PMC:29006 JSONTXT

{"project":"2_test","denotations":[{"id":"11056716-9032045-23487244","span":{"begin":10999,"end":11001},"obj":"9032045"},{"id":"11056716-8885950-23487245","span":{"begin":11557,"end":11559},"obj":"8885950"}],"text":"Inhaled nitric oxide in persistent pulmonary hypertension of the \t\t newborn refractory to high-frequency ventilation \n\nAbstract\nBackground:\nThis study was designed to evaluate the effect of nitric oxide \t\t\t\t(NO) on the management of neonates with severe persistent pulmonary \t\t\t\thypertension refractory to high-frequency oscillatory ventilation.\n\nMethods:\nThe birth weight and the gestational age of infants \t\t\t\twere 3125.5 ± 794 g (mean ± SD) and 39 ± 2.4 weeks, respectively. All \t\t\t\tneonates were ventilated for an average of 137.5 min (range 90-180 min) prior to \t\t\t\tNO therapy. The mean oxygenation index (OI) of all neonates prior to NO was \t\t\t\t46.3 ± 5 (mean ± SEM). NO was initially administered at 20 parts per \t\t\t\tmillion (ppm) for at least 2 h and increased gradually by 2 ppm to a maximum of \t\t\t\t80 ppm.\n\nResults:\nEighteen infants (75%) responded and six (25%) did not respond to \t\t\t\tthe treatment. Three neonates died in the responding group, while all the \t\t\t\tnon-responders died (P = 0.0001). The survival rate was 62.5% among all \t\t\t\tneonates. NO significantly decreased OI (P \u003c 0.0001) and improved \t\t\t\tthe arterial/alveolar (a/A) oxygen ratio (P \u003c 0.0001) within the \t\t\t\tfirst 2 h of NO therapy in 61.1% of the responders. However, the OI and the a/A \t\t\t\toxygen ratio remained almost the same throughout the treatment in the \t\t\t\tnon-responders and the non-survivors.\n\nConclusion:\nInhaled NO at 20 ppm, following adequate ventilation for 2 h without \t\t\t\tsignificant response, could be used to identify the majority of the \t\t\t\tnon-responders in order to seek other alternatives. \n\nIntroduction\nA wide range of life-threatening lung diseases are characterized by \t\t compromised capacity of the lung to match ventilation and perfusion. This \t\t results in poor oxygenation of arterial blood and significant hypoxemia. \t\t Pulmonary hypertension and poor myocardial function often play a role in the \t\t pathophysiology of pulmonary disease [1]. Several \t\t vasodilator agents have been shown to decrease pulmonary vascular resistance, \t\t but their use was limited by concomitant decreases in systemic vascular \t\t resistance and worsening of intrapulmonary shunt [2]. \t\t Recently, selective pulmonary vasodilation with inhalational nitric oxide (INO) \t\t has been demonstrated in both clinical and experimental settings [3,4,5].\nThis pilot study was conducted to evaluate the effect of INO in the \t\t management of neonates with severe persistent pulmonary hypertension refractory \t\t to high-frequency oscillatory ventilation.\n\nMethods\n\nSubjects\nBetween October 1994 and June 1997, 24 consecutive neonates with \t\t\t persistent pulmonary hypertension of the newborn (PPHN) who failed \t\t\t high-frequency oscillatory ventilation were enrolled in this study. The \t\t\t diagnosis of PPHN was made clinically and confirmed by echocardiogram (either \t\t\t right-to-left or bidirectional flow at the ductal or arterial level, or \t\t\t estimated pulmonary pressures from a tricuspid regurgitation jet, being greater \t\t\t than two-thirds of the systemic arterial pressures). The studied neonates had \t\t\t birthweights of 3125.5 ± 794 g (mean ± SD), and gestational ages of \t\t\t 39 ± 2.4 weeks (mean ± SD). There were 12 females and 12 males, and 22 \t\t\t were born outside the hospital. All neonates were ventilated for an average of \t\t\t 137.5 min (range 90–180 min) prior to INO therapy with 3100 A high-frequency \t\t\t oscillatory ventilator (HFOV; Sensor Medics, Yorba Linda, California, USA). \t\t\t Metabolic alkalosis was induced with a bicarbonate infusion. Sedation with \t\t\t morphine and/or midazolam and neuromuscular blockade with pancuronium were \t\t\t used. Synthetic surfactant (Exosurf Neonatal, The Wellcome Foundation Ltd, \t\t\t London, UK) was administered to all neonates with respiratory distress syndrome \t\t\t (RDS) and meconium aspiration syndrome (MAS). Dopamine and dobutamine were used \t\t\t to maintain a mean arterial pressure between 45 and 55 mmHg.