Diagnosis Of Persistent Pulmonary Hypertension Research Articles

Echocardiographic markers at diagnosis of persistent pulmonary hypertension of the newborn.

Clinical parameters along with echocardiographic markers are used to interrogate the haemodynamics in persistent pulmonary hypertension of the newborn (PPHN). The aim of this study was to compare different echocardiographic markers in recent cohort of newborn infants with and without PPHN. In this retrospective study, common echocardiographic markers were examined in infants>34weeks' gestation with PPHN (cases) and without PPHN (controls). Infants with congenital heart disease were excluded. Binary regression testing was used to evaluate echocardiographic markers predicting PPHN and death. In addition, diagnostic accuracy testing of echocardiographic markers using ROC was also performed. Intra-observer reliability for echocardiographic markers was examined using coefficient of variation (CoV) and intraclass correlation. Fifty-two infants were studied; 22 (42 %) infants with PPHN had significantly higher oxygen requirement, oxygenation index and ventilation days when compared with controls. Echocardiographic markers such as TR Vmax, S/D TR, PAAT, TAPSE and eccentricity index (EI) were significantly different between cases and controls. Receiver operator characteristics analysis of echocardiographic markers revealed TR Vmax 0.96 (0.9-1.0), S/D TR 0.95 (0.87-1.0) and end systolic EI 0.94 (0.87-1.0). These markers were found to predict death in this cohort of infants. CoV and Intra-observer reliability was good for various echocardiographic markers. Among the various echocardiographic markers studied, TR Vmax when present along with S/D TR and end systolic EI had good intra-observer reliability and were diagnostic of PPHN and predicted death in this cohort. Future trials could use these markers in studies examining PPHN.

Risk Factors and Mortality in Newborns with Persistent Pulmonary Hypertension: A Six-Year Single-Center Experience.

Persistent pulmonary hypertension (PPHT) of the newborn is a disorder of circulatory transition resulting in high pulmonary vascular resistance with extrapulmonary right-to-left shunts causing hypoxemia. In this study, our aim was to evaluate the risk factors, administered treatments, and mortality of patients followed in our neonatal intensive care unit (NICU) due to PPHT over the past six years. Patients diagnosed with PPHT and followed in the NICU between January 2017 and November 2022 were included in the study. The sociodemographic characteristics, diagnoses that could lead to pulmonary hypertension, the presence of congenital anomalies, the duration of respiratory support treatment and hospital follow-up, treatments administered for PPHT, and mortality rates were evaluated. Out of 21 patients diagnosed with persistent pulmonary hypertension, 9 of them (42.9%) were male. The mean gestational age of the patients was 37.6±3.7 weeks, and their birth weight was 3006±819grams. The APGAR scores at 1 and 5 minutes were 4(2-7) and 6(3-8), respectively. Risk factors during the antenatal period included fetal distress (38.1%), oligohydramnios (23.8%), intrauterine growth restriction (23.8%), gestational diabetes (14.3%), preeclampsia (4.8%), and chorioamnionitis (4.8%). The median duration of invasive mechanical ventilation for cases requiring respiratory support was 20.1 days, while the median duration of non-invasive ventilation was 3.7 days. Patients with a diagnosis of persistent pulmonary hypertension were treated with inhaled nitric oxide (iNO) in 76.2% of cases, milrinone in 66.7% of cases, sildenafil in 52.4% of cases, and iloprost in 14.3% of cases. The length of hospital stay for patients was 38.4 days, and 9 (42.9%) patients died. The patients who died had severe PPHT along with fetal inflammatory response syndrome (FIRS), congenital heart disease, pulmonary hypoplasia, pneumothorax, hypoxic-ischemic encephalopathy (HIE), and congenital anomalies. Persistent pulmonary hypertension, characterized by severe hypoxemia, is a neonatal emergency that necessitates early intervention, effective treatment of the underlying cause to prevent potential short-term and long-term morbidities and mortality. Effective treatment of the underlying cause in patients diagnosed with PPHT could reduce morbidity and mortality. It is inevitable to avoid the loss of patients with major abnormalities, severe comorbidities, and unpreventable organ dysfunctions.

