Pierre Lequien

Alveolar capillary dysplasia: a cause of persistent pulmonary hypertension of the newborn

Abstract. The term alveolar capillary dysplasia refers to complex vascular abnormalities which have recently been identified in some infants with persistent pulmonary hypertension. We report four cases admitted to our institution for severe pulmonary hypertension unresponsive to maximal cardiorespiratory support, including high-frequency ventilation, inhaled nitric oxide and extracorporeal membrane oxygenation. The four infants died of refractory hypoxaemia. The diagnosis of alveolar capillary dysplasia was established by necropsy. We have used these cases as an opportunity for a thorough review of the literature containing comments regarding aetiology, pathophysiology, clinical presentation, associated malformations and treatment trials. Conclusion: alveolar capillary dysplasia should be ruled out in all newborn infants presenting severe idiopathic pulmonary hypertension associated with malformations. Open lung biopsy may prevent from using costly, invasive and probably ineffective procedures such as extracorporeal membrane oxygenation.

Two years' follow-up of newborn infants after extracorporeal membrane oxygenation (ECMO)

OBJECTIVE Extracorporeal membrane oxygenation (ECMO) is a technique of extracorporeal oxygenation used in newborn infants with refractory hypoxemia after failure of maximal conventional medical management, when mortality risk is higher than 80%. We retrospectively reviewed all the neonates treated by ECMO between October 1991 and September 1997 in our newborn intensive care unit. METHODS Fifty-seven patients were treated with ECMO for severe respiratory failure: congenital diaphragmatic hernia (CDH) (n=23), neonatal sepsis (NS) (n=14), meconium aspiration syndrome (MAS) (n=12), and others (n=8). Mean gestational age and birth weight were 38+/-2 weeks and 3200+/-500 g, respectively. Oxygenation index was 61+/-8. Both venovenous (n=28) or venoarterial ECMO (n=29) were used. The mean time at ECMO initiation was 47 h (range 8 h-2 months). The mean duration was 134+/-68 h. In each case of VA ECMO, carotid reconstruction was performed. Survival at 2 years was 40/57 (70%) (CDH 12/23 (52%), NS 11/14 (79%), MAS 12/12 (100%), others 5/8). Follow-up at 2 years was available in 36 survivors. RESULTS Neurodevelopmental outcome was not related to the initial diagnosis: normal neurologic development (n=30), cerebral palsy (n=5), and neurologic developmental delay (n=1). Two patients remained oxygen dependant at 2 years, and four required surgical treatment for severe gastroesophageal reflux. Respiratory and digestive sequelae were more frequent in the CDH group (P<0.01). Patency and flow of the repaired carotid artery was assessed in 20 infants at 1 year of age using Doppler ultrasonography: normal (n=10), <50% stenosis (n=9), and >50% stenosis (n=1). CONCLUSION ECMO increased survival of newborn infants with refractory hypoxemia. However, higher a survival rate and lower morbidity were found in non-CDH infants than in congenital diaphragmatic hernia.

Acquired pulmonary vein stenosis as a cause of life-threatening pulmonary hypertension

We report the case of an infant born prematurely at 27 weeks gestational age with life-threatening pulmonary hypertension crisis as a result of left upper pulmonary vein stenosis. Surgical treatment consisted of a lobectomy, which is a safe and effective procedure. Evidence strongly suggests that the venous stenosis may have resulted from hypertonic drugs infused through an umbilical catheter facing the upper left venous-atrial junction.

Combined effects of inhaled nitric oxide and hyperoxia on pulmonary vascular permeability and lung mechanics.

Objective: To determine whether inhaled nitric oxide (NO) may alter pulmonary vascular permeability and respiratory function in an In vivo model. Design: Prospective, randomized, controlled, experimental study. Setting: University experimental pharmacology laboratory. Subjects: Mechanically ventilated newborn piglets, 1 to 2 days old, exposed to 100% oxygen for 76 hrs. Interventions: The piglets were randomly assigned either to a treatment group receiving 20 ppm inhaled NO from the onset of ventilation (n = 5) or to a control group (n = 6) receiving no treatment Measurements and Main Results : The main variables studied were gas exchange (Pao 2 /FIO 2 ratio, lung diffusing capacity), respiratory mechanics (static compliance of the respiratory system, stat, quasi-static hysteresis area, functional residual capacity), and pulmonary vascular permeability assessed by simultaneous intravenous administration of iodine-125-labeled albumin and chromium-51-labeled red blood cells. Extravascular albumin space of the lung and dry lung weight were significantly higher in the NO group vs. the control group (albumin space, 1.08 ± 0.16 vs. 0.70 ± 0.26 [SD] mUkg body weight [p <.05]; dry lung weight, 3.20 ± 0.34 vs. 2.66 ± 0.14 g/kg body weight [p <.05]). . Moreover, the hysteresis area was higher from 24 hrs of NO exposure. Conversely, NO inhalation altered neither the extravascular lung water content (12.98 ± 2.79 mUkg body weight in the NO group vs. 12.18 ± 2.26 mukg body weight in the control group [not significant]) nor the main respiratory mechanical variables f (static compliance, functional residual capacity) and gas exchange (lungdiffusing capacity, Pao 2 /FIO 2 ratio). Conclusion: These results do not support the hypothesis that NO inhalation combined with hyperoxia can alter the main lungfunction variables in neonates. However, it may Induce an increase in lung vascular protein leakage. The pathophysiologic consequences of this finding remain to be elucidated.