\n\nStudy protocol\nNeonates were enrolled after informed consent was obtained from \t\t\t parents. At enrollment, postductal arterial blood samples were drawn for \t\t\t determination of pH, blood gas tensions, and methemoglobin saturation (270 \t\t\t Cooxime, Ciba-Corning, Diagnostics, Medfield, Massachusetts, USA) 10 min prior \t\t\t to the treatment with INO and every 2–4 h thereafter. The mean oxygenation index \t\t\t of all neonates [OI = mean airway pressure × fractional inspired \t\t\t concentration of oxygen (FiO2)/post-ductal partial pressure of \t\t\t arterial oxygen (PaO2)] during high-frequency ventilation and before \t\t\t starting INO was 46.3 ± 5 (mean ± SEM). The NO gas (AHG, Jeddah, Saudi \t\t\t Arabia) used in this study was certified at a concentration of 800 ppm NO with \t\t\t \u003c 1% contamination by other oxides of nitrogen. NO gas was introduced into \t\t\t the ventilator circuit via an adaptor positioned on the inspiratory port of the \t\t\t Fisher and Paykel humidification chamber. Thus, NO was mixed with the bias flow \t\t\t gas of the oscillator and subsequently delivered to the neonate via the \t\t\t inspiratory limb of the ventilator circuit. The resulting concentration of the \t\t\t inhaled NO and NO2 was verified in-line by using an electrochemical \t\t\t sensor (Pulmonox, Tofield, Alberta, Canada). Exhaled gas was scavenged; the \t\t\t oxygen concentration was analyzed continuously before it reached the \t\t\t neonate's endotracheal tube. Nitric oxide was initially administered at \t\t\t 20 ppm for at least 2 h. If there was no response while the neonate was on high \t\t\t ventilatory support and FIO2 of 1.0, INO was increased gradually by \t\t\t 2 ppm to a maximum of 80 ppm. If there was a response, INO was maintained at \t\t\t 20 ppm and FIO2 was gradually decreased to 0.6, provided the \t\t\t PaO2 was 80–120 mmHg. Nitric oxide then was weaned to \t\t\t discontinuation. Ventilatory parameters thereafter were weaned and HFOV was \t\t\t replaced by a conventional ventilator. An arterial/alveolar oxygen (a/A) ratio \t\t\t less than 0.22 was used to define failure of HFOV and INO therapy, if INO \t\t\t reached 80ppm on high ventilatory support.\n\nStatistical analysis\nStatistical analysis was performed with the assistance of the \t\t\t Department of Biostatistics. Normally distributed continuous variables were \t\t\t analyzed with the Student's t-test. Variables without a normal \t\t\t distribution were analyzed with the Wilcoxon signed rank test. This study has \t\t\t been approved by the Department of Pediatrics Research Committee and the King \t\t\t Faisal Specialist Hospital and Research Centre's Research Advisory \t\t\t Council.\n\nResults\nOf the 24 consecutive neonates treated with both HFOV and INO, 18 \t\t (75%) responded and 6 (25%) did not respond to the treatment. Three neonates \t\t died in the responding group, while all the non-responders died (P \t\t =0.0001). The survival rate was 62.5% among all neonates.\nThe underlying diseases of the responders and non-responders are \t\t depicted in Table 1. In addition to severe PPHN, six \t\t neonates had birth asphyxia, 13 had MAS, three had congenital diaphragmatic \t\t hernia (CDH) and two had RDS. Of the 13 neonates with MAS, 12 responded to INO, \t\t while none of the infants with CDH responded to INO therapy.