If We Cannot Use Nitric Oxide for Newborn Persistent Pulmonary Hypertension, is Oral Sildenafil Therapeutic? A Single-center Experience

Background: Persistent pulmonary hypertension is still an issue in newborn period with different treatment strategies. In this study, we aimed to evaluate the three-year experience of a neonatal intensive care unit on use of sildenafil citrate for treating newborns with persistent pulmonary hypertension. Methods: Twenty-nine newborn patients with the diagnosis of persistent pulmonary hypertension solely treated by sildenafil citrate (2 mg/kg per dose, orally, three times a day) in intensive care unit of a private hospital between 2018 and 2021 were retrospectively analyzed. Results: The newborns that underwent sildenafil treatment and the newborns that received no treatment had statistically similar length of hospital stay (p = 0.188). The premature newborns had significantly lower systolic and diastolic blood pressure than the term newborns on their first day of sildenafil treatment (p = 0.001 for both). The premature newborns had significantly lower systolic, diastolic, and right ventricular systolic pressure than the term newborns on their day of hospital discharge (p = 0.003, p = 0.013 and p = 0.001 respectively). The premature newborns had significantly lower systolic, diastolic, and right ventricular systolic pressure on their day of hospital discharge than their first day of sildenafil treatment (p = 0.039, p = 0.041 and p = 0.043 respectively). The term newborns had also significantly lower systolic, diastolic, and right ventricular systolic pressure on their day of hospital discharge than their first day of sildenafil treatment (p = 0.001 for each). Conclusions: Sildenafil citrate can be considered as an efficient and safe alternative for the treatment of persistent pulmonary hypertension in newborn at the in tertiary neonatal intensive care units without nitric oxide and devices.

Role of brain-type natriuretic peptide in rapid diagnosis and prognosis of persistent pulmonary hypertension of the newborn

Objective The diagnosis of persistent pulmonary hypertension of the newborn (PPHN) can often be difficult to make, especially in a clinical setting in which pediatric echocardiography is not readily available. This study aims at investigating the value of plasma brain-type natriuretic peptide (BNP) level as a noninvasive test in the diagnosis, prognosis, and differentiation of PPHN from other respiratory diseases in newborns with respiratory distress (RD). Patients and methods We used a prospective cohort study with three groups. One group was diagnosed with PPHN by clinical and echocardiographic criteria (PPHN group: n=20). The second group had been diagnosed with respiratory disease; however, PPHN was ruled out by having no evidence of elevated pulmonary pressure by echocardiography (RD group: n=20). The third group had no respiratory disease and was breathing room air (RA group: n=20). Plasma BNP levels were measured by Ray Bio BNP Enzyme Immunoassay Kit at study entry for all groups and upon recovery for PPHN cases. Results There was no difference between groups regarding gestational age, postnatal age, sex, birth weight, and mode of delivery. Initial BNP levels (pg/ml) were significantly elevated in the PPHN group relative to both the RA and RD groups. There was no difference in the initial plasma BNP level between the RD and RA groups. Plasma BNP levels declined significantly in the PPHN group upon recovery. Plasma BNP levels correlated with the gradient of the tricuspid regurgitation jet and the mean pulmonary artery pressure. Plasma BNP levels were higher, although insignificant, in PPHN because of underdevelopment. The mean plasma BNP level in septic babies was higher; however, this was insignificant, still the number of cases was low (two cases). Conclusion Plasma BNP levels were elevated in infants with PPHN but not in infants with other forms of RD. Follow-up plasma BNP level showed significant decline after recovery of PPHN cases. Elevated plasma BNP levels in term or near-term infants with RD should increase the suspicion of PPHN.

Impact of Respiratory Morbidities on Neurodevelopmental Outcome of Late Preterm Infants.

This study aims to evaluate impact of respiratory and other neonatal comorbidities on neurodevelopmental outcome in late preterm infants (LPT). Retrospective study of LPT infants (34 (0/7)-36 (6/7) weeks' gestation) discharged from the New York University Langone Medical Center neonatal intensive care unit, during January 2006 to December 2010 and received follow-up care up to 2 years of age. Neonatal morbidities were correlated with neurodevelopmental outcomes and assessed by performance on the Mullen Scales of Early Learning during three developmental follow-up visits. A total of 99 LPT completed neurodevelopmental assessment up to 2 years of age. Infants with diagnosis of moderate-to-severe respiratory distress syndrome showed a significantly lower performance in the visual reception on the second (p<0.01) and third visit (p=0.02), as well as lower performance in the receptive language (visit 2, p=0.02; visit 3, p<0.01). A diagnosis of persistent pulmonary hypertension was found to be associated with significantly lower performance in the visual reception at all visits (p<0.01; p=0.02; p=0.02) and in the receptive language on the second and third visit (p=0.03; p=0.02). Combined respiratory morbidities were also associated with lower developmental scores in fine motor (visit 2, p<0.01; visit 3, p=0.04) as well as expressive language (visit 3, p=0.02). LPT with significant respiratory morbidities are at higher risk for long-term developmental delays, mainly affecting cognitive developmental domains.