Combined effects of inhaled nitric oxide (iNO) and oxidant agents on the production of methemoglobinemia in newborn piglets

Objective: To investigate the effects of the association of inhaled nitric oxide (iNO) and oxidant drugs (acetaminophen, phytomenadione, and EMLA cream) on methemoglobinemia during the neonatal period. Design: Prospective, randomized, experimental study. Setting: University Experimental Pharmacology laboratory. Subjects: Sixty newborn piglets weighing 1.5‐2.0 Kg. Interventions: Twelve groups of five piglets were anaesthetized, mechanically ventilated, and studied for 3 hrs. Eight groups received iNO (40 ppm or 80 ppm) alone or in association with a single intravenous dose of acetaminophen (120 mg/kg propacetamol), phytomenadione (5 mg vitamin K1) or EMLA cream (2.5 g) applied to the ventral lower abdomen for 3 hrs. Three other groups received, respectively, acetaminophen, phytomenadione, or EMLA cream without iNO. The last group (control group) received neither drugs nor iNO. Measurements and Main Results: Methemoglobinemia was measured before the beginning of each experiment, 30 mins later, and every hour for 3 hrs. There was no significant difference in methemoglobinemia at any time between groups receiving acetaminophen (0.90% ± 0.12%), phytomenadione (0.88% ± 0.11%), or EMLA cream alone (0.97% ± 0.11%) and the control group (0.92% ± 0.12%). At 3 hrs, methemoglobinemia was slightly but significantly increased in group receiving iNO alone (1.04% ± 0.17% at 40 ppm iNO and 1.14% ± 0.16% at 80 ppm iNO; p < .05). Conversely, methemoglobinemia increased as a function of time in groups in which iNO was associated to drug administration and was significantly greater than the control group at 3 hrs (80 ppm iNO + acetaminophen, 2.80% ± 0.47%; 80 ppm iNO + phytomenadione, 2.38% ± 0.45%; 80 ppm iNO + EMLA cream, 2.33% ± 0.46%; p < .001). Conclusions: These results demonstrate that if oxidant drugs (acetaminophen, phytomenadione, or EMLA cream) did not increase blood methemoglobinemia in neonatal piglets, their association with iNO caused an increase in methemoglobin. Special care should be taken to monitor methemoglobinemia when iNO is combined to such drugs in newborn infants.

Effects of inhaled nitric oxide on gas exchange and acute lung injury in premature lambs with moderate hyaline membrane disease

OBJECTIVE The purpose of this study was to examine whether inhaled nitric oxide (iNO) may change lung injury in moderate hyaline membrane disease (HMD). METHODS Fifteen moderately premature lambs (128 days gestation, term=147 days) were randomly assigned to treatment with 20 ppm inhaled NO (n=7) from the onset of ventilation or control (n=8). Except for inhaled NO, treatments were intentionally similar to those applied in clinical situations. After porcine surfactant administration (Curosurf, 100 mg/kg), mechanical ventilator settings were modified during the course of the study to maintain PaCO(2) between 40 and 50 mmHg and post-ductal SpO(2) between 90 and 95%. The main studied parameters were gas exchanges parameters, respiratory mechanics (static compliance and functional residual capacity) and pulmonary vascular permeability and/or filtration rate indices. RESULTS We found that 20 ppm of inhaled NO for 5 h significantly reduce ventilatory and oxygen requirements, but only during the first hour of mechanical ventilation. No increase in extravascular lung water content (5.41+/-0.96 vs. 5.46+/-1.09 ml/g bloodless dry lung in the control group and in the NO group, respectively) and no impairment of the respiratory mechanics could be found in the NO-treated group. However, inhaled NO increased the albumin lung leak index in this model (6.09+/-1.51 in the NO-treated group vs. 4.08+/-1.93 in the control group; P<0.05). CONCLUSIONS Our results do not therefore support a detrimental effect of short-term exposure to low doses of NO inhalation in moderate HMD. However, it may induce an increase in lung vascular protein leakage. The pathophysiological consequences of this finding remain to be elucidated.

Contribution à l'étude de la prise en charge des grands prématurés en France métropolitaine (à l'exception de l'Île-de-france)

Background. — Regionalization of perinatal care is one of the purposes of the last ‘Plan du Gouvernement pour la Perinatalite’ (French Governments Perinatal Project). The aims of the study are first to investigate the site of admission of the very low birth weight infants and secondly to analyze postnatal transfer policies. Population and methods. — Neonatal units in France (excluding the Ile-de-France area), using exogenous surfactant were asked for their number of intensive care cots (1–5, 6–10, more than 10) and for the yearly rate of admission preterms less than 33 weeks gestational age. They were also classified as academic or not. Results. — One hundred and six out of 129 units participated. Ten units were excluded because they did not use surfactants. Among the 71 non academic units, the number of intensive care cots was less than six in 5771 (80%) vs 125 (4%) in the academic units. There was no relationship between the number of admissions and transfer policy. In 29 units with less than six cots, and in 20 of those with 20 admissions or less, transfer occurred exceptionally or never. Conclusions. — The concept of “critical mass”, usually recommended to ensure expertise, is not warranted in most French neonatology units. It is worrysome to state that many small units do not transfer any children or do it for a limited number. On the other hand, a majority of the infants transferred post-natally could have drawn benefit from in utero transfer. From these data, it is possible to assume that regionalization of perinatal care is far from achieved in most parts of the French territory.

DOES INHALED NITRIC OXIDE MODIFY LUNG DIFFUSING CAPACITY AND MECHANICS IN EXPERIMENTAL HYALINE MEMBRANE DISEASE (HMD)? 2073

DOES INHALED NITRIC OXIDE MODIFY LUNG DIFFUSING CAPACITY AND MECHANICS IN EXPERIMENTAL HYALINE MEMBRANE DISEASE (HMD)? 2073

EFFECTS OF INHALED NITRIC OXIDE (NO) IN PREMATURE LAMBS WITH MODERATE HYALINE MEMBRANE DISEASE (HMD). † 1467

Gas exchange improvment by low dose NO inhalation without increase of vascular permeability was reported by Kinsella et al. in experimental severe HMD (Pediatr Res 1995; 38: 337A). Our hypothesis was that inhaled NO could be deleterious in less severe respiratory failure by increasing pulmonary blood flow and/or altering vascular permeability. The effects of inhaled NO on gas exchange and lung vascular permeability in moderate HMD were studied. Eighteen moderatly premature lambs (130 days gestation, term=147 days) were randomly assigned to treatment with 20 ppm inhaled NO from the onset of ventilation(HO) or control. After porcine surfactant administration (Curosurf® 100 mg/kg), ventilator was set to maintain PaCO2 values between 40 and 50 mmHg and SpO2 values between 90 and 95%. After 4 hours,125 I-labeled albumine and 51Cr-tagged red blood cells were injected. One hour later, gamma-counting was performed on lung tissue and blood. Wet and dry weights of blood and lung were measured. Pulmonary edema was assessed by measurement of extravascular lung water content (Qwl) normalized for bloodless dry lung weight. Vascular permeability was evaluated by the Lung Leak Index (LLl) measurement (Am Rev Respir Dis. 1993; 148: 1194-203). Oxygenation (OI = Mean Airway Pressure*FiO2/PaO2) and ventilatory index (VI = Mean Airway Pressure*Respiratory Rate) were calculated at 1 and 5 hours. OI was significantly lower after 1 hour of ventilation in the NO vs. control group. However, OI and ventilatory requirement were not significantly different after 5 hours of ventilation. In spite of similar extravascular lung water content in both groups, vascular protein leak was increased in NO group. In conclusion, no benefit of short term NO inhalation (5 hours) could be demontrated for gas exchange in premature lambs with moderate HMD. Moreoever increased lung vascular protein leak in the NO group suggests an alteration of vascular permeability. Benefits of long term NO inhalation should be demonstrated before its clinical use in moderate HMD.Table

Can Prophylaxis of Peri Intraventricular Hemorrhage (PIVH) by Indomethacin Treatment in Very Low Birth Weight (VLBW) Newborns Be Explained by PDA Closure? A Meta-Analysis

Can Prophylaxis of Peri Intraventricular Hemorrhage (PIVH) by Indomethacin Treatment in Very Low Birth Weight (VLBW) Newborns Be Explained by PDA Closure? A Meta-Analysis