Severe Persistent Pulmonary Hypertension Research Articles

Altered guanylyl-cyclase activity in vitro of pulmonary arteries from fetal lambs with congenital diaphragmatic hernia.

Nitric oxide (NO) plays a major role in the modulation of perinatal pulmonary vascular tone. Congenital diaphragmatic hernia (CDH), a major cause of severe persistent pulmonary hypertension of the newborn (PPHN), is often refractory to inhaled NO. Alterations in NO/cyclic guanosine 3',5' monophosphate (cGMP)-mediated pulmonary vasodilatation may contribute to PPHN in CDH. We assessed NO/cGMP-mediated pulmonary vasorelaxation in vitro in 140-d gestational lamb fetuses with surgically created left CDH (term = 147 d) to age-matched controls. Relaxation of fourth generation intralobar pulmonary artery rings in response to the endothelium-dependent vasodilator, acetylcholine (ACh), and to the specific inhibitor of cGMP-phosphodiesterase (PDE), zaprinast, did not differ between the two groups. By contrast, relaxation in response to the calcium ionophore A23187 was impaired in CDH as compared with control animals. Relaxation in response to the NO donor sodium nitroprusside (SNP) (a direct activator of soluble guanylyl cyclase [sGC]) was also impaired in CDH animals as compared with controls. Repeating the challenge increased vasorelaxation in response to SNP in CDH as compared with control animals. Immunohistochemistry revealed the presence of endothelial NO-synthase in the endothelium of pulmonary arteries from both control and CDH animals. We conclude that endothelium-dependent vasodilatation in response to ACh and A23187 was differently affected in the fetal surgical CDH-lamb model. Furthermore, activity of sGC but not that of PDE was impaired in CDH animals. PPHN and decreased inhaled NO responsiveness in CDH may involve decreased sGC activity.

Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide

Objective: To determine the medical and neurodevelopmental outcome of children with moderately severe persistent pulmonary hypertension of the newborn (PPHN) treated with or without inhaled nitric oxide (I-NO). Study design: Term infants with PPHN and a baseline oxygenation index of 24 ± 9 at study entry were randomly assigned to early treatment with placebo or initial doses of I-NO (5, 20, and 80 ppm). Outcome was measured at ~1 year by frequency of hospitalization, growth, and neurodevelopmental and audiologic evaluation. Results: Of 155 children enrolled, 144 survived, and there was follow-up for 133. No significant differences between the placebo and the I-NO groups were seen in any long-term outcome. Rehospitalization occurred in 22%, and growth did not differ. The composite neurodevelopment and audiologic outcome showed impairment in 46% of the infants. There were major neurologic abnormalities in 13%, cognitive delays in 30%, and hearing loss in 19% of the infants. Conclusions: Moderately severe PPHN at 24 hours after birth is associated with high rates of rehospitalization and disability at 1 year. Adverse outcomes were the same in I-NO and control groups. (J Pediatr 2002;140:306-10)

Plasma Cyclic Guanosine Monophosphate Reflecting the Severity of Persistent Pulmonary Hypertension of the Newborn