\nInhalation of NO significantly decreased OI (P \u003c 0.0001) \t\t and improved the a/A ratio (P \u003c 0.0001) within the first 2 h of INO \t\t therapy in 61.1% of the responders, and the remaining responded gradually \t\t during the INO treatment. However, OI and a/A ratio remained almost the same \t\t throughout the treatment in the non-responders and the non-survivors (Tables \t\t 2 and 3). Four of the responders \t\t (two with MAS and two with RDS) became INO-dependent and required \t\t phosphodiesterase inhibitor (dipyridamole) to wean them from INO. Tolazoline \t\t was unsuccessfully attempted in two neonates in the referring hospitals. \t\t Methemoglobin and nitrogen dioxide were maintained below 5% during INO therapy. \t\t The average age when INO was started was 2.6 days (range 1–11 days). The mean \t\t duration of INO used in all neonates was 4.6 days (range 1–10 days). Three \t\t neonates responded to INO but died of other causes. The first neonate had \t\t severe intracranial hemorrhage, Klebsiella pneumoniae sepsis, renal \t\t failure and, consequently, brain death. The second neonate had Escherichia \t\t coli sepsis and interstitial lung disease. The lung biopsy revealed a \t\t diffuse alveolar damage. The third neonate developed multiple pneumatoceles in \t\t both lungs and the lung biopsy showed proliferative phase of diffuse alveolar \t\t damage. Subsequent lung tissue culture was positive for \t\t methicillin-resistant Staphylococcal aureus.\nTable 1 The underlying diseases of all infants\nTable 2 Comparison between responders and non-responders OI, oxygenation index; a/A, arterial/alveolar oxygen ratio; INO, \t\t\t\tinhalational nitric oxide. All values shown as mean ± SEM; \t\t\t\t*P \u003c 0.05.\nTable 3 Comparisons between survivors and non-survivors OI, oxygenation index; a/A, arterial/alveolar oxygen ratio; INO, \t\t\t\tinhalational nitric oxide. All values shown as mean ± SEM; *P \u003c 0.05.\n\nDiscussion\nPPHN is a common endpoint of several very different pathophysiological \t\t mechanisms. It is extremely important to understand the underlying etiology of \t\t PPHN, as therapeutic interventions must be tailored to specific circumstances; \t\t for example, PPHN associated with hyaline membrane disease should first be \t\t treated with surfactant therapy.\nMaintenance of adequate circulating blood volume, systemic vascular \t\t resistance, and optimal lung inflation are essential for the management of \t\t PPHN. High-frequency ventilation has been introduced as a mode of therapy in \t\t PPHN. There were no randomized studies of HFOV in the management of infants \t\t with PPHN, but attention has been focused on the potential of HFOV to reduce \t\t the need for extracorporeal membrane oxygenation (ECMO). A number of reports \t\t identify a number of infants who, although referred for ECMO, survived without \t\t using this type of intervention [6,7].\nA comparison between HFOV and INO in reducing the need for ECMO has \t\t been studied. Kinsella et al [8] combined HFOV \t\t and INO in the treatment of infants with hypoxic respiratory failure and PPHN \t\t who were ECMO candidates. These authors found no difference in the need for \t\t ECMO or death in the INO group compared with the HFOV group, and they suggest \t\t that combined treatment with INO and HFOV may improve outcome.\nIn this study, we found that 75% of infants with PPHN who failed HFOV \t\t responded to INO therapy and 62.5% survived to discharge. Recently, the NINOS \t\t Study Group has conducted a study to evaluate whether INO would reduce the \t\t incidence of death or the need for ECMO in infants with hypoxic respiratory \t\t failure [9]. HFOV was used in 55% of the infants. The \t\t authors found that treatment with INO resulted in a significant reduction in \t\t the combined incidence of death in less than 120 days or the need for ECMO. \t\t Moreover, Roberts et al [10] studied 58 \t\t full-term infants with severe hypoxemia and PPHN who were randomized to receive \t\t either INO or nitrogen. They found that INO improved systemic oxygenation in \t\t these infants and they suggest that INO may reduce the need for more invasive \t\t treatment.