[Perinatal care for extremely preterm infants. Considerations of the "risks in pregnancy" department]. / Prise en charge de la prématurité extrême. Réflexions du département hospitalo-universitaire (DHU) « risques et grossesse ¼.

Decisions regarding whether to initiate or forgo intensive care for extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients and must be taken into account. After a short review of these factors, we present the thoughts and proposals of the Risks and Pregnancy department. The proposals are to limit emergency decisions, to better take into account other factors than gestational age and prenatal predicted fetal weight in assessing the prognosis, to introduce multidisciplinary consultation in the evaluation and proposals that will be discussed with the parents, and to separate prenatal steroid therapy from decision-making regarding whether or not to administer intensive care.

Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase.

BACKGROUND: Cellular quiescence is a state of reversible proliferation arrest that is induced by anti-mitogenic signals. The endogenous cardiac glycoside ouabain is a specific ligand of the ubiquitous sodium pump, Na,K-ATPase, also known to regulate cell growth through unknown signalling pathways. METHODS: To investigate the role of ouabain/Na,K-ATPase in uncontrolled neuroblastoma growth we used xenografts, flow cytometry, immunostaining, comet assay, real-time PCR, and electrophysiology after various treatment strategies. RESULTS: The ouabain/Na,K-ATPase complex induced quiescence in malignant neuroblastoma. Tumour growth was reduced by >50% when neuroblastoma cells were xenografted into immune-deficient mice that were fed with ouabain. Ouabain-induced S-G2 phase arrest, activated the DNA-damage response (DDR) pathway marker γH2AX, increased the cell cycle regulator p21(Waf1/Cip1) and upregulated the quiescence-specific transcription factor hairy and enhancer of split1 (HES1), causing neuroblastoma cells to ultimately enter G0. Cells re-entered the cell cycle and resumed proliferation, without showing DNA damage, when ouabain was removed. CONCLUSION: These findings demonstrate a novel action of ouabain/Na,K-ATPase as a regulator of quiescence in neuroblastoma, suggesting that ouabain can be used in chemotherapies to suppress tumour growth and/or arrest cells to increase the therapeutic index in combination therapies.

Effect of ibuprofen on bilirubin-albumin binding in vitro at concentrations observed during treatment of patent ductus arteriosus.

BACKGROUND: In vitro studies have shown that ibuprofen (IBU) may interfere with bilirubin-albumin binding at concentrations of 100 microg/mL and above. OBJECTIVES: The present study evaluates the in vitro bilirubin displacement over the range of IBU plasma concentrations observed in vivo during curative treatment of patent ductus arteriosus in preterm infants. METHODS: Considering that individual plasma concentrations obtained during the clinical development of IBU in preterm infants were ranging between 10 and 70 microg/mL and exceptionally above 100 microg/mL, we used the modified peroxidase method to determine total and unbound bilirubin concentrations without IBU and with IBU over this specific concentration range. RESULTS: Total bilirubin and albumin concentrations were respectively 6.6 mg/dL and 2.87 g/dL in pooled newborn plasma. No displacement of bilirubin from its albumin binding sites by IBU was observed over a range of concentrations from 10 to 100 microg/mL. Only a concentration of 200 microg/mL significantly increased the unbound bilirubin by 1.5-fold (p=0.0008). CONCLUSIONS: This in vitro study confirms displacement of bilirubin by a high IBU concentration of 200 microg/mL, however it retrieves no significant displacement over a range of concentrations up to and including 100 microg/mL, i.e. within the range of in vivo concentrations at the recommended dose regimen.

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method.

OBJECTIVE: Intravenous ibuprofen (IBU) has been found to be as effective as indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants and has been associated with fewer adverse effects in comparative phase III studies. The dose regimen used (10-5-5 mg/kg/day) was based on limited pharmacokinetic data and no phase II study was available to determine the optimal dose of IBU for this indication. The present study was designed to determine the minimum effective dose regimen (MEDR) of IBU (one course) required to close ductus arteriosus in preterm infants. METHOD: A double-blind dose-finding study was conducted using the continual reassessment method, a Bayesian sequential design. Two distinct target closure rates were initially chosen according to postmenstrual age (PMA) at birth: 80% in infants with a PMA of 27-29 weeks, and 50% in infants with a PMA < 27 weeks. Forty neonates (20 in each PMA group) with PDA were treated between days 3 and 5 of life. Four different dose regimens were tested: loading doses of 5, 10, 15 or 20 mg/kg, followed by two doses (1/2 loading dose) at 24-h intervals. Efficacy was evaluated by echocardiography 24 h after the third infusion. RESULTS: In infants with a PMA of 27-29 weeks, the estimated MEDR was 10-5-5 mg/kg with a final estimated probability of success of 77% (95% credibility interval: 56-92%). The 15-7.5-7.5 mg/kg dose regimen had a better estimated probability of success (88%, 95% credibility interval: 68-97%), but resulted in more minor renal adverse effects. In contrast, in infants with a PMA < 27 weeks, the estimated MEDR was 20-10-10 mg/kg with an estimated probability of success of 54.8% (95% credibility interval: 22-84%), whereas the conventional dose regimen resulted in a low estimated probability of success (30.6%, 95% credibility interval: 13-56%). In these infants, compared with those with a PMA of 27-29 weeks, minor renal adverse effects were more frequent from the 10-5-5 mg/kg/day dose regimen and did not appear to be clearly dose related. CONCLUSION: This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.

