Michel Berner

Inhaled Nitric Oxide Versus Aerosolized Iloprost in Secondary Pulmonary Hypertension in Children With Congenital Heart Disease Vasodilator Capacity and Cellular Mechanisms

Background —Inhaled nitric oxide (iNO) has been used to assess the vasodilator capacity of the pulmonary vascular bed in children with congenital heart disease and elevated pulmonary vascular resistance. Inhaled iloprost is a pulmonary vasodilator for the long-term treatment of pulmonary hypertension (PHT). Because these 2 vasodilators act through different pathways (release of cGMP or cAMP, respectively), we compared the pulmonary vasodilator capacity of each. Methods and Results —A total of 15 children with congenital heart disease and PHT who had elevated pulmonary vascular resistance (preoperative, n=10; immediately postoperative, n=5) were first given 20 ppm of iNO for 10 minutes; then, after baseline values were reached again, they were given aerosolized iloprost at 25 ng · kg−1 · min−1 for another 10 minutes. Finally, iNO and iloprost were given simultaneously for 10 minutes. With iNO, the pulmonary vascular resistance and systemic vascular resistance ratio decreased from 0.48±0.38 to 0.27±0.16 (P <0.001). Similarly, iloprost decreased the ratio from 0.49±0.38 to 0.26±0.11 (P <0.05). The combination had no additional effect on the resistance ratio. Plasma cGMP increased from 17.6±11.9 to 34.7±21.4 nmol/L during iNO (P <0.01), and plasma cAMP increased from 55.7±22.9 to 65.1±21.2 nmol/L during iloprost inhalation (P <0.05). Conclusions —In children with PHT and congenital heart disease, both iNO and aerosolized iloprost are equally effective in selectively lowering pulmonary vascular resistance through an increase in cGMP or cAMP, respectively. However, the combination of both vasodilators failed to prove more potent than either substance alone. Aerosolized iloprost might be an alternative to iNO for early testing of vascular reactivity and for the postoperative treatment of acute PHT.

Incidence of Early Neonatal Mortality and Morbidity After Late-Preterm and Term Cesarean Delivery

OBJECTIVE. To determine the age-stratified risk of intrapartum and neonatal mortality as well as morbidities of clinical relevance after elective cesarean delivery (ECD). METHODS. This work was a cohort study including 56 549 prospectively recorded late-preterm and term deliveries. We analyzed the effect of cesarean delivery (CD) before the onset of labor on the following multiple neonatal outcomes before hospital discharge, compared with planned vaginal delivery (PVD) and emergency CD: mortality, birth depression, special care admission, and respiratory morbidity. We adjusted for confounders by multivariate analysis and stratified the risk according to gestational age (GA). RESULTS. Mortality and morbidities had a strong GA-related trend with the lowest incidences consistently found between 38 and 40 weeks of gestation independent of delivery mode. Compared with infants delivered via PVD, infants delivered via ECD had significantly higher rates of mortality (adjusted risk ratio [aRR]: 2.1), risk of special care admission (aRR: 1.4), and respiratory morbidity (aRR: 1.8) but not of depression at birth (aRR: 1.1). Compared with emergency CD, newborns delivered via ECD had less depression at birth (aRR: 0.6) and admission to special care (aRR: 0.8), but mortality (aRR: 0.8) and respiratory morbidity (aRR: 1.0) rates were similar. CONCLUSIONS. Gestational age–specific risk estimates are lowest between 38 and 40 weeks and should be included in the informed-consent process. The information should also be used to allow for appropriate preparation with respect to adequate staff and equipment. ECD is consistently associated with increased intrapartum and neonatal mortality, risk of admission, and respiratory morbidity compared with PVD and has no advantage over emergency CD in terms of mortality. Neonatal morbidities are lower after ECD than emergency CD only with term births. Our data provide evidence that ECD should not be performed before term.

Continuous low dose inhaled nitric oxide for treatment of severe pulmonary hypertension after cardiac surgery in paediatric patients.

OBJECTIVE--To assess the effect of inhaled nitric oxide (NO) on severe postoperative pulmonary hypertension in children after surgical repair of a congenital heart defect. DESIGN--A pilot study of NO administration to 7 consecutive children who required adrenergic support and in whom postoperative mean pulmonary artery pressure was more than two thirds of mean systemic pressure and persisted despite alkalotic hyperventilation. SETTING--Routine care after cardiac surgery for congenital heart disease in a multidisciplinary paediatric intensive care unit. METHODS--Continuous inhalation of NO, initially at 15 ppm. Therefore, daily attempts at complete weaning or at reducing NO to the lowest effective dose. RESULTS--In 6 of the 7 children NO inhalation selectively decreased mean (SD) pulmonary artery pressure from 51 (12) to 31 (9) mm Hg (P < 0.05) while mean systemic arterial pressure was unchanged (68 (10) v 71 (7) mm Hg) (NS) and the arteriovenous difference in oxygen content decreased from 6.7 (0.9) to 4.8 (0.8) vol% (P < 0.05). Concomitantly PaO2 increased from 158 (98) to 231 (79) mm Hg) (P < 0.05). The seventh child showed no response to NO up to 80 ppm, could not be weaned from cardiopulmonary bypass, and died in the operating room. In responders, attempts at early weaning from NO inhalation always failed and NO at concentrations of less than 10 ppm was continuously administered for a median of 9.5 days (range 4 to 16 days) until complete weaning was possible from a mean dose of 3.9 (2.9) ppm. Methaemoglobinaemia remained below 2% and nitrogen dioxide concentrations usually ranged from 0.1 to 0.2 ppm. One child later died and five were discharged. A few months after surgery Doppler echocardiography (and catheterisation in one) showed evidence of regression of pulmonary hypertension in all 5. CONCLUSIONS--Inhalation of NO reduced pulmonary artery pressure in children with severe pulmonary hypertension after cardiac surgery and this effect was maintained over several days at concentrations carrying little risk of toxicity.