To study prevalence of persistent pulmonary hypertension in newborn with meconium aspiration syndrome in western Rajasthan, India: a prospective observational study

Aim: To study the prevalence of persistent pulmonary hypertension (PPHN) in newborn with meconium aspiration syndrome (MAS) in western Rajasthan, India.Material and methods: Hundred full-term newborns who had features of MAS at birth were included in this survey and were evaluated for PPHN using laboratory investigations, including pulse oximetry, ABG, chest X-ray, ECG and 2D color echocardiography.Results: Nineteen neonates showed PPHN, of them 16 had a shunt reversal at PFO level and the rest at PDA level. Most of these newborns were delivered by emergency cesarean section and were unplanned. A majority of neonates of PPHN (84.21%) were diagnosed within 48 h of life and 73.69% had Downey’s score more than 6. Neonates of PPHN had mean PH 7.21 ± 0.07, mean PCO2 53.73 ± 6.8, mean PaO2 61.10 ± 10.61 and mean PaO2/FiO2 144.03 ± 46.31.Conclusions: PPHN is a genuine problem in MAS-born neonates and is commonly seen in neonates born by unplanned and unmonitored delivery, and the prevalence of PPHN can be reduced by providing good antenatal care, regular follow up of high-risk pregnancy. 2D echocardiography is an important point of care in the diagnosis of PPHN in nursery and should be promoted in nurseries of developing countries as being engaged in developed countries for more reliable treatment.

50 Years Ago in The Journal of Pediatrics: Pulmonary Arterial Pressure Changes in Human Newborn Infants from Birth to 3 Days of Age

Emmanouilides GC, Moss AJ, Duffie ER, Adams FH. J Pediatr 1964;65:327-33 Some clinical “facts” are uncontested; for example that pulmonary artery pressure and resistance fall in the first few days after birth. Nonetheless, in the early 1960s, this was suspected but not firmly known and Emmanouilides et al figured it out. How? By performing umbilical artery catheterizations on sleeping healthy newborns with 5F nasogastric tubes, passing them to the thoracic descending aorta and into the pulmonary artery via the ductus arteriosus. Pressure recordings and oximetry were used to define catheter location and provide study measurements. Elegant graphs showed the decline of pulmonary artery pressure and resistance day by day as well as the intrinsic variability of the rate of decline. Parental consent was obtained, but in this era institutional review boards did not uniformly exist. As arresting as the narrative of this paper are the references, which highlight contemporary investigations in newborns and in the laboratory that tease out elements of the transitional circulation and the physiology behind the new diagnosis of persistent pulmonary hypertension of the newborn. It is perhaps no accident that the authors of this paper, and the key references, produced the first truly authoritative textbooks in the field of pediatric cardiology. The contrast between the investigative era of this study and today are striking. One wonders if institutional review board approval could be obtained; morbidity to the study subjects is not reported. Nonetheless, families trusted the study physicians and one assumes that the families believed the knowledge obtained from the study would benefit many children other than their own, which it has. The skill of the investigators was high, performing bedside catheterizations without waking sleeping infants and without fluoroscopic guidance, recording physiologic data, and obtaining oximetry data with equipment far inferior and slower than contemporary devices. The lesson I take from rereading this seminal paper is to leave no piece of knowledge in medicine unexamined. The knowledge came from somewhere: pioneering efforts that might now be considered unethical, medical mistakes that under scrutiny led to revisions in technique, and, perhaps most important, imaginative thinking about how to use existing tools to answer clinical questions deemed critical. Today, pulse oximetry and echocardiography can provide similar (though less accurate) data; nonetheless, we interpret these studies based on “what we already know.” Well, 50 years ago, we did not know for sure the time course of change in pulmonary artery pressure.

Pharmacology of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn and Suboptimal Response to Inhaled Nitric Oxide*