The aim of the study was to examine the relationship between the plasma concentration of cyclic guanosine monophosphate (cGMP) and pulmonary pressure and hypoxia defined by oxygenation index (OI) in newborn infants with severe persistent pulmonary hypertension (PPHN) on inhaled nitric oxide (NO). In this prospective study, 18 newborn infants having Doppler ultrasound-diagnosed PPHN and treated with NO were investigated. The ratio of pulmonary artery to systemic artery pressure (PAP/SAP) and OI was assessed before treatment and at 0.5, 1, 12, and 24 h from the beginning of NO. At these time points, plasma concentrations of cGMP could be determined in 11 patients. The association of birth asphyxia as assessed by Apgar 1 min and 5 min and plasma cGMP before the NO treatment was examined. The initial median plasma concentration of cGMP was 37.3 pmol/ml (IQR 13.3–79.6). After the start of NO, cGMP increased significantly within 60 min (p = 0.003) and peaked at 12 h. Initial plasma cGMP was associated with Apgar score (1 and 5 min). OI decreased within 30 min of NO and PAP/SAP within 60 min. Persistent high PAP/SAP after 1 h of NO was associated with low cGMP concentration (r = 0.70, p = 0.02). We conclude that a significant increase in plasma cGMP is already evident after 60 min of NO therapy. This effect is accompanied by changes in oxygenation index and in pulmonary artery pressure. Initial plasma concentrations of cGMP were associated with hypoxia assessed as Apgar score.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN PRESENTING AS THE PRIMARY MANIFESTATION OF INTRACRANIAL ARTERIOVENOUS MALFORMATION OF THE VEIN OF GALEN

Arteriovenous malformations of the Vein of Galen continue to present diagnostic and therapeutic challenges in the neonatal period. Approximately 40-50% of all malformations of the Vein of Galen present in the neonatal period, usually with congestive heart failure. These neonates represent the most severe cases and are also the most difficult to manage. We report a case of a neonate with a Vein of Galen Malformation who presented with cyanosis, a cardiac murmur, and severe persistent pulmonary hypertension of the newborn. Cardiac failure developed later in the patient's course. The degree of pulmonary hypertension on echocardiography was used to time endovascular embolization of the Vein of Galen Malformation. Following embolization, his pulmonary hypertension subsided dramatically. We speculate that pulmonary hypertension associated with Vein of Galen Malformations has been underestimated in the morbidity and demise of these neonates, and should be more aggressively monitored and treated.

Congenital diaphragmatic hernia: the surgeon's perspective.

1. Erik D. Skarsgard, MD* 2. Michael R. Harrison, MD† 1. 2. *Assistant Professor of Surgery and Pediatrics, Division of Pediatric Surgery, Lucile Packard Children’s Hospital, Stanford University School of Medicine, Palo Alto, CA. 3. 4. †Professor of Surgery and Pediatrics, Division of Pediatric Surgery, UC San Francisco, San Francisco, CA. After completing this article, readers should be able to: 1. Describe other conditions that should be sought following prenatal diagnosis of congenital diaphragmatic hernia (CDH). 2. Describe the procedures that optimize the outcome for CDH upon delivery of the infant. 3. Delineate the two most significant prenatal ultrasonographic predictors of postnatal mortality from CDH. 4. Describe the standard of care for those who have CDH that can be managed without extracorporeal membrane oxygenation. 5. Delineate the overall survival rate associated with CDH diagnosed antenatally. Congenital diaphragmatic hernia (CDH) is a simple anatomic defect in which a hole in the diaphragm allows abdominal viscera to herniate into the thorax. The physiologic consequences of this defect may be mild and minimally symptomatic at birth, but often they are severe and may result in neonatal fatality, usually from irreversible pulmonary hypoplasia or severe persistent pulmonary hypertension. Prenatal diagnosis has facilitated the early recognition of this condition, and much has been learned about the “natural history” of fetal diaphragmatic herna that has allowed recent identification of accurate fetal prognostic indicators of neonatal outcome. The incidence of CDH is estimated to be 1 per 2,000 to 5,000 births. Its incidence in stillborns is less well studied, but it is important in understanding the contribution of associated congenital defects to the so-called “hidden mortality” that is associated with prenatal diagnosis. Population-based studies of CDH among liveborn, stillborn, and spontaneously aborted fetuses suggests that approximately 30% of fetuses who have CDH will die before birth, usually from chromosomal or lethal nonpulmonary malformations. Even among those fetuses who have CDH and survive to birth, the incidence of associated life-threatening malformations is higher in those in whom the diagnosis is made antenatally, especially if it is made before 25 weeks’ gestation. The reason for this observation is unclear, but an earlier gestational event that …