[Oxygen weaning]. / Sevrage de l'oxygène.

Oxygen weaning is a controversial problem which can be summarized in three questions: what do we expect from oxygen supplementation? what are the optimal targets? with what sort of monitoring? We shall try to evaluate these different questions assuming the uncertainty of the proposed answers and the short-lived character of them.

[Prenatal risk evaluation, parent information and mode of delivery]. / Evaluation des risques en anténatal, information des parents et prise en charge de l'accouchement.

Perinatal networks, antenatal administration of glucosteroids, postnatal administration of surfactant, and new techniques for mechanical ventilation, have considerably improved the prognosis of extremely preterm infants. Such recent progress in perinatology had enabled neonatologists to provide intensive care for infants born after 24 and 28 weeks of gestation. This practice raises serious medical and ethical issues. The optimal mode of delivery of such newborns is not well established mainly because available studies are retrospective and subjected to biases. Moreover, perinatologists are implicated in the continuing discussion on ethical issues that modify clinical practices.

[Extremely preterm infants: resuscitation criteria in the delivery room and dialogue with parents before birth]. / Critères de réanimation des prématurissimes en salle de naissance: quel discours en anténatal?

The resuscitation of extremely preterm infants presents complex medical, social and ethical issues for the families and the health professionals. The principle of a systematic resuscitation "temporary intensive care" does not prohibit the question of a limit in terms of gestational age and birth weight. In France, a do not resuscitate order (comfort care alone) is appropriate for newborns weighing less than 500g and/or with a gestational age of less than 24 weeks' since the mortality is nearly 100%. The survival of infants born at 24 weeks' gestational age remains low with significant risks of chronic medical problems and neurodevelopmental disabilities. The decisions regarding the extent of resuscitative efforts depend on antenatal factors, condition of the neonate at birth and the parental opinion. Before the delivery, parents should receive appropriate information about survival and risks of adverse long-term outcome. The physician should follow the parents' desires whenever the parents' decision would not obviously violate the infants' best interests. However, they must be informed that decisions about neonatal management made before the delivery can have to be changed in the delivery room, depending on the condition of the neonate at birth. At 25 weeks of gestational age, the prognosis is better and the resuscitation should be more intensive.

Congenital idiopathic chylothorax in neonates: chemical pleurodesis with povidone-iodine (Betadine).

Chylothorax is defined as an accumulation of chyle in the pleural space. This condition usually occurs after an operation, the congenital idiopathic form being rare (1/15000 births). Recovery is observed within four to six weeks of diagnosis in most cases. Treatment is either conservative or surgical. Four cases are reported of congenital chylothorax (three idiopathic, one accompanied by diffuse lymphangectasia) managed by chemical pleurodesis (intrapleural injection of povidone-iodine). Tolerance was satisfactory: unaltered thyroid function in the three cases explored; one case of transient generalised oedema. Treatment was deemed successful in three of the four cases. One child died from renal failure (unrelated to the chemical pleurodesis). Pleurodesis by povidone-iodine appears to be well tolerated and may represent a good alternative to mechanical abrasion or surgery for congenital idiopathic chylothorax. Its use for refractory chylothorax may also decrease the morbidity related to prolonged hospital stay.

Impact of delayed repair and elective high-frequency oscillatory ventilation on survival of antenatally diagnosed congenital diaphragmatic hernia: first application of these strategies in the more "severe" subgroup of antenatally diagnosed newborns.