Persistent pulmonary hypertension of the newborn is a common problem with significant morbidity and mortality. Inhaled nitric oxide is the standard care, but up to 40% of neonates are nonresponders. Milrinone is a phosphodiesterase III inhibitor which increases the bioavailability of cyclic adenosine monophosphate and has been shown to improve pulmonary hemodynamics in animal experimental models. The primary objective was to investigate the pharmacological profile of milrinone in persistent pulmonary hypertension of the newborn. Secondary objectives were to delineate short-term outcomes and safety profile. An open label study of milrinone in neonates with persistent pulmonary hypertension of the newborn was conducted. Patients received an intravenous loading dose of milrinone (50 μg/kg) over 60 mins followed by a maintenance infusion (0.33-0.99 μg/kg/min) for 24-72 hrs. Physiologic indices of cardiorespiratory stability and details of cointerventions were recorded. Serial blood milrinone levels were collected after the bolus, following initiation of the maintenance infusion to determine steady state levels, and following discontinuation of the drug to determine clearance. Echocardiography was performed before and after (1, 12 hrs) milrinone initiation. Milrinone. Eleven neonates with a diagnosis of persistent pulmonary hypertension of the newborn who met eligibility criteria were studied. The median (SD) gestational age and weight at birth were 39.2 ± 1.3 wks and 3481 ± 603 g. The mean (± sd) half-life, total body clearance, volume of distribution, and steady state concentration of milrinone were 4.1 ± 1.1 hrs, 0.11 ± 0.01 L/kg/hr, 0.56 ± 0.19 L/kg, and 290.9 ± 77.7 ng/mL. The initiation of milrinone led to an improvement in PaO2 (p = 0.002) and a sustained reduction in FIO2 (p < 0.001), oxygenation index (p < 0.001), mean airway pressure (p = 0.03), and inhaled nitric oxide dose (p < 0.001). Although a transient reduction in systolic arterial pressure (p < 0.001) was seen following the bolus, there was overall improvement in base deficit (p = 0.01) and plasma lactate (p = 0.04) with a trend towards lower inotrope score. Serial echocardiography revealed lower pulmonary artery pressure, improved right and left ventricular output, and reduced bidirectional or right-left shunting (p < 0.05) after milrinone treatment. The pharmacokinetics of milrinone in persistent pulmonary hypertension of the newborn is consistent with published data. The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide. These data support the need for a randomized controlled trial in neonates.

Outcomes of neonates requiring extracorporeal membrane oxygenation for irreversible pulmonary dysplasia

Neonates with an irreversible pulmonary dysplasia such as alveolar capillary dysplasia, surfactant protein deficiency, and pulmonary lymphangiectasis may have a deteriorating clinical course requiring cardiopulmonary support with extracorporeal membrane oxygenation. These neonates are often difficult to distinguish from those with persistent pulmonary hypertension of the newborn. The objective of this study was to identify clinical variables that distinguish infants with irreversible pulmonary dysplasia from those with persistent pulmonary hypertension of the newborn before, and while receiving, extracorporeal membrane oxygenation support. A retrospective analysis of the Extracorporeal Life Support Registry from 2000 to 2010 was performed. A total of 114 extracorporeal membrane oxygenation centers providing data to the Extracorporeal Life Support Registry. All neonates day of life 0-31 reported to the Extracorporeal Life Support Registry with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn were identified. None. Patient demographics, pre-extracorporeal membrane oxygenation variables, and survival were analyzed. Univariate analysis was performed using Student's t test or Fisher's exact test, and variables found to be significant underwent multivariate analysis by logistic regression. Neonates with irreversible pulmonary dysplasia were placed on extracorporeal membrane oxygenation later (day of life 5.3 vs. 3.0, p = .045) and for a longer duration (11.1 vs. 6.8 days, p < .001) than those with persistent pulmonary hypertension of the newborn. Initiation of extracorporeal membrane oxygenation at day of life ≥5 (p = .026) and a duration of extracorporeal membrane oxygenation ≥10 days (p = .003) were independent predictors of irreversible pulmonary dysplasia by multivariate analysis. No differences in demographics, blood gas values, or vascular access were observed. Survival to discharge was significantly lower for neonates with irreversible pulmonary dysplasia (3%) vs. persistent pulmonary hypertension of the newborn (81%, p < .001). Although neonates with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn have similar presentations, those with irreversible pulmonary dysplasia require extracorporeal membrane oxygenation support later in the perinatal period and for a longer duration. For neonates with a diagnosis of persistent pulmonary hypertension of the newborn, irreversible pulmonary dysplasia should be considered when extracorporeal membrane oxygenation is initiated on day of life ≥5 and/or the duration of extracorporeal membrane oxygenation ≥10 days.

Diagnosis and differential diagnosis of neonatal continuous pulmonary hypertension

Persistent pulmonary hypertension of the newborn is a critical illness in neonatal period.Rational treatments are based on the correct diagnosis and differential diagnosis. In this paper, the clinical manifestations and diagnosis of persistent pulmonary hypertension of the newborn, the relationship between the relevant clinical diagnostic procedures, auxiliary examination method and the common need to identify the disease are described, with emphasis on Echocardiographic diagnosis of pulmonary hypertension. Key words: Pulmonary hypertension; Diagnosis; Differential diagnosis; Doppler echocardiography; Infant, newborn