Infant lung function after inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn

Our objectives were to determine whether the use of inhaled nitric oxide (iNO) for severe persistent pulmonary hypertension of the newborn (PPHN) causes impaired lung function during infancy. We therefore performed a prospective study of lung function in 22 infants after neonatal intensive care unit (NICU) discharge who had been treated for severe persistent pulmonary hypertension of the newborn (PPHN) with (n = 15) or without (n = 7) iNO, and compared these findings in lung function to those of healthy control infants (n = 18). Five infants with interstitial lung disease (ILD) were included to assure that the pulmonary function tests (PFT) were sensitive enough to detect abnormalities of lung function in this age group. We measured passive respiratory mechanics and functional residual capacity (FRC) using a commercially available system. All data were expressed as means and standard deviation. Statistical analysis was performed by analysis of variance (ANOVA). A Bonferroni multiple comparisons test was used for variables that showed overall group differences. Twenty-two infants were studied during follow-up 4–12 months after NICU discharge. None of the infants were acutely ill, and only one infant was on 0.25 L of oxygen per minute at the time of study. We found no differences in lung function between the treatment groups (iNO + mechanical ventilation (MV), or MV alone), or between either treatment group and healthy control infants of the same age. We were able to detect significant differences in functional residual capacity adjusted for weight or height, and compliance of the respiratory system adjusted for weight or lung volume in the ILD infants compared to the healthy controls or infants who had PPHN, indicating that these PFTs were sensitive enough to determine abnormal lung function in this age group. We conclude that inhaled nitric oxide therapy for the treatment of severe PPHN does not alter lung function as determined by lung volume and passive respiratory mechanics measurements during early infancy. Pediatr Pulmonol. 1999; 28:24–30. © 1999 Wiley-Liss, Inc.

Inhaled nitric oxide in persistent pulmonary hypertension of the newborn refractory to high-frequency ventilation.

BACKGROUND: This study was designed to evaluate the effect of nitric oxide (NO) on the management of neonates with severe persistent pulmonary hypertension refractory to high-frequency oscillatory ventilation. METHODS: The birth weight and the gestational age of infants were 3125.5 +/- 794 g (mean +/- SD) and 39 +/- 2.4 weeks, respectively. All neonates were ventilated for an average of 137.5 min (range 90-180 min) prior to NO therapy. The mean oxygenation index (OI) of all neonates prior to NO was 46.3 +/- 5 (mean +/- SEM). NO was initially administered at 20 parts per million (ppm) for at least 2 h and increased gradually by 2 ppm to a maximum of 80 ppm. RESULTS: Eighteen infants (75%) responded and six (25%) did not respond to the treatment. Three neonates died in the responding group, while all the non-responders died (P = 0.0001). The survival rate was 62.5% among all neonates. NO significantly decreased OI (P < 0.0001) and improved the arterial/alveolar (a/A) oxygen ratio (P < 0.0001) within the first 2 h of NO therapy in 61.1% of the responders. However, the OI and the a/A oxygen ratio remained almost the same throughout the treatment in the non-responders and the non-survivors. CONCLUSION: Inhaled NO at 20 ppm, following adequate ventilation for 2 h without significant response, could be used to identify the majority of the non-responders in order to seek other alternatives.

Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10-80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51+/-21 vs 23+/-17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45+/-20 vs 20+/-17, P < .0001), 'idiopathic' PPHN (39+/-14 vs 14+/-9, P < .0001), and sepsis (55+/-25 vs 26+/-20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI=41+/-16 vs 28+/-18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI=58+/-25 vs 46+/-32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age > or =34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants.

Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension

Objective: To describe the outcome of a group of term newborn infants treated with inhaled nitric oxide for severe persistent pulmonary hypertension. Study design: We performed a prospective longitudinal medical and neurodevelopmental follow-up of 51 infants treated as neonates for persistent pulmonary hypertension of the newborn with inhaled nitric oxide. The original number of treated infants was 87, of whom 25 died in the neonatal period; of 62 infants who survived, 51 were seen at 1 year of age and 33 completed a 2-year evaluation. Statistical analysis used population medians, means, and standard deviations for parameters assessed. Paired t tests and chi-square analysis were used to compare outcomes measured at 1 year with assessments at 2 years for the 32 infants seen at both 1- and 2-year visits. Results: At 1-year follow-up median growth percentiles were 20%, 72.5%, and 50% for weight, length, and occipitofrontal circumference, respectively. Thirteen of 51 infants (25.5%) were <5th percentile in weight. Nine of 51 infants (17.6%) had feeding problems (need for gastrostomy feeding or gastroesophageal reflux), and 14 (27.5%) had a clinical diagnosis of reactive airways disease. Infant development as measured by the Bayley Scales of Infant Development was 104 ± 16 for the mental development index and 97 ± 20 for the psychomotor index. Six of 51 infants (11.8%) were found to have severe neurologic handicaps, defined as a Bayley score on either the mental development or psychomotor index of <68, abnormal findings on neurologic examination, or both. Fewer children (6.1% vs 15.7%) required supplemental oxygen at 2 years compared with 1 year, and performance on the psychomotor index of the Bayley Scales improved significantly. Conclusions: One- and 2-year follow-up of a cohort of infants with persistent pulmonary hypertension of the newborn who were treated with inhaled nitric oxide had an 11.8% (1 year) and 12.1% (2-year) rate of severe neurodevelopmental disability. There are ongoing medical problems in these infants including reactive airways disease and slow growth that merit continued close longitudinal follow-up. (J Pediatr 1997;131:70-5)

Echocardiographic evidence of improved hemodynamics during inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn.

To evaluate the cardiovascular effects of inhaled nitric oxide (NO) on the systemic and pulmonary circulations, 25 consecutive infants with severe persistent pulmonary hypertension of the newborn (PPHN) underwent serial echocardiographic evaluations before and during inhaled NO therapy. Estimation of the systolic pulmonary artery pressure (SPAP) was derived from measurement of a tricuspid regurgitant jet using Bernoulli's equation. We also derived a pulmonary/systemic pressure ratio to evaluate overall cardiopulmonary effects. Paired measurements of estimated SPAP decreased from 62.0 +/- 3.8 mmHg to 44.7 +/- 4.3 mmHg (p < 0.01) during inhaled NO therapy. The pulmonary/systemic pressure ratio decreased from 0.98 +/- 0.06 to 0.59 +/- 0.04 during NO therapy (p < 0.01), indicating a significant decline in the vascular resistance between the two circulations. These changes also correlated with changes in the extrapulmonary shunt patterns at the ductus arteriosus and foramen ovale seen during inhaled NO therapy. The decreased right-to-left shunting was accompanied by a parallel (64%) improvement in systemic oxygenation, with the alveolar-arterial oxygen gradient (A-a DO2) falling from 591 +/- 14 mmHg to 380 +/- 33 mmHg (p < 0.01). We found echocardiography to be a useful clinical tool for evaluating and monitoring pulmonary artery pressure in infants with PPHN. Measurement of the SPAP and the pulmonary/systemic pressure ratio gave a quantitative estimation of the severity of PPHN, and the extrapulmonary shunt flow patterns at the ductus arteriosus and foramen ovale gave qualitative estimates of its severity. Inhaled NO increased pulmonary blood flow and oxygenation and improved the systemic cardiopulmonary hemodynamics in this group of infants.