\nIn this study, we found that 61.1% of the responders responded within \t\t the first 2h after the initiation of INO and their response sustained to the \t\t end of the treatment and the remaining neonates showed a gradual response \t\t throughout the course of INO. Similarly Goldman et al [11] evaluated INO in a group of 25 severely hypoxic term \t\t neonates and identified four patterns of response. Two neonates did not \t\t respond, nine neonates who responded well initially then failed within 24 h, 11 \t\t neonates responded and sustained that response, and three neonates responded to \t\t INO but required high doses for prolonged periods of time. We also found that \t\t 25% failed INO therapy, most likely as a result of severe pulmonary hypoplasia \t\t seen in CDH, and severe lung damage due to severe hypoxia as in asphyxia and \t\t RDS. A number of studies have noted a general lack of a sustained improvement \t\t in oxygenation in response to INO in the management of CDH [12,13,14]. In \t\t this study ECMO was not used as an alternative therapy for the INO \t\t non-responders because it was not available in our hospital for neonates.\nIt has been observed that some infants who showed a dramatic response \t\t to INO developed a decrease in oxygenation when INO was discontinued. This \t\t response may reflect downregulation of endogenous nitric oxide synthase \t\t activity secondary to the administration of exogenous nitric oxide [15]. In addition INO may increase the concentration of \t\t phosphodiesterase, which then degrades cyclic GMP when INO is discontinued, \t\t resulting in vaso-constriction. In this study, four infants became \t\t INO-dependent and successfully weaned from INO following the use of \t\t phosphodiesterase inhibitor (dipyridamole) [16]. Study \t\t of the mechanism of INO dependency may give insight into new therapies that \t\t augment the pulmonary vasodilatory effect of INO and the activity of the \t\t endogenous NO system.\nIn conclusion, the administration of INO at 20ppm, following adequate \t\t ventilation for a maximum of 2h without significant response could be used to \t\t identify the majority of the non-responders. In these situations, other means \t\t of therapy, such as ECMO, could be considered. "}

{"project":"Colil","denotations":[{"id":"T1","span":{"begin":11557,"end":11559},"obj":"8885950"},{"id":"T2","span":{"begin":10999,"end":11001},"obj":"9032045"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/docs/sourcedb/PubMed/sourceid/"}],"text":"Inhaled nitric oxide in persistent pulmonary hypertension of the \t\t newborn refractory to high-frequency ventilation \n\nAbstract\nBackground:\nThis study was designed to evaluate the effect of nitric oxide \t\t\t\t(NO) on the management of neonates with severe persistent pulmonary \t\t\t\thypertension refractory to high-frequency oscillatory ventilation.\n\nMethods:\nThe birth weight and the gestational age of infants \t\t\t\twere 3125.5 ± 794 g (mean ± SD) and 39 ± 2.4 weeks, respectively. All \t\t\t\tneonates were ventilated for an average of 137.5 min (range 90-180 min) prior to \t\t\t\tNO therapy. The mean oxygenation index (OI) of all neonates prior to NO was \t\t\t\t46.3 ± 5 (mean ± SEM). NO was initially administered at 20 parts per \t\t\t\tmillion (ppm) for at least 2 h and increased gradually by 2 ppm to a maximum of \t\t\t\t80 ppm.\n\nResults:\nEighteen infants (75%) responded and six (25%) did not respond to \t\t\t\tthe treatment. Three neonates died in the responding group, while all the \t\t\t\tnon-responders died (P = 0.0001). The survival rate was 62.5% among all \t\t\t\tneonates. NO significantly decreased OI (P \u003c 0.0001) and improved \t\t\t\tthe arterial/alveolar (a/A) oxygen ratio (P \u003c 0.0001) within the \t\t\t\tfirst 2 h of NO therapy in 61.1% of the responders. However, the OI and the a/A \t\t\t\toxygen ratio remained almost the same throughout the treatment in the \t\t\t\tnon-responders and the non-survivors.