Congenital intrathoracic neuroblastoma presenting as persistent pulmonary hypertension in a newborn

doi: 10.1007/s12519-011-0288-2 ©Children's Hospital, Zhejiang University School of Medicine, China and Springer-Verlag Berlin Heidelberg 2011. All rights reserved. A female infant, weighing 2740 g, was vaginally born at 42 weeks of gestation. The Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. After birth, the infant immediately developed respiratory distress, and required conventional ventilation, with an initial peak positive pressure of 15 cmH2O, positive end-expiratory pressure of 4 cmH2O, frequency of 40/min, and supplemental oxygen of 100%. A chest radiograph taken within the first hour following birth revealed retained fetal lung fluid with homogenous round opacity at the right upper lung (Fig. A). At 3 hours of life, she developed severe hypoxemia with 75% of pre-ductal saturation (SpO2) and 64% of post-ductal SpO2, leading to a clinical diagnosis of persistent pulmonary hypertension of the newborn (PPHN). Her respiration support was substantially changed to high frequency oscillatory ventilation with a mean airway pressure of 12 cmH2O, delta-pressure of 40 cmH2O, frequency of 10 Hz, and supplemental oxygen of 100%. The results of an arterial blood gas taken at 6 hours of life were PaCO2 79 mmHg, PaO2 54 mmHg, and pH 7.12. Serial chest X-rays at 24 hours of life revealed disappeared fetal lung fl uid and the round opacity became more obvious (Fig. B). At 3 days of life, she was weaned from supplemental oxygen, inotropic therapy, and sedative drugs, and respiratory support was switched to conventional ventilation at her 4 days of life. Computed tomography demonstrated a posterior mediastinal mass with faint internal calcifications and tracheal displacement (Fig. C). Ventilator dependency suspected to be secondary to an airway obstruction led to the attending physician performing a thoracotomy on the 12th day, which revealed a tumor which was later removed. Histology of the tumor showed small round cells in a pseudorosette formation, compatible with a poorly differentiated neuroblastoma (Fig. D). Unfortunately, the patient died of septicemia 2 months later. Congenital neuroblastoma is the most common malignant solid tumor in newborns, accounting for 54% of all neonatal malignancies. However, intrathoracic lesion is very rare in this age group. All reported neonatal intrathoracic neuroblastomas have presented with respiratory symptoms and required respiratory Congenital intrathoracic neuroblastoma presenting as persistent pulmonary hypertension in a newborn

Referral pattern of neonates with persistent pulmonary hypertension for extracorporeal membrane oxygenation in UK: are we following the guidelines?: Abstract G78 Table 1

Aims The authors reviewed the pre-extracorporeal membrane oxygenation (ECMO) management of the neonates with persistent pulmonary hypertension (PPHN) with the aim to detect any deficiencies and to formulate strategies to improve practice. Methods Retrospective review of all case notes of neonates with PPHN needing ECMO from May 2006 to July 2008 (26 months). Results Sixty neonates (37 females and 23 male) with the diagnosis of PPHN were referred for ECMO in the study period. Mean age of referral was 3.3 (range 0.2–36) days. Mean weight of the babies was 3.36 (range of 2.08–4.77) kg. 30 (50%) babies had meconium aspiration syndrome, 16 (27%) had sepsis, 3 (5%) had congenital diaphragmatic hernia, and 11 (18%) had other diagnosis. The authors analysed the indications for ECMO referrals including indices of severity, ventilatory strategies, different measures taken for treating pulmonary hypertension and the complications seen during their clinical course. The following table shows the conventional management for PPHN received by babies in referral hospitals before ECMO. Oxygenation index (OI) at the time of referral ranged from 18 to 133. There was no documentation of OI in 18 (30%) cases. 11/18 patients had insufficient data to calculate OI. Based on the UK ECMO trail the threshold of OI for referral for ECMO is 40. 25/49 (51%) babies were referred with an OI of >40. 20/49 (40%) of babies were referred when the OI was >50. There was a wide regional variation in threshold for referral with regards to OI and also use of conventional management for PPHN in neonates in the UK. Mean duration of high pressure and FiO2 before commencement of ECMO was 24 (2–72) h. 19/60 (32%) babies developed pneumothorax in the referral hospitals. Conclusion The authors noted significant number of babies were referred at very high OI and after prolonged high ventilatory settings with high incidence of pneumothoraces from tertiary referral centres, resulting in increased duration of ECMO course. Our study signifies the importance of increasing the awareness in neonatologists and paediatricians about the indications for ECMO referral to avoid unnecessary delay and complications.

