Safety and tolerability of subcutaneous treprostinil in newborns with congenital diaphragmatic hernia and life-threatening pulmonary hypertension.

BACKGROUND: Prolonged pulmonary hypertension (PH) is highly predictive for pulmonary morbidity and death in infants with congenital diaphragmatic hernia (CDH). OBJECTIVES: To report the effects and tolerability of subcutaneous treprostinil in newborns with severe CDH and late life-threatening PH. METHODS: We recorded clinical and echocardiography data before and after starting subcutaneous treprostinil, on patients with severe CDH and late PH, refractory to inhaled nitric oxide and oral sildenafil. RESULTS: 14 patients were treated with treprostinil (gestational age: 39.1±2.0weeks; birth weight: 3200±600g). Prior to treatment, the pre- and post-ductal SpO2 difference (Δ SpO2) was 14±10%. Treprostinil was initiated at a median age of 12days [5-157]. After starting treprostinil, ΔSpO2 decreased to 3% at day 7 (p<0.05), and the mean blood flow velocities in the right pulmonary arteries increased by 110% (p<0.05). 2 of the 14 patients died. At the age of follow up (12months to 3years), the 12 surviving infants were all weaned from respiratory support and discharged home. CONCLUSION: The subcutaneous treprostinil improves pulmonary hemodynamics and outcomes in infants with CDH and life-threatening PH. We suggest that the treatment should be considered in infants with severe CDH and late PH. TYPE OF STUDY: Case series with no comparison group. LEVEL OF EVIDENCE: Level IV.

[Congenital diaphragmatic hernia: respiratory and vascular outcomes]. / Hernie de coupole diaphragmatique : devenir respiratoire et vasculaire pulmonaire.

Congenital diaphragmatic hernia (CDH) is a life-threatening anomaly associated with a variable degree of pulmonary hypoplasia (PH) and persistent pulmonary hypertension (PPH). Despite remarkable advances in neonatal resuscitation and intensive care, and new postnatal treatment strategies, the rates of mortality and morbidity in the newborn with CDH remain high as the result of severe respiratory failure secondary to PH and PPH. Later, lung function assessments show obstructive and restrictive impairments due to altered lung structure and lung damage due to prolonged ventilatory support. The long-term consequences of pulmonary hypertension are unknown. Other problems include chronic pulmonary aspiration caused by gastro-oesophageal reflux and respiratory manifestations of allergy such as asthma or rhinitis. Finally, failure to thrive may be caused by increased caloric requirements due to pulmonary morbidity. Follow-up studies that systematically assess long-term sequelae are needed. Based on such studies, a more focused approach for routine multidisciplinary follow-up programs could be established. It is the goal of the French Collaborative Network to promote exchange of knowledge, future research and development of treatment protocols.

[Consequences of premature rupture of the membranes in the perinatal lung]. / Physiopathologie des conséquences respiratoires néonatales de la rupture prématurée des membranes: application à la prise en charge néonatale.

Early premature rapture of the membranes (PROM) during pregnancy is associated with a high risk of perinatal morbidity and mortality. Early PROM impairs lung structures and function through 3 mechanisms : 1) oligo-hydramnios ; 2) fetal inflammatory syndrome ; and 3) prematurity. Thus, the related causes of respiratory failure at birth after PROM are: hyaline membrane disease, persistent pulmonary hypertension induced by impaired endothelial function and/or lung hypoplasia, materno-fetal infection, and bronchopulmonary dysplasia resulting at least in part from the fetal inflammatory syndrome. Severity of the respiratory morbidity is largely unpredictable. Even if gestational age at PROM is considered as a prognostic factor, survival without morbidity exist after PROM as early as 18 weeks GA. Better knowledge of the pathophysiology improved the outcome of the preterm infants born after early PROM. Optimal management of the respiratory failure including minimizing barotrauma is required to prevent from bronchopulmonary dysplasia.

[Maternal and foetal anaesthesia for ex utero intrapartum treatment (EXIT) procedure]. / Anesthésie maternofoetale pour "ex utero intrapartum" traitement (EXIT) procédure: à propos de deux cas.

The ex utero intrapartum treatment (EXIT) procedure is a surgical procedure maintaining utero-placental circulation during caesarean section. Anaesthetic implications are described: foetal transplacental anaesthesia to avoid first breathing and to permit surgical procedure on obstructed foetal airway, deep maternal haemodynamically stable anaesthesia to relax uterine smooth muscle during a long caesarean procedure but avoiding post-partum haemorrhage. Volatile anaesthesia with sevoflurane seems to be adequate for these aims. Two cases are described.

Pulmonary vasodilator effects of norepinephrine during the development of chronic pulmonary hypertension in neonatal lambs.

BACKGROUND: This experimental study was performed to determine the effects of norepinephrine on: (i) the pulmonary vascular tone during the development of pulmonary hypertension (PH) in the fetus and (ii) the circulatory adaptation at birth after chronic intrauterine PH. METHODS: Chronically instrumented fetal lambs were randomized into two groups: (i) a group with PH obtained by antenatal partial ligation of the ductus arteriosus (DA) (n=9) and (ii) a control group without DA ligation (n=6). Pulmonary vascular responses to norepinephrine (1.5 microg min(-1)) were measured in utero 7 days after surgery. At day 8 post-surgery, after delivery, animals were ventilated for 3 h with oxygen 100%. The group with PH was randomly assigned to receive norepinephrine or saline. RESULTS: Mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were higher in the PH group (P<0.01). Norepinephrine-induced decrease in PVR was more pronounced in the PH group than in the control group (63 vs 35%, respectively; P<0.01). In the PH group, the decrease in PVR during mechanical ventilation was greater in the animals receiving norepinephrine than in the animal receiving saline (from 1.05 (0.12) to 0.1 (0.02) vs from 1.04 (0.1) to 0.2 (0.04) mm Hg ml(-1) min(-1), respectively; P<0.01). After 3 h of ventilation, mean PVR in the PH lambs treated by norepinephrine was similar to those measured in the control lambs. Aortic pressure was higher in the group treated with norepinephrine. CONCLUSION: The data suggest that norepinephrine may improve post-natal pulmonary adaptation in the newborn with persistent PH both by increasing systemic vascular pressure and by increasing pulmonary blood flow.