Response to inhaled nitric oxide and high frequency oscillatory ventilation in septic newborns with severe pulmonary hypertension. † 1618

Although inhaled nitric oxide (INO) and high frequency oscillatory ventilation (HFOV) are effective therapies in severe persistent pulmonary hypertension of the newborn (PPHN), the efficacy of these therapies in neonates with sepsis and PPHN are unknown. To determine the response rate to INO and HFOV and to identify factors associated with poor responses in septic newborns we analyzed the data from a multicenter trial of INO and HFOV in neonates with PPHN. Criteria for enrollment included: gestational age ≥ 34 weeks, Pa02 60 torr led to treatment with the alternative or combined therapy (INO+HFOV). Of 205 neonates enrolled in this study, 22 were identified as septic by blood culture (20 with group B strep). Eleven infants improved and survived without ECMO(Responders). Of the eleven responders, 4 responded to INO, 3 responded to HFOV, 4 required INO and HFOV. Eleven infants did not respond and were treated with ECMO (N=8 with 5 deaths)or died without ECMO (N=3). There were no differences in AaD02 and blood pressure between responders and non-responders at study entry. However, non-responders had lower pH (7.43±.08 vs. 7.13±.19,P 7.31 at study entry responded and 100% survived without ECMO. We conclude that: 1. septic newborns with severe PPHN have a 50% response rate to treatment strategies which include INO and HFOV; 2. non-response to these therapies is associated with high mortality (73%) despite ECMO therapy; and 3. metabolic acidosis is a marker of poor responsiveness.

Interpreting the clinical trials of extracorporeal membrane oxygenation in the treatment of persistent pulmonary hypertension of the newborn

We review the findings of prospective randomized controlled clinical trials which have compared the efficacy of extracorporeal membrane oxygenation (ECMO) with conventional ventilator-based therapy (CT) in the treatment of severe persistent pulmonary hypertension of the newborn (PPHN). Initial trials in Michigan and Boston were non-conventional in their design, conduct and analysis; as a result their interpretation proved to be highly controversial. We review the relevant statistical issues and, in their light, discuss the implications of a third trial with a more conventional randomized design which has recently been completed in the UK.

Morphine pharmacokinetics during continuous infusion of morphine sulfate for infants receiving extracorporeal membrane oxygenation.

To determine a) if serum morphine concentration changes during the first 3 hrs of extracorporeal membrane oxygenation (ECMO); and b) if absorption of morphine onto the membrane oxygenator is responsible for these changes. Also, morphine clearance during the first 5 days of ECMO was studied. Prospective, open-label study with consecutive patient enrollment. Neonatal intensive care unit at a university-affiliated, children's hospital. Eleven neonates with severe persistent pulmonary hypertension of the newborn receiving continuous intravenous infusions of morphine sulfate and requiring ECMO. Blood samples were obtained from the subjects and ECMO circuits at predetermined time intervals. Serum morphine concentration was determined using high-performance liquid chromatography. Morphine concentrations were no different from baseline at 5 mins, 1 hr, or 3 hrs after beginning ECMO. There was no significant difference in morphine concentration from samples taken immediately proximal and distal to the membrane oxygenator at 5 mins, 1 hr, and 3 hrs after the start of ECMO. Morphine clearance was calculated on days 1, 3, and 5 of ECMO. The mean value for morphine clearance was 11.7 +/- 9.3 (SD) ml/min/kg (range 2.6 to 34.5). The initiation of ECMO does not lead to a significant decrease in serum morphine concentration and there is no uptake of morphine onto the membrane oxygenator of the ECMO circuit. Morphine clearance for infants receiving ECMO is variable.

Perinatal asphyxia, hypoxia, ischemia and hearing loss. An overview.