Parto cesáreo e outros riscos para hipertensão pulmonar persistente do recém-nascido

To evaluate risks for persistent pulmonary hypertension in the newborn, confirmed by echocardiography, associated with cesarean deliveries and other factors. Cohort of all deliveries >36 weeks within a period of 23 months. A nested case-control study was performed in a subset of the cohort, involving newborns admitted into neonatal intensive care unit with diagnosis of persistent pulmonary hypertension matched with normal controls, with application of questionnaires to mothers to identify risks. Logistic regression was used to calculate odds ratios. From 9452 newborns, 8388 (88.7%) were delivered by cesarean and 1064 (11.3%) by vaginal delivery. Questionnaires were applied to 173 mothers. Infants from cesareans had a fivefold increased risk of persistent pulmonary hypertension of the newborn: 42 (0.5%) versus 1 case (0.09%) in the vaginal group (OR 5.32, p=0.027). No interactions were found between smoking, parity, arterial hypertension and labor before cesarean section and persistent pulmonary hypertension of the newborn. First minute Apgar score <7 and maternal diabetes were related to increased risk. Reducing cesarean deliveries could prevent many cases of serious persistent pulmonary hypertension of the newborn.

Pulmonary Dysfunction and Therapeutic Hypothermia in Asphyxiated Newborns: Whole Body versus Selective Head Cooling

Compared with whole body cooling (WBC), selective head cooling (SHC) of asphyxiated newborns presumably allows effective brain cooling with less systemic hypothermia and potentially fewer systemic adverse effects. It is not known if pulmonary dysfunction, one of the potential adverse systemic effects of therapeutic hypothermic neuroprotection, differs with the method of cooling. We sought to investigate if pulmonary mechanics and gas exchange during therapeutic hypothermia differ between WBC and SHC. The severity of pulmonary dysfunction was determined in 59 asphyxiated newborns receiving therapeutic hypothermic neuroprotection by either SHC ( N = 31) or WBC ( N = 28). Ventilatory parameters and simultaneous alveolar-arterial oxygen gradient (A-a DO (2)) and partial pressure of carbon dioxide, arterial (PaCO (2)) were measured before the start of cooling (baseline), and at 4, 8, 12, 24, 48, and 72 hours of cooling. The diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was established by echocardiography. Clinical monitoring and treatment during cooling, whether SHC or WBC, were similar. All (96%) but two infants (from the SHC group) required mechanical ventilation of varying duration during cooling, and nine infants (15%) developed PPHN. The baseline ventilator pressures requirement, and A-a DO (2) were similar among the 48 ventilated infants without PPHN (WBC 23, SHC 25) at the start of cooling. Ventilatory requirements remained modest and did not differ with the method of cooling. Similar numbers of infants without PPHN were able to be extubated after improvement in respiratory status while being cooled (WBC 42.8% versus SHC 37.9%, P = 0.79, odds ratio [OR] 1.2, 95% confidence interval [CI] 0.4 to 3.5). Nine infants (WBC 5, SHC 4) developed PPHN. Six of the nine (WBC 4, SHC 2) required inhaled nitric oxide therapy, and one infant from the WBC group subsequently required extracorporeal membrane oxygenation. The incidence of PPHN was similar in both the WBC and SHC groups (17.8% versus 12.9%, P = 0.72, OR 1.5, 95% CI 0.3 to 6.1). Pulmonary dysfunction is common but not severe in asphyxiated infants during therapeutic hypothermia. Pulmonary mechanics and gas exchange do not differ with the method of achieving hypothermia.

Asymmetric dimethyl arginine and symmetric dimethyl arginine levels in infants with persistent pulmonary hypertension of the newborn

We investigated whether infants with persistent pulmonary hypertension had elevated levels of asymmetric dimethyl arginine, an endogenous inhibitor of nitric oxide synthase, and symmetric dimethyl arginine, a regioisomer. Prospective observational cohort study. A 10-bed neonatal intensive care unit in a tertiary referral center. Forty five infants >34 wks gestation and <2 wks old admitted to our intensive care unit. Samples of urine on days 1, 3, and 5 were analyzed by high-performance liquid chromatography to determine asymmetric dimethyl arginine and symmetric dimethyl arginine levels. The clinical progression and treatment of the infants were noted. Twenty-nine infants had a clinical diagnosis of persistent pulmonary hypertension confirmed on echocardiography, and there were 16 control infants. Median asymmetric dimethyl arginine levels on day 1 were significantly higher in the persistent pulmonary hypertension group (n = 29), 14.8 (10.3-21.7) mmol.mmol creatinine(-1).L(-1), compared with controls (n = 16), 3.6 (1.4-5.2) mmol.mmol creatinine(-1).L(-1) (p < .001). Asymmetric dimethyl arginine levels decreased to control levels by day 5 (p = .33). Symmetric dimethyl arginine levels were significantly higher than controls on day 1, 31.0 (21.7-65.9) vs. 14.7 (4.1-20.2) mmol.mmol creatinine(-1).L(-1) (p = .001) and day 3, 34.7(20.3-42.5) mmol.mmol creatinine(-1).L(-1) (p = .0001) and by day 5 had decreased significantly (p = .007) back to 16.7 (12.3-23.8) mmol.mmol creatinine(-1).L(-1), which was not significantly different than the control group values. These results support the hypothesis that asymmetric dimethyl arginine and symmetric dimethyl arginine levels are elevated in patients with persistent pulmonary hypertension. Thus, endogenous inhibition of nitric oxide synthase by asymmetric dimethyl arginine may be responsible for the development of persistent pulmonary hypertension, suggesting novel therapeutic options in persistent pulmonary hypertension.