Successful management of severe chylothorax with argon plasma fulguration and fibrin glue in a premature infant.

Post-traumatic neonatal chylothorax is a rare entity. Management includes medical and surgical treatment. We describe here a newborn who developed a severe chylothorax after repair of an oesophageal atresia. The chylothorax was treated successfully by a combination of argon beam coagulation of the mediastinum and fibrin glue application. However, the patient developed complete thrombosis of the left femoral vein with clot extension to the inferior vena cava which resolved after infusion of recombinant tissue plasminogen activator (rt-PA). The use of argon plasma coagulation and mediastinal fibrin glue application for treating postoperative chylothorax appears to be attractive and is easy to perform even in small premature infants and may replace a more extensive surgical procedure. However, the coagulation profile should be monitored and special care should be taken to prevent vascular thrombosis after surgery.

Effects of catecholamines on the pulmonary circulation in the ovine fetus.

High levels of circulating catecholamines are found in the fetus, and fetal stress and birth induce a marked surge in catecholamine secretion. Little is known about the role of catecholamines on the fetal pulmonary circulation. To determine the effects of catecholamines on the pulmonary vascular tone, we tested the hemodynamic response to norepinephrine and dopamine infusion in chronically prepared late-gestation fetal lambs. We found that norepinephrine infusion (0.5 microg. kg(-1). min(-1)) increased pulmonary artery pressure (PAP) by 10 +/- 1% (P < 0.01), left pulmonary artery blood flow by 73 +/- 14% (P < 0.01), and decreased pulmonary vascular resistance (PVR) by 33 +/- 6% (P < 0.01). The pulmonary vasodilator effect of norepinephrine was abolished after nitric oxide synthase inhibition. Dopamine infusion at 5 microg. kg(-1). min(-1) did not significantly change PVR. Conversely, dopamine infusion at 10 microg. kg(-1). min(-1) increased PAP (P < 0.01) and progressively increased PVR by 30 +/- 14% (P < 0.01). These results indicate that catecholamines may modulate basal pulmonary vascular tone in the ovine fetus. We speculate that catecholamines may play a significant role in the maintenance of the fetal pulmonary circulation and in mediating changes in the transitional pulmonary circulation.

[Congenital hernia of the diaphragm. A retrospective study of 123 cases recorded in the Neonatal Medicine Department, URHC in Lille between 1985 and 1996]. / Les hernies congénitales des coupoles diaphragmatiques. Etude rétrospective de 123 observations recueillies dans le service de médecine néonatale du CHRU de Lille entre 1985 et 1996.

BACKGROUND: During the last ten years, new therapeutic strategies have been used in order to improve the management of congenital diaphragmatic hernia (CDH). CDH is associated with pulmonary hypoplasia, abnormal pulmonary vascular reactivity and pulmonary immaturity. Between 1985 and 1990, mechanical hyperventilation and early surgery were provided systematically. Since 1991, the management of CDH in our institution has involved a preoperative stabilization with exogenous surfactant replacement, gentle ventilation, high-frequency oscillation, nitric oxide or extracorporeal membrane oxygenation. PURPOSE: To analyse the impact of the new therapeutic strategy on the survival and outcome of newborns with CDH. METHODS: Retrospective review of all infants with CDH admitted to our institution from 1985 through 1996. Mortality and morbidity were compared between period I (1985-1990) and period II (1991-1996). RESULTS: Between 1985 and 1996, 123 neonates were admitted to our Neonatal Department. Nine of them had another severe congenital malformation and were excluded from the study. Survival was 23% (12/52) in period I and 56% (35/62) in period II (p < 0.001). In period II, complications were more frequent among survivors in whom an extracorporeal membrane oxygenation was required (13 infants): bronchopulmonary dysplasia 77% (10/13), gastroesophageal reflux 61% (8/13), and hypotrophy 61% (8/13). CONCLUSION: These data demonstrate a significant improvement in survival in CDH since the implementation of new therapeutic modalities. Nevertheless, a significant morbidity exists among the infants who survive a severe respiratory failure.

[For or against the early use of nasal continuous positive pressure and exogenous surfactant in hyaline membrane disease. Physiopathologic arguments]. / Pour ou contre une utilisation précoce de la pression positive continue nasale et du surfactant exogène au cours de la maladie des membranes hyalines. Arguments physiopathologiques.

The use of nasal CPAP in the treatment of respiratory distress syndrome in very premature newborns follows pathophysiological basis. The authors emphasize the usefulness of nasal CPAP and surfactant in the treatment of respiratory distress syndrome. The aim of this strategy is to reduce alveolar atelectasis, thus reducing the incidence and the severity of respiratory distress syndrome, together with a possible reduction of the incidence of bronchopulmonary dysplasia.