A prospective clinical study on inhaled nitric oxide therapy for neonates in Japan

BACKGROUND: This is the first report about a prospective clinical investigation to study the efficacy and safety of nitric oxide (NO) inhalation in infants with persistent pulmonary hypertension of the newborn (PPHN) in Japan. METHODS: Patients in the present study had to meet the following entry criteria: (i) they had to be younger than 7 days of age; (ii) they had to have evidence of PPHN as defined by echocardiograph; (iii) they had to have severe systemic hypoxemia under mechanical ventilation at 100% oxygen supplementation; and (iv) they had to have a failure to respond to conventional therapies. Patients were excluded from this trial if they had any of the following: hypoplastic lung, structural cardiac lesions or severe multiple anomalies. RESULTS: Nitric oxide inhalation therapy was performed in 68 infants who had severe PPHN at 18 hospitals between May 1995 and May 1997. At birth, 21 of 68 infants (31%) weighed less than 1,500 g and 39 infants weighed more than 2,500 g. The diagnoses associated with PPHN were as follows: 27 infants had meconium aspiration syndrome, 15 infants had dry lung syndrome, nine infants had congenital diaphragmatic hernia, six infants had respiratory distress syndrome, three infants had pneumonia and eight infants had other diagnoses. The mean oxygenation index (OI) before NO inhalation therapy in 68 infants was 43.2; 55 infants (81%) had good responses. CONCLUSIONS: These results may be valuable for further randomized controlled and double-blind trials in Japan to evaluate whether NO inhalation therapy is more effective than conventional therapy in infants with severe PPHN.     

Preventive management of hypoglycemia in very low-birthweight infants following indomethacin therapy for patent ductus arteriosus

BACKGROUND: To evaluate the effects of an increase in glucose infusion rate of 2 mg/kg per min from the basal infusion rate on the prevention of hypoglycemia in very low-birthweight (VLBW) infants, following indomethacin therapy for patent ductus arteriosus (PDA). METHODS: Forty VLBW infants with PDA were given indomethacin 0.2 mg/kg intravenously up to three doses. In 15 of the 40 infants (supplemented group: between April 1995 and March 1996) the glucose infusion rate was increased in 2 mg/kg per min increments from the basal rate just before the initial indomethacin administration, compared with 25 historical control infants who received a fixed glucose infusion rate during the first 12 h after the initial dose. We evaluated the changes in blood glucose levels and glucose infusion rates in both groups. RESULTS: In the control group 11 of 25 (44%) infants had a blood glucose value below 40 mg/dL between 12 and 60 h (mean 32.7 h). In contrast only two out of 15 infants in the supplemented group reached the glucose level below 40 mg/dL between 72 and 96 h but both two were light-for-dates infants (defined as birthweight below the 10th percentile for gestational age on the standard intrauterine growth curve). Blood glucose values in the supplemented group were significantly higher than those in the control group between 12 and 96 h. However, glucose infusion rates were similar before and between 72 and 96 h. CONCLUSIONS: This retrospective study shows that an increase in glucose infusion rate of 2 mg/kg per min, in addition to the pre-existing stable maintenance glucose intake, might prevent against the occurrence of unexpected hypoglycemia in VLBW infants following indomethacin therapy.     

Nitric oxide inhalation and nitric oxide synthase inhibitor supplement for endotoxin-induced hypotension

BACKGROUND: This study was performed to determine whether a combined therapy of nitric oxide (NO) inhalation and nitric oxide synthase (NOS) inhibitor is effective in experimental animals with endotoxin-induced refractive hypotension accompanied by pulmonary hypertension. METHODS: Escherichia coli lipopolysaccharide (1 mg/kg) was administered to 10 newborn piglets to induce endotoxemia. The experiment then began 60 min later, when the systemic arterial pressure dropped. The inhalation of 20 p.p.m. NO at 60 and 120 min of endotoxemia created a control group. Another group was also administered N w-nitro-L-arginine (L-NNA; 5 mg) after the first NO inhalation at 60 min of endotoxemia (the L-NNA group). Pulmonary arterial pressure, systemic arterial pressure and cardiac output were measured and compared among the groups. RESULTS: Three of the 5 piglets in the control group died of hypotensive shock, while in the L-NNA group the systemic arterial pressure recovered to pre-endotoxin administration levels. The L-NNA group produced a further increase in pulmonary arterial pressure against which NO inhalation was effective. CONCLUSION: Nitric oxide inhalation alone carries a potential risk of further lowering systemic arterial pressure in a piglet with hypotension induced by endotoxin, whereas the combined therapy resulted in the recovery of the blood pressure to pre-endotoxin levels. The combined therapy was simultaneously effective against pulmonary hypertension.     