Brain-Type Natriuretic Peptide in the Diagnosis and Management of Persistent Pulmonary Hypertension of the Newborn

The diagnosis of persistent pulmonary hypertension (PPHN) can often be difficult to make, especially in a clinical setting in which pediatric echocardiography is not readily available. A noninvasive test that could differentiate PPHN from other cardiorespiratory disease would be very useful in the early management of the disease, because it would allow rapid identification of those infants at greatest risk of requiring the services of a level 3 nursery. Brain-type natriuretic peptide (BNP) is an endogenous peptide hormone secreted by the cardiac ventricles in response to increased wall stress and related ventricular filling pressures. The purpose of this study was to determine if BNP levels are elevated in newborns with PPHN and therefore may be used as a marker for differentiating PPHN from other forms of respiratory disease during the early newborn period. We used a prospective cohort design with 3 groups. One group was diagnosed with PPHN by clinical and echocardiographic criteria (PPHN group: n = 15). The second group had been diagnosed with respiratory disease; however, PPHN had been ruled out by having no evidence of elevated pulmonary pressure by echocardiography (RD group: n = 17). The third group had no respiratory disease and was breathing room air (RA group: n = 15). BNP levels were measured with a point-of-care fluorescence immunoassay at various time intervals between birth and 150 hours of life. There were no differences between groups for birth weight, gestational age, gender, race, Apgar scores at 1 minute, or age at time of initial blood sampling. Initial BNP levels (pg/mL) were elevated in the PPHN group relative to both the RA and RD groups (median [25%, 75%]: PPHN group = 1610 [1128, 1745]; RD group = 132 [76, 327]; RA group = 248 [127, 395]). There was no difference in the initial BNP level between the RA and RD groups. BNP levels remained elevated in the PPHN group over both groups for the first 4 days of life. BNP levels correlated with the gradient of the tricuspid regurgitation jet and with the ratio of tricuspid regurgitation jet gradient to mean blood pressure. BNP levels were not affected by administration of dopamine or dobutamine. BNP weakly correlated with the oxygenation index but not with the alveolar-arterial oxygenation gradient. Our findings indicate that BNP levels are elevated in infants with PPHN but not in infants with other forms of respiratory distress not associated with PPHN. Elevated BNP levels in term or near-term infants with respiratory distress should increase the suspicion of PPHN. Serial determination may also be helpful in monitoring the clinical course of such infants.

Effect of Initial Nitric Oxide Concentration on Outcome in Infants with Persistent Pulmonary Hypertension of the Newborn

A randomized nonblinded comparison of two treatment groups was performed to determine whether treatment of infants with persistent pulmonary hypertension of the newborn using a continuous 6-ppm dose of inhaled nitric oxide (iNO) changes the likelihood of death or utilization of extracorporeal membrane oxygenation (ECMO) when compared to infants treated with 20 ppm iNO for 4 h followed by 6 ppm. Twenty-nine infants with a gestational age ≥34 weeks and a diagnosis of persistent pulmonary hypertension of the newborn were enrolled during the 3- year study period. The relative risk (20/6 vs. 6 ppm) for treatment with ECMO was 3.11 (p = 0.02), for death it was 2.80 (p = 0.32), and for either death or ECMO it was 3.42 (p = 0.006). There was no apparent advantage of treatment with a higher dosage of iNO at the initiation of therapy in the reduction of death or utilization of ECMO. These data suggest that a continuous lower dose of iNO results in a comparable improvement in oxygenation as a short exposure of higher dose iNO at the initiation of therapy.