\n\nConclusion:\nInhaled NO at 20 ppm, following adequate ventilation for 2 h without \t\t\t\tsignificant response, could be used to identify the majority of the \t\t\t\tnon-responders in order to seek other alternatives. \n\nIntroduction\nA wide range of life-threatening lung diseases are characterized by \t\t compromised capacity of the lung to match ventilation and perfusion. This \t\t results in poor oxygenation of arterial blood and significant hypoxemia. \t\t Pulmonary hypertension and poor myocardial function often play a role in the \t\t pathophysiology of pulmonary disease [1]. Several \t\t vasodilator agents have been shown to decrease pulmonary vascular resistance, \t\t but their use was limited by concomitant decreases in systemic vascular \t\t resistance and worsening of intrapulmonary shunt [2]. \t\t Recently, selective pulmonary vasodilation with inhalational nitric oxide (INO) \t\t has been demonstrated in both clinical and experimental settings [3,4,5].\nThis pilot study was conducted to evaluate the effect of INO in the \t\t management of neonates with severe persistent pulmonary hypertension refractory \t\t to high-frequency oscillatory ventilation.\n\nMethods\n\nSubjects\nBetween October 1994 and June 1997, 24 consecutive neonates with \t\t\t persistent pulmonary hypertension of the newborn (PPHN) who failed \t\t\t high-frequency oscillatory ventilation were enrolled in this study. The \t\t\t diagnosis of PPHN was made clinically and confirmed by echocardiogram (either \t\t\t right-to-left or bidirectional flow at the ductal or arterial level, or \t\t\t estimated pulmonary pressures from a tricuspid regurgitation jet, being greater \t\t\t than two-thirds of the systemic arterial pressures). The studied neonates had \t\t\t birthweights of 3125.5 ± 794 g (mean ± SD), and gestational ages of \t\t\t 39 ± 2.4 weeks (mean ± SD). There were 12 females and 12 males, and 22 \t\t\t were born outside the hospital. All neonates were ventilated for an average of \t\t\t 137.5 min (range 90–180 min) prior to INO therapy with 3100 A high-frequency \t\t\t oscillatory ventilator (HFOV; Sensor Medics, Yorba Linda, California, USA). \t\t\t Metabolic alkalosis was induced with a bicarbonate infusion. Sedation with \t\t\t morphine and/or midazolam and neuromuscular blockade with pancuronium were \t\t\t used. Synthetic surfactant (Exosurf Neonatal, The Wellcome Foundation Ltd, \t\t\t London, UK) was administered to all neonates with respiratory distress syndrome \t\t\t (RDS) and meconium aspiration syndrome (MAS). Dopamine and dobutamine were used \t\t\t to maintain a mean arterial pressure between 45 and 55 mmHg.\n\nStudy protocol\nNeonates were enrolled after informed consent was obtained from \t\t\t parents. At enrollment, postductal arterial blood samples were drawn for \t\t\t determination of pH, blood gas tensions, and methemoglobin saturation (270 \t\t\t Cooxime, Ciba-Corning, Diagnostics, Medfield, Massachusetts, USA) 10 min prior \t\t\t to the treatment with INO and every 2–4 h thereafter. The mean oxygenation index \t\t\t of all neonates [OI = mean airway pressure × fractional inspired \t\t\t concentration of oxygen (FiO2)/post-ductal partial pressure of \t\t\t arterial oxygen (PaO2)] during high-frequency ventilation and before \t\t\t starting INO was 46.3 ± 5 (mean ± SEM). The NO gas (AHG, Jeddah, Saudi \t\t\t Arabia) used in this study was certified at a concentration of 800 ppm NO with \t\t\t \u003c 1% contamination by other oxides of nitrogen. NO gas was introduced into \t\t\t the ventilator circuit via an adaptor positioned on the inspiratory port of the \t\t\t Fisher and Paykel humidification chamber. Thus, NO was mixed with the bias flow \t\t\t gas of the oscillator and subsequently delivered to the neonate via the \t\t\t inspiratory limb of the ventilator circuit. The resulting concentration of the \t\t\t inhaled NO and NO2 was verified in-line by using an electrochemical \t\t\t sensor (Pulmonox, Tofield, Alberta, Canada). Exhaled gas was scavenged; the \t\t\t oxygen concentration was analyzed continuously before it reached the \t\t\t neonate's endotracheal tube. Nitric oxide was initially administered at \t\t\t 20 ppm for at least 2 h. If there was no response while the neonate was on high \t\t\t ventilatory support and FIO2 of 1.0, INO was increased gradually by \t\t\t 2 ppm to a maximum of 80 ppm. If there was a response, INO was maintained at \t\t\t 20 ppm and FIO2 was gradually decreased to 0.6, provided the \t\t\t PaO2 was 80–120 mmHg. Nitric oxide then was weaned to \t\t\t discontinuation. Ventilatory parameters thereafter were weaned and HFOV was \t\t\t replaced by a conventional ventilator. An arterial/alveolar oxygen (a/A) ratio \t\t\t less than 0.22 was used to define failure of HFOV and INO therapy, if INO \t\t\t reached 80ppm on high ventilatory support.