Management of meconium-related ileus in very low-birthweight infants

BACKGROUND: Although administration of a water-soluble contrast enema has been recognized to be effective for meconium-related ileus, there have been no definitive management guidelines for very low-birthweight infants. METHODS: Between 1998 and 2004, 10 infants without cystic fibrosis were treated for meconium-related ileus at Toyohashi Municipal Hospital. Their treatment and clinical course were reviewed retrospectively. RESULTS: The average gestational age and birthweight of the 10 infants was 27 weeks and 788 g, respectively. The average age at initiation of treatment with a water-soluble contrast enema was 6.8 days. Intestinal obstruction was relieved by the enema in eight of 10 patients, while one underwent laparotomy and one died without any improvement of obstruction. In both neonates for whom the enema failed, rectal examination and rectal irrigation had been performed for several days before the enema was administered at the age of 14 and 15 days, respectively. In contrast, the enema was administered at the age of 1-11 days in neonates for whom this treatment was successful. Obstruction was relieved if the contrast medium reached the distal ileum, but enemas without reflux into the distal ileum failed to improve the obstruction. Contrast medium passed through the ileocecal valve to reach the distal ileum in all procedures done under fluoroscopy, but the medium failed to reach the ileum in most of the procedures done without fluoroscopy. CONCLUSION: Although administration of water-soluble contrast enemas can be effective for meconium-related ileus, reflux into the terminal ileum is essential for bowel obstruction to improve, so it is desirable to perform the procedure under fluoroscopic guidance.     

Polyethylene skin wrapping accelerates recovery from hypothermia in very low-birthweight infants

BACKGROUND: Thermal management of the very low-birthweight (VLBW) infant is a cornerstone of neonatology because thermal stress is an important determinant of survival. This prospective study was designed to determine the effects of polyethylene occlusive skin wrapping on heat loss in VLBW infants admitted to the neonatal intensive care unit (NICU) promptly after birth. METHODS: Thirty consecutively inborn infants weighing <1500 g were allocated to a wrap or non-wrap group within an incubator after admission to the NICU. Axillary and incubator temperatures were taken on arrival at 1 and 2 h. RESULTS: Infants in the wrap group reached a normal axillary temperature faster then non-wrap infants and required lower incubator temperatures. CONCLUSIONS: Polyethylene film wrapping effectively helps to correct hypothermia in VLBW infants admitted to the NICU.     

Nitric oxide further attenuates pulmonary hypertension in magnesium-treated piglets

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) commonly appears as a complication of several pulmonary and non-pulmonary diseases. The hypoxia possibly inhibits Ca2+ +/- dependent K+ channels, thus resulting in membrane depolarization of pulmonary smooth muscle cells, which leads to the opening of Ca2+ channels and Ca2+ entry, resulting in contraction of the vascular smooth muscle. However, magnesium (Mg2+) is an antagonist of Ca2+. We studied the effect of magnesium sulfate on the treatment of hypoxia-induced pulmonary hypertension and compared to the site of action of nitric oxide (NO). METHODS: Zero-day-old piglets were used in each experiment. The effects of Mg2+ were tested in each hypoxic, normoxic and hyperoxic states. Once the desired physical state was achieved, Mg2+ was administered at a dose of 100 mg/kg approximately every 10 min. In order to determine the exact mechanism of the Mg2+, Nw-nitro-l-arginine (LNNA), a NO synthase-inhibitor, was administered simultaneously with Mg2+ in some of the experiments. RESULTS: There was a significant correlation between the percent reduction of the pulmonary arterial pressure (PAP) caused by magnesium and the level of oxygen (O2) present in the pulmonary artery. The greatest amount of reduction was seen in the hypoxic condition where the least amount of O2 is found. A further reduction in the PAP was seen when NO was given at the end of the Mg2+ trials. There was no significant reduction seen in the systemic arterial pressure. CONCLUSIONS: Inhaled NO further reduced the PAP in piglets already treated with Mg2+.     