Birth hypoxia, asphyxia and ischemia have often been thought to be major causes of early hearing loss or deafness. The purpose of the present review is to focus on the role of these particular factors for perinatal auditory disorders. On the whole, only a small proportion of neonatal hearing loss is caused by perinatal factors. The exact etiology of neonatal hearing loss in children with complicated deliveries is difficult to evaluate due to the large number of causative factors that might be involved. After reviewing the literature covering the past 15-20 years, it is not possible to say that we understand the relative importance of different factors and their interactions. However, in the majority of studies, birth asphyxia is not correlated with hearing loss in babies with complicated deliveries Prolonged artificial ventilation, the presence of severe hypoxic ischemic encephalopathy or persistent pulmonary hypertension are important factors. The brain is more susceptible to anoxia than the ear and both are more likely to be damaged after prolonged pre-, peri- and postnatal hypoxia-ischemia than pure hypoxia during delivery. Perinatal hypoxia is more likely to cause a temporary hearing loss than a permanent one. Preterm babies are more vulnerable than term babies. The total number of risk factors, e.g. medicated by total length of stay in the neonatal intensive care unit and length of artificial ventilation, is the best predictor of risk for hearing loss of perinatal origin. The similarities between hearing loss and cerebral palsy are pointed out; only 8% of the cases of cerebral palsy are considered to be caused by conditions during delivery.

TWO-YEAR FOLLOW-UP OF INFANTS WITH SEVERE PERSISTENT PULMONARY HYPERTENSION TREATED WITH INHALED NITRIC OXIDE. † 1693

We prospectively followed the neurodevelopmental (ND), hearing and pulmonary outcomes of 30 survivors (GA 31-42 wks) treated with inhaled nitric oxide (iNO). They met echocardiographic and clinical criteria for severe persistent pulmonary hypertension (PPHN) and were treated with 6 to 20 ppm NO(M = 76 hrs). Diagnoses were meconium aspiration (14), diaphragmatic hernia(1), asphyxia (4), sepsis (11), pulmonary hypoplasia (1), and congenital syndromes (2). Follow-up assessments were by Bayley Scales, auditory brainstem response or behavioral audiometry. The ND outcome was considered normal if both motor (PDI) and mental (MDI) scores were >84, suspect if either PDI or MDI was <84, and abnormal if both were <84. Three infants were lost to follow-up. The evaluations of the remaining 27 infants (median age = 20 mos) are shown below. Table

Inhaled Nitric Oxide During Extracorporeal Membrane Oxygenation for the Treatment of Severe Persistent Pulmonary Hypertension of the Newborn

Inhaled nitric oxide (NO) as a complementary treatment was studied in 10 neonates during extracorporeal membrane oxygenation (ECMO) therapy of various persistent pulmonary hypertension of the newborn (PPHN)-associated diseases. At individually different levels of inhaled NO (20-80 ppm), the mean Pao2 increased by 59.7% in 6 responders, but it remained unchanged in 4 nonresponders. Adverse side effects of the NO inhalation were tolerable. It was associated with a reversible decrease of the mean arterial blood pressure in 1 patient. During prolonged NO inhalation, the methemoglobin (met-Hb) level increased to 0.9-4.6% in 6 patients. Based on these preliminary results, we conclude that inhaled NO during ECMO can improve oxygenation in some PPHN patients. Further studies with control groups are needed to determine whether inhaled NO can shorten ECMO treatment or improve the rate of survival among PPHN patients.

Inhaled nitric oxide for avoidance of extracorporeal membrane oxygenation in the treatment of severe persistent pulmonary hypertension of the newborn

Inhaled nitric oxide (NO) is thought to provide a noninvasive therapeutic alternative to extracorporeal membrane oxygenation (ECMO) in the treatment of persistent pulmonary hypertension of the newborn (PPHN). Since January 1993, we have studied inhalation of NO in PPHN patients meeting the ECMO criteria of our institution. We focused on the questions of whether or not the need for ECMO could be obviated and whether differences could be found between NO responders and nonresponders. NO gas was delivered via conventional IPPV ventilation in incrementally increasing concentrations from 20 to 80 ppm. NO therapy was attempted in ten ECMO candidates with clinical and echocardiographical evidence of PPHN (mean OI 51.9, SD 10.4). At various NO levels (30-60 ppm), five patients showed a significant increase in mean PaO2 (range 32.9-85.9 mmHg). Improvement was transient in three patients (6-10 h) and prolonged in two others (54-80 h); in the latter cases, ECMO was avoided. Five patients did not respond at all to treatment. Responders and nonresponders differed in their mean respiratory tidal volume (8.9 vs 4.18 ml/kg, P <0.05). In our study, inhalation of NO obviated the necessity of ECMO therapy in only two out of ten PPHN patients. Thus, we would discourage any overoptimistic expectations about the effectiveness of NO therapy in PPHN until larger clinical trials have been performed.