\n\nStatistical analysis\nStatistical analysis was performed with the assistance of the \t\t\t Department of Biostatistics. Normally distributed continuous variables were \t\t\t analyzed with the Student's t-test. Variables without a normal \t\t\t distribution were analyzed with the Wilcoxon signed rank test. This study has \t\t\t been approved by the Department of Pediatrics Research Committee and the King \t\t\t Faisal Specialist Hospital and Research Centre's Research Advisory \t\t\t Council.\n\nResults\nOf the 24 consecutive neonates treated with both HFOV and INO, 18 \t\t (75%) responded and 6 (25%) did not respond to the treatment. Three neonates \t\t died in the responding group, while all the non-responders died (P \t\t =0.0001). The survival rate was 62.5% among all neonates.\nThe underlying diseases of the responders and non-responders are \t\t depicted in Table 1. In addition to severe PPHN, six \t\t neonates had birth asphyxia, 13 had MAS, three had congenital diaphragmatic \t\t hernia (CDH) and two had RDS. Of the 13 neonates with MAS, 12 responded to INO, \t\t while none of the infants with CDH responded to INO therapy.\nInhalation of NO significantly decreased OI (P \u003c 0.0001) \t\t and improved the a/A ratio (P \u003c 0.0001) within the first 2 h of INO \t\t therapy in 61.1% of the responders, and the remaining responded gradually \t\t during the INO treatment. However, OI and a/A ratio remained almost the same \t\t throughout the treatment in the non-responders and the non-survivors (Tables \t\t 2 and 3). Four of the responders \t\t (two with MAS and two with RDS) became INO-dependent and required \t\t phosphodiesterase inhibitor (dipyridamole) to wean them from INO. Tolazoline \t\t was unsuccessfully attempted in two neonates in the referring hospitals. \t\t Methemoglobin and nitrogen dioxide were maintained below 5% during INO therapy. \t\t The average age when INO was started was 2.6 days (range 1–11 days). The mean \t\t duration of INO used in all neonates was 4.6 days (range 1–10 days). Three \t\t neonates responded to INO but died of other causes. The first neonate had \t\t severe intracranial hemorrhage, Klebsiella pneumoniae sepsis, renal \t\t failure and, consequently, brain death. The second neonate had Escherichia \t\t coli sepsis and interstitial lung disease. The lung biopsy revealed a \t\t diffuse alveolar damage. The third neonate developed multiple pneumatoceles in \t\t both lungs and the lung biopsy showed proliferative phase of diffuse alveolar \t\t damage. Subsequent lung tissue culture was positive for \t\t methicillin-resistant Staphylococcal aureus.\nTable 1 The underlying diseases of all infants\nTable 2 Comparison between responders and non-responders OI, oxygenation index; a/A, arterial/alveolar oxygen ratio; INO, \t\t\t\tinhalational nitric oxide. All values shown as mean ± SEM; \t\t\t\t*P \u003c 0.05.\nTable 3 Comparisons between survivors and non-survivors OI, oxygenation index; a/A, arterial/alveolar oxygen ratio; INO, \t\t\t\tinhalational nitric oxide. All values shown as mean ± SEM; *P \u003c 0.05.\n\nDiscussion\nPPHN is a common endpoint of several very different pathophysiological \t\t mechanisms. It is extremely important to understand the underlying etiology of \t\t PPHN, as therapeutic interventions must be tailored to specific circumstances; \t\t for example, PPHN associated with hyaline membrane disease should first be \t\t treated with surfactant therapy.