Methaemoglobinaemia after inhalation of nitric oxide in infant with pulmonary hypertension

A 41-week baby girl was delivered by emergency caesarean section because of severe fetal distress. Because she was covered with thick meconium and immediate suctioning via endotracheal tube produced meconium, the trachea was washed with surfactant. Apgar scores were 2 and 7. On admission to the neonatal unit her arterial blood gas determination revealed pH 6·89, pO2 10·6 kPa, pCO2 9·4 kPa, HCO3 10 mmol/L, base excess –24 mmol/L. We started mechanical ventilation (Hamming II, Senko-ikakikai, Tokyo, Japan) and infusion of dopamine, dobutamine, morphine, and a volume expander, and instilled surfactant into the endotracheal tube. Blood oxygen saturation fluctuated 40–100% by pulse oximeter and that at the leg was more than 20% lower than that at the arm. She showed severe cyanosis despite bagging with 100% oxygen. A working diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was made. At 4 h of age nitric oxide (NO) was started from an intended dose of 20 parts per million (ppm). Effective peak inspiratory concentrations of NO were monitored with Ecoline Plus (Nichion-Irikakikai, Chiba, Japan). At 24 h of age, on discontinuing the NO the oxygen saturation dropped immediately, then NO was restarted and increased up to 80 ppm. From 36 h urination was obtained and transcutaneous oxygen pressure began to stabilise at 13·3 kPa but oxygen saturation still fluctuated. At 50 h of age, however, she developed deep central cyanosis although arterial blood gas analysis revealed pH 7·5, pO2 50·7 kPa, and an oxygen saturation of 100%. A methaemoglobin level was 40%. Then NO was decreased and discontinued after 1 h and 1 mg/kg of methylene blue was infused over 8 min, resulting in a reduction in the methaemoglobin concentration to 3·9% over the next 20 min. Blood oxygen saturation transiently decreased from 90 to 65% during the methylene blue infusion (figure), urine of the patient dyed blue for 3 days, and the skin looked dark brown for 1 month. However, discontinuation of NO did not lead to rebound hypoxia or pulmonary hypertension and there were no further episodes of methaemoglobinaemia. Cranial magnetic resonance imaging at 4 weeks of age revealed no finding suggestive of hypoxic damage. She can hold her head up in the supine position at 4 months of age.

Surgical repair of transposition of the great arteries in neonates with persistent pulmonary hypertension

Pulmonary hypertension due to persistent fetal circulation is rarely associated with transposition of the great arteries and intact ventricular septum. Previous attempts at management of affected neonates using prostaglandin E1 and balloon atrial septotomy followed by surgical repair have been largely unsuccessful. Between September 1992 and April 1995, 45 neonates underwent repair of transposition of the great arteries with the arterial switch operation. Two patients (4%) with transposition of the great arteries and intact ventricular septum presented with profound reversed differential desaturation and right-to-left shunting at the level of the ductus arteriosus after balloon atrial septotomy. A diagnosis of persistent pulmonary hypertension was established and both neonates entered an experimental management protocol using inhaled nitric oxide and rapid arterial switch operation. Preoperative hemodynamic stabilization was achieved in 1 patient using 40 parts per million of inhaled nitric oxide, whereas the other required in addition extracorporeal membrane oxygenation for severe biventricular dysfunction. Both underwent successful surgical repair 4 to 5 days after admission, but received postoperatively 1 week of inhaled nitric oxide therapy for persistent pulmonary hypertension. Follow-up echocardiography at 3 months showed good biventricular function and normal geometry of the ventricular septum, suggesting low pulmonary artery pressure, in both. A management protocol using inhaled nitric oxide and extracorporeal membrane oxygenation followed by the arterial switch operation was successfully used in neonates with transposition of the great arteries, intact ventricular septum, and persistent pulmonary hypertension. Wider use of preoperative and postoperative inhaled nitric oxide may improve the surgical outcome of this difficult subset of patients.

Early changes in the neonatal circulatory transition

To define the course of neonatal circulatory transition and to identify clinically relevant echocardiographic measurements in the diagnosis of persistent pulmonary hypertension, we prospectively studied 32 healthy term infants from 30 minutes to 24 hours after birth with color and quantitative Doppler echocardiography on the first day of life, and compared them with 33 term infants supported by mechanical ventilation for respiratory failure. Color Doppler imaging included measurements of cardiac output, left pulmonary artery flow, aortopulmonary pressure difference, ductal flow, left-to-right color-flow jet area of the ductus arteriosus, and ductal flow characteristics. In healthy infants the majority of measurable changes in cardiopulmonary hemodynamics had occurred by 8 hours after birth, although some degree of right-to-left ductal shunting was found up to 12 hours after birth. In the infants with respiratory failure, ductal flow and maximum aortopulmonary pressure difference measurements at 8, 12, and 24 hours showed a significant delay in ductal closure and a high incidence of persistent pulmonary hypertension, which correlated well with the severity of their respiratory failure. Factors such as aortopulmonary pressure difference, prolonged right-to-left shunting with decreased left pulmonary artery flow, and failure to develop a left-to-right ductal color-flow jet were found to be practical markers for assessing the course of neonatal circulatory transition in sick term infants.