Variable oxygenation response to inhaled nitric oxide in severe persistent pulmonary hypertension of the newborn.

The causes of variable responsiveness to inhaled nitric oxide (NO) in Persistent Pulmonary Hypertension of the Newborn (PPHN) are unknown. The changes in the severity of respiratory failure after the onset of inhaled NO (maximal dose 20 ppm) were studied in 13 consecutive neonates with severe PPHN. Response was defined as a sustained decrease of alveolar-arterial oxygen gradient (AaDO2) by > 20%, or a decrease in oxygenation index (OI) by > 40%. Six neonates had a rapid response within 30 min, three had an intermediate response within 8 h, and three had a delayed response within 12 h after the onset of NO. Three infants with birth asphyxia responded rapidly to inhaled NO. One infant with sepsis did not respond, and two with suspected sepsis had a delayed response. The infants with Meconium Aspiration Syndrome and idiopathic PPHN had a variable response time. Twelve neonates required 4 to 14 days of mechanical ventilation and survived. Infants with PPHN may benefit from a trial of inhaled NO therapy that exceeds 30 min. The variability of the response time to inhaled NO is likely to be multifactorial and dependent on the disease process associated with PPHN.

Tolazoline-Assisted Doppler Echocardiography Confirming Normal Pulmonary Venous Return in a Neonate with Severe Persistent Pulmonary Hypertension

In a critically ill neonate, pulsed and color-flow Doppler echocardiography was able to document normal pulmonary venous return after an intravenous dose of tolazoline hydrochloride. Differential diagnosis was between persistent pulmonary hypertension of the newborn and obstructed total anomalous pulmonary venous return. Once normal pulmonary venous return was clearly documented, all therapeutic efforts were directed at the infant's lung disease.

Magnesium sulphate as an alternative and safe treatment for severe persistent pulmonary hypertension of the newborn.

Eleven newborns admitted consecutively to the neonatal unit with respiratory failure and severe persistent pulmonary hypertension (PPHN) were included in a clinical trial to assess the efficacy of magnesium sulphate (MgSO4) in the treatment of PPHN. A loading dose of 200 mg/kg MgSO4 was given over 20 minutes, followed by a continuous infusion of 20-150 mg/kg/hour to obtain a magnesium blood concentration between 3.5 and 5.5 mmol/l. Mean (SD) duration of treatment was 75.5 (19.8) hours. No other vasodilatory drug was administered before or during the treatment and patients were not hyperventilated. Mean (SEM) PaO2 values significantly increased from 42.6 (8.8) before treatment to 70.3 (24.1) mm Hg after 24 hours, with no change in pH or PCO2. Oxygen index and alveolar-arterial oxygen gradient (A-aDO2) were significantly lower after 24 hours; respectively, 46.8 (15.2) to 28.0 (9.0) and 624.3 (11.3) to 590 (58) mm Hg. Mean airway pressure could be significantly reduced from 19.5 (3.1) to 13.9 (3.9) cm H2O after 72 hours. Mean ventilatory time support was 131 hours and mean total oxygen dependency 10 days. No systemic hypotension nor any other adverse effect were noted. All infants survived and the neurodevelopmental assessment was normal at 6 and 12 months of age. It is concluded that magnesium sulphate is a non-aggressive and low-cost treatment of short duration which is easy to apply. It may have a role in the various treatment of PPHN.