMed2003

Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus.

Platelet-derived growth factor (PDGF) is a potent smooth muscle cell mitogen that may contribute to smooth muscle hyperplasia during the development of chronic pulmonary hypertension (PH). We studied changes in PDGFalpha- and beta-receptor and ligand expression in lambs with chronic intrauterine PH induced by partial ligation of the ductus arteriosus (DA) at gestational age 124-128 days (term = 147 days). Western blot analysis performed on whole lung homogenates from PH animals after 8 days of DA ligation showed a twofold increase in PDGFalpha- and beta-receptor proteins compared with age-matched controls (P < 0.05). Lung PDGF-A and -B mRNA expression did not differ between PH and control animals. We treated PH animals with NX1975, an aptamer that selectively inhibits PDGF-B, by infusion into the left pulmonary artery for 7 days after DA ligation. NX1975 reduced the development of muscular thickening of small pulmonary arteries by 47% (P < 0.05) and right ventricular hypertrophy (RVH) by 66% (P < 0.02). Lung PDGFalpha- and beta-receptor expression is increased in perinatal PH, and NX1975 reduces the increase in wall thickness of small pulmonary arteries and RVH in this model. We speculate that PDGF signaling contributes to structural vascular remodeling in perinatal PH and that selective PDGF inhibition may provide a novel therapeutic strategy for the treatment of chronic PH.

Animals↗
PubMed2003

Noninvasive delivery of inhaled nitric oxide therapy for late pulmonary hypertension in newborn infants with congenital diaphragmatic hernia.

OBJECTIVE: To determine the incidence of late pulmonary hypertension (late PH) in congenital diaphragmatic hernia (CDH) and whether prolonged treatment with noninvasive inhaled NO therapy delivered through a nasal cannula (NC) would sustain pulmonary vasodilation during a period of transition from mechanical ventilation to spontaneous breathing. STUDY DESIGN: We collected data on all patients with a diagnosis of CDH admitted to the Children's Hospital, Denver, from January 1996 through December 2001. Patients who had suprasystemic pulmonary hypertension when inhaled NO was discontinued before extubation were treated with inhaled NO delivered with the nasal cannula. RESULTS: Newborn infants (n = 47) with CDH were treated during this time period. Short-term (<3 months) and long-term (>1 year) survival was 85% and 75%, respectively; 30 newborn infants were treated with inhaled NO (64%). Inhaled NO was successfully discontinued in 16 patients before extubation, and 10 (21%) were treated with inhaled NO through NC after extubation because of pulmonary hypertension and marked hypoxemia when trials off inhaled NO were performed. Nasopharyngeal NO concentrations were 5.4 +/- 0.5 ppm and 2.4 +/- 0.4 ppm with inhaled NO measured proximally in the delivery device at 10 and 5 ppm, respectively. CONCLUSIONS: Late PH occurs in a significant subset of newborn infants with CDH. Noninvasive inhaled NO treatment may reduce the duration of mechanical ventilation while safely treating late PH.

Administration, Inhalation↗
PubMed2002

Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus.

Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function and modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling before birth. To determine whether lung VEGF expression is decreased in an experimental model of persistent pulmonary hypertension of the newborn (PPHN), we measured lung VEGF and VEGF receptor protein content from fetal lambs 7-10 days after ductus arteriosus ligation (132-140 days gestation; term = 147 days). In contrast with the surge in lung VEGF expression during late gestation in controls, chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78%. To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits VEGF(165). Compared with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and pulmonary vascular resistance by 22 and 50%, respectively, caused right ventricular hypertrophy, and increased wall thickness of small pulmonary arteries. EYE001 treatment reduced lung endothelial nitric oxide synthase protein content by 50% and preferentially impaired the pulmonary vasodilator response to ACh, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression and that selective inhibition of VEGF(165) mimics the structural and physiological changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developing lung and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.

Animals↗
PubMed2002

Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics.

OBJECTIVE: High-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) have been reported to improve oxygenation in children with acute hypoxemic respiratory failure (AHRF), but their roles in the treatment of AHRF remains unknown. The use of HFOV improves oxygenation by increasing lung recruitment. iNO can improve oxygenation in AHRF, but it may have limited efficacy in patients with poor lung inflation. Based on these findings, we hypothesized that the combined treatment of HFOV and inhalation of low-dose NO would improve oxygenation and survival in children with severe AHRF compared with children treated with conventional mechanical ventilation (CMV) or either treatment alone. SETTING: Tertiary pediatric intensive care units at seven academic centers. DESIGN: Post hoc analysis of data from children enrolled in a multicenter, randomized, masked study of the use of iNO in the treatment of AHRF. PATIENTS: A total of 108 pediatric patients with AHRF defined as an oxygenation index of >15 twice within 6 hrs. Mode of ventilation (HFOV or CMV) was determined by the patient's physician based on guidelines to maximize oxygenation. The patient was then randomized to treatment with or without iNO. Comparisons were made between patients who were treated with HFOV plus iNO (n = 14), HFOV alone (n = 12), CMV plus iNO (n = 35), and CMV alone (n = 38). INTERVENTIONS: Ventilation with CMV or HFOV with or without iNO. MEASUREMENTS AND MAIN RESULTS: We found that the change in Pao /Fio ratio was greatest in the HFOV plus iNO group compared with the other treatment groups at 4 hrs (p =.02) and 12 hrs (p =.01). After 24 hrs of treatment, both HFOV plus iNO and HFOV alone resulted in greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.005). After 72 hrs, treatment with HFOV alone resulted in a greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.03). There was no difference in predefined treatment failures between treatment groups. CONCLUSIONS: We conclude that the combination of HFOV with iNO causes a greater improvement in oxygenation than either treatment strategy alone in children with severe AHRF. We speculate that the enhanced lung recruitment by HFOV enhances the effects of low dose iNO on gas exchange.

Administration, Inhalation↗
PubMed2002

Chronic hypertension impairs flow-induced vasodilation and augments the myogenic response in fetal lung.

We hypothesized that altered vasoreactivity in perinatal pulmonary hypertension (PH) is characterized by abnormal responses to hemodynamic stress, including the loss of flow-induced vasodilation and an augmented myogenic response. Therefore, we studied the acute hemodynamic effects of brief compression of the ductus arteriosus (DA) in control fetal lambs and in lambs during exposure to chronic PH. In both groups, acute DA compression decreased pulmonary vascular resistance (PVR) by 20% at baseline (day 0). After 2 days of hypertension, acute DA compression paradoxically increased PVR by 50% in PH lambs, whereas PVR decreased by 25% in controls. During the 8-day study period, PVR increased during acute DA compression in PH lambs, whereas acute DA compression continued to cause vasodilation in controls. Brief treatment with the nitric oxide (NO) synthase inhibitor nitro-L-arginine (L-NA) increased basal PVR in control but not PH lambs, suggesting decreased NO production in PH lambs. Chronic hypertension increased the myogenic response after L-NA in PH lambs, whereas the myogenic response remained unchanged in controls. The myogenic response was inhibited by nifedipine in PH lambs, suggesting that the myogenic response is dependent upon the influx of extracellular calcium. We conclude that chronic PH impairs flow-induced vasodilation and increases the myogenic response in fetal lung. We speculate that decreased NO signaling and an augmented myogenic response contributes to abnormal vasoreactivity in PH.

Animals↗