Antenatal steroid treatment prevents severe hyperkalemia in very low-birthweight infants*

BACKGROUND: Hyperkalemia is seen quite often in very low-birthweight (VLBW) infants and concentrations sometimes become high enough to cause cardiac arrhythmia. The purpose of the present study was to identify factors that increase serum concentrations of potassium in VLBW infants. METHODS: Retrospective comparative analysis was performed on 140 VLBW infants who had been admitted to the Toho University Perinatal Center between January 1993 and December 1999 and needed mechanical ventilation for respiratory distress. Serum concentrations of potassium at 24 and 48 h of age were compared in two groups of infants, those whose mothers did and did not receive antenatal steroid treatment. Risk factors for severe hyperkalemia were analyzed by multiple linear regression models and Pearson's partial correlation analysis. RESULTS: Antenatal steroid treatment reduced serum potassium concentrations significantly at 24 and 48 h, as well as the incidence of cardiac arrhythmia and necessity for glucose insulin treatment for severe hyperkalemia. Multiple linear regression showed the serum potassium concentration at 24 h of age was associated with antenatal steroid hormone treatment, 24 h fluid intake volume, serum sodium concentrations at 24 h, gestational weeks and sampling site. Serum concentration of potassium at 48 h of age was associated with blood urea nitrogen, gestational week, serum sodium concentration at 48 h of age and fluid intake between 24 and 48 h of age. Urine output volume and serum creatinine concentrations were not correlated with potassium concentrations at either age. CONCLUSION: Antenatal steroid hormone treatment can reduce early hyperkalemia in VLBW infants and also the incidence of cardiac arrhythmia and the use of glucose insulin treatment.     

Changes of the physiological parameters of very low-birthweight infants with chronic lung disease treated with dexamethasone

BACKGROUND: Dexamethasone is widely used for the treatment of chronic lung disease (CLD), but its mechanism of action is still not clearly understood. METHODS: Respiratory status, bodyweight, blood pressure, urine volume, fluid intake and nutrient intake were investigated in 12 infants with CLD during treatment with dexamethasone. RESULTS: The mean gestational age of the patients was 26.3 +/- 2.5 weeks and their mean birthweight was 807 +/- 232 g. Treatment with dexamethasone was started at a mean age of 41 +/- 23 days. The ventilatory index (VI) improved after treatment was started. Blood pressure and urine volume increased significantly after treatment, but weight gain was poor during this time. Fluid and nutrient intake did not change before and after treatment. The degree of improvement in the VI after treatment was significantly correlated with an increase in urine volume. CONCLUSIONS: The results suggest that a rise in blood pressure as a result of dexamethasone treatment and the subsequent diuretic effect of this rise may play a role in improvement in respiratory status.     

Three-year follow up of term and near-term infants treated with inhaled nitric oxide

BACKGROUND: The present study describes the outcome at 3 years in term and near-term infants treated with inhaled nitric oxide (iNO) for persistent pulmonary hypertension of the newborn (PPHN). METHODS: The study population consisted of 18 infants delivered at 34 weeks by best obstetric estimate who were admitted to the neonatal intensive care units with a diagnosis of PPHN. RESULTS: Eighteen infants (mean gestational age 38.5 +/- 2.6 weeks, mean birthweight 3015 +/- 587 g) were treated with iNO. The mean oxygenation index before iNO was 27.2 +/- 15.2. Responses to iNO were classified into three groups: (i) early response in eight infants; (ii) late response in two; and (iii) poor response in eight infants. Three infants died within seven postnatal days. Fifteen surviving infants were followed up to 3 years. The mean developmental scale was 98.4 +/- 9.0. One infant was diagnosed with severe neurodevelopmental disability due to cerebral palsy. Another infant was diagnosed with mild neurodevelopmental disability because of a low developmental scale. No infant showed significant hearing loss. Five infants had reactive airway disease (RAD) at 18 months, these infants required a significantly longer duration of mechanical ventilation in their neonatal period than non-RAD infants (P = 0.02). The frequency of survival with normal neurodevelopmental outcome was significantly higher in the early response group than the late or poor response groups (P = 0.03). CONCLUSION: In iNO-treated PPHN, mortality and neurodevelopmental outcome were associated with response to iNO, and pulmonary outcome was associated with duration of mechanical ventilation.     

Variable oxygenation response to inhaled nitric oxide in severe persistent pulmonary hypertension of the newborn

The causes of variable responsiveness to inhaled nitric oxide (NO) in Persistent Pulmonary Hypertension of the Newborn (PPHN) are unknown. The changes in the severity of respiratory failure after the onset of inhaled NO (maximal dose 20ppm) were studied in 13 consecutive neonates with severe PPHN. Response was defined as a sustained decrease of alveolar-arterial oxygen gradient (AaD0₂) by > 20%, or a decrease in oxygenation index (OI) by > 40%. Six neonates had a rapid response within 30min, three had an intermediate response within 8h, and three had a delayed response within 12 h after the onset of NO. Three infants with birth asphyxia responded rapidly to inhaled NO. One infant with sepsis did not respond, and two with suspected sepsis had a delayed response. The infants with Meconium Aspiration Syndrome and idiopathic PPHN had a variable response time