\nMaintenance of adequate circulating blood volume, systemic vascular \t\t resistance, and optimal lung inflation are essential for the management of \t\t PPHN. High-frequency ventilation has been introduced as a mode of therapy in \t\t PPHN. There were no randomized studies of HFOV in the management of infants \t\t with PPHN, but attention has been focused on the potential of HFOV to reduce \t\t the need for extracorporeal membrane oxygenation (ECMO). A number of reports \t\t identify a number of infants who, although referred for ECMO, survived without \t\t using this type of intervention [6,7].\nA comparison between HFOV and INO in reducing the need for ECMO has \t\t been studied. Kinsella et al [8] combined HFOV \t\t and INO in the treatment of infants with hypoxic respiratory failure and PPHN \t\t who were ECMO candidates. These authors found no difference in the need for \t\t ECMO or death in the INO group compared with the HFOV group, and they suggest \t\t that combined treatment with INO and HFOV may improve outcome.\nIn this study, we found that 75% of infants with PPHN who failed HFOV \t\t responded to INO therapy and 62.5% survived to discharge. Recently, the NINOS \t\t Study Group has conducted a study to evaluate whether INO would reduce the \t\t incidence of death or the need for ECMO in infants with hypoxic respiratory \t\t failure [9]. HFOV was used in 55% of the infants. The \t\t authors found that treatment with INO resulted in a significant reduction in \t\t the combined incidence of death in less than 120 days or the need for ECMO. \t\t Moreover, Roberts et al [10] studied 58 \t\t full-term infants with severe hypoxemia and PPHN who were randomized to receive \t\t either INO or nitrogen. They found that INO improved systemic oxygenation in \t\t these infants and they suggest that INO may reduce the need for more invasive \t\t treatment.\nIn this study, we found that 61.1% of the responders responded within \t\t the first 2h after the initiation of INO and their response sustained to the \t\t end of the treatment and the remaining neonates showed a gradual response \t\t throughout the course of INO. Similarly Goldman et al [11] evaluated INO in a group of 25 severely hypoxic term \t\t neonates and identified four patterns of response. Two neonates did not \t\t respond, nine neonates who responded well initially then failed within 24 h, 11 \t\t neonates responded and sustained that response, and three neonates responded to \t\t INO but required high doses for prolonged periods of time. We also found that \t\t 25% failed INO therapy, most likely as a result of severe pulmonary hypoplasia \t\t seen in CDH, and severe lung damage due to severe hypoxia as in asphyxia and \t\t RDS. A number of studies have noted a general lack of a sustained improvement \t\t in oxygenation in response to INO in the management of CDH [12,13,14]. In \t\t this study ECMO was not used as an alternative therapy for the INO \t\t non-responders because it was not available in our hospital for neonates.\nIt has been observed that some infants who showed a dramatic response \t\t to INO developed a decrease in oxygenation when INO was discontinued. This \t\t response may reflect downregulation of endogenous nitric oxide synthase \t\t activity secondary to the administration of exogenous nitric oxide [15]. In addition INO may increase the concentration of \t\t phosphodiesterase, which then degrades cyclic GMP when INO is discontinued, \t\t resulting in vaso-constriction. In this study, four infants became \t\t INO-dependent and successfully weaned from INO following the use of \t\t phosphodiesterase inhibitor (dipyridamole) [16]. Study \t\t of the mechanism of INO dependency may give insight into new therapies that \t\t augment the pulmonary vasodilatory effect of INO and the activity of the \t\t endogenous NO system.\nIn conclusion, the administration of INO at 20ppm, following adequate \t\t ventilation for a maximum of 2h without significant response could be used to \t\t identify the majority of the non-responders. In these situations, other means \t\t of therapy, such as ECMO, could be considered. "}