Inhaled Nitric Oxide to Test the Vasodilator Capacity of the Pulmonary Vascular Bed in Children With Long-Standing Pulmonary Hypertension and Congenital Heart Disease

Nitric oxide-induced vasodilator capacity greatly varies among children with pulmonary hypertension and elevated vascular resistance. The decline of this selective response seems to parallel the progression of established vascular disease and thus may be helpful for the selection of patients for operation.

Home-based versus hospital-based postnatal care: a randomised trial

Objective  To compare a shortened hospital stay with midwife visits at home to usual hospital care after delivery.

Relief of severe pulmonary hypertension after closure of a large ventricular septal defect using low dose inhaled nitric oxide

A 16-month-old girl developed severe pulmonary hyptertension after closure of a large ventricular septal defect. All conventional therapeutic measures failed; an attempt to add nitric oxide at a continous low dose to the inspired gas allowed resolution of pulmonary hypertension and low cardiac output. This report documents that continuous inhalation of low dose nitric oxide is capable of selective resolution of pulmonary hypertension following cardiac surgery for a large septal defect in a child. This suggests that a transient dysfunction in the release of nitric oxide by the pulmonary endothelial cell is responsible for the vasoconstriction.

Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ.

Background Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. Methodology/Principal Findings We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon-γ. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-γ. Conclusion/Significance Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero. Ex vivo treatment of leukocytes from premature neonates with interferon-γ reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis.

Long term inhalation of iloprost in a child with primary pulmonary hypertension: an alternative to continuous infusion

Primary pulmonary hypertension is a rare disease in childhood associated with a poor prognosis. However, during the past 10 years, pulmonary vasodilator treatment has somewhat improved its prognosis. Long term continuous infusion of prostacyclin (epoprostenol) has been shown to improve physical capacity and to reduce mortality in primary and secondary pulmonary hypertension. It has been reported in adults that daily repetitive inhalation of iloprost, a prostacyclin analogue, seems also suitable for long term therapy of pulmonary hypertension. Repetitive inhalation of iloprost was administered to a 5 year old boy with severe primary pulmonary hypertension. He showed continuous clinical improvement without any side effects over the three years of treatment. This treatment may offer an alternative to continuous intravenous prostacyclin infusion and obviates the need for a permanent central venous catheter.

Hemodynamic effects of amrinone in children after cardiac surgery

The hemodynamic effects of amrinone were assessed in seven children following cardiac surgery. Amrinone was administered as a bolus of 1 mg kg−1 body wt., followed by continuous infusion at 10 μg kg−1 min−1 for 1 h and two stepwise increases to 20 and 40 μg kg−1 min−1 for 30 min each. Hemodynamic data were obtained and plasma concentrations of amrinone measured 1 h after the bolus dose and immediately before each increment of the infusion rate. Amrinone levels ranged from 0.7 to 2.3 mgl−1. Administration of amrinone lowered systemic vascular resistance from 20.0±4.3 to 16.5±4.6 mmHgl−1 min−1m−2 (p<0.05) and reduced mean arterial pressure from 71.7±9.5 to 62.6±13.5 mmHg (p<0.05) at the highest infusion rate, confirming the known vasodilative effect of the drug. However, these effects did not result in a statistically significant increase in stroke volume (35.0±7.5 to 35.5±7.0 ml m−2, NS) or cardiac index (3.10±0.50 to 3.20±0.40 l min−1 m−2). One additional patient, in whom a higher loading dose was tried in order to achieve a higher plasma concentration, developed systemic hypotension. A correlation was established between the plasma concentrations of amrinone and the percentage decrease in systemic resistance (r=0.70,p<0.05). These results suggest that in children after open heart surgery, amrinone acts primarily as a systemic vasodilator, with questionable inotropic effect. Accordingly, its use should be restricted to children with severe cardiac failure and documented highly elevated afterload.

The Hemodynamic Effect of Phentolamine and Dobutamine after Open-Heart Operations in Children: Influence of the Underlying Heart Defect

The hemodynamic effects of phentolamine alone and in combination with dobutamine were studied in the immediate postoperative period in two groups of children. Group 1 (N = 6; mean age, 152 months) had open-heart operation for acquired mitral valve disease. Group 2 (N = 6; mean age, 60 months) had intracardiac repair for tetralogy of Fallot. Before drug administration, cardiac index did not differ between groups, but patients with tetralogy of Fallot had a higher heart rate and smaller stroke volume index; systemic vascular resistance was high in both groups. With phentolamine (10 micrograms/kg/min), cardiac index and stroke volume index increased similarly in both groups (+ 13% for cardiac index in Group 1, +9% in Group 2), while systemic vascular resistance, pulmonary vascular resistance, and pulmonary wedge pressure decreased. When dobutamine (5 micrograms/kg/min) was added, there was a further increase in cardiac index in both groups, but it was greater in Group 1 (+17% vs +12%, p less than 0.01, compared with phentolamine alone; +33% vs +22%, p less than 0.01, compared with control). Systemic vascular resistance remained unchanged and heart rate increased in both groups, so that the left ventricular stroke work index increased. Although stroke volume index increased significantly with dobutamine in Group 1 (+11%, p less than 0.01), it remained unchanged in Group 2 (+3%, not significant). Thus in Group 2, dobutamine increased cardiac index only by increasing heart rate. This suggests that the relatively small, noncompliant left ventricle in patients with tetralogy of Fallot cannot further respond to inotropic drugs by increasing stroke volume index.