OBJECTIVE: a) To analyze the influence of a new management strategy on the outcome of neonates with antenatally diagnosed congenital diaphragmatic hernia (CDH); b) to determine early prognosis respiratory factors with the new strategy. DESIGN: Retrospective study. SETTING: Level III perinatal center. PATIENTS AND METHOD: Between 1985 and 1997, 51 consecutive neonates with antenatally diagnosed CDH were admitted to our level III neonatal intensive care unit. Before 1992 (period 1; n = 19), we used conventional mechanical ventilation and early surgery requiring transfer. Since 1992 (period 2; n = 32), we prospectively tested a new approach including (a) systematically use of high-frequency oscillatory ventilation (HFOV) regardless of the initial clinical severity, (b) delayed surgery following stabilization requiring transfer to a different surgical unit, but (c) no transfer of unstable patients with surgery under HFOV in our neonatal intensive care unit (n = 10). The two cohorts were comparable in terms of potential ante and postnatal prognostic indicators. RESULTS: Survival was improved with the new strategy: 21/32 (66%) vs. 5/19 (26%); P < 0.02. This improvement between periods 1 and 2 was due to a decrease in both preoperative and postoperative deaths in the later period. The better survival during period 2 was associated with the appearance of very late deaths, frequent pleural effusions, and the survival of more severe forms having evolved to a chronic respiratory insufficiency. Survivors were ventilated for longer time with longer duration of oxygen supplementation. The best oxygenation index (OI), alveolar arterial difference and oscillation amplitude (P/P) during the first 24 h, but not the best PaCO2, were the most reliable prognostic indicators during period 2. An OI < or = 10 with a P/P < or = 55 cmH2O was associated with a very good prognosis (94% survival). CONCLUSIONS: The prognosis of antenatally diagnosed CDH was improved by systematic HFOV on admission, no systematic transfer, and delayed surgery. This improvement is associated with modification of postnatal outcome.

Detection of positional airway obstruction in neonates by acoustic reflection.

In neonates intubated with an uncuffed endotracheal tube (ETT), positional changes of the head may induce obstruction (side position-related ETT obstruction [SPRO]) due to abutment of the beveled distal ETT orifice against the tracheal wall. We studied whether the acoustic reflection (ACR) method, a 4-s measurement that maps cross-sectional area as a function of the distance along the ETT and the airways, could detect SPRO. Eleven preterm newborns intubated with 2.5-mm ETTs and clinically suspected of having SPRO were studied with the head oriented to the left and to the right. In all patients there was a marked decrease in the ACR-measured area beyond the distal tip of the ETT in the presence of obstruction (decrease = 38 +/- 22% [mean +/- SD] of the ETT inside area), while the ACR-measured area increased markedly in the absence of obstruction (increase = 49 +/- 17%). For six of the 11 infants, we also recorded the maximal flow produced by a set mechanical inflation pressure. This maximal flow decreased in the presence of obstruction (decrease = 47 +/- 18%), and was constantly associated with a decrease in ACR-measured area beyond the ETT. In conclusion, ACR measurement is an efficient method for diagnosing positional ETT obstruction in intubated newborns.

Estimation of inspiratory pressure drop in neonatal and pediatric endotracheal tubes.

Endotracheal tubes (ETTs) constitute a resistive extra load for intubated patients. The ETT pressure drop (DeltaP(ETT)) is usually described by empirical equations that are specific to one ETT only. Our laboratory previously showed that, in adult ETTs, DeltaP(ETT) is given by the Blasius formula (F. Lofaso, B. Louis, L. Brochard, A. Harf, and D. Isabey. Am. Rev. Respir. Dis. 146: 974-979, 1992). Here, we also propose a general formulation for neonatal and pediatric ETTs on the basis of adimensional analysis of the pressure-flow relationship. Pressure and flow were directly measured in seven ETTs (internal diameter: 2.5-7.0 mm). The measured pressure drop was compared with the predicted drop given by general laws for a curved tube. In neonatal ETTs (2.5-3.5 mm) the flow regime is laminar. The DeltaP(ETT) can be estimated by the Ito formula, which replaces Poiseuille's law for curved tubes. For pediatric ETTs (4.0-7.0 mm), DeltaP(ETT) depends on the following flow regime: for laminar flow, it must be calculated by the Ito formula, and for turbulent flow, by the Blasius formula. Both formulas allow for ETT geometry and gas properties.

Corticosteroids and chronic lung disease in extremely immature infants: a dilemma.

What is the balance of benefits and risks of dexamethasone in extremely immature infants? The answer remains unclear. We feel that the risks of "early" treatment outweigh the benefits, because many infants who would not develop CLD will be treated. Treatment between day 7 and day 14 seems more appropriate to us, as it focuses on infants with a high risk of developing CLD. However, the lungs may be already somewhat damaged when starting treatment, whose expected benefit is a shortened duration of mechanical ventilation and a decreased incidence of CLD. The risks for growth and brain development are not clearly assessed. Both 7-day courses and pulse therapy are effective, but no comparison of these 2 schedules has been published. We therefore do not know whether pulse therapy provides the same benefits as 7-day courses with fewer risks for growth or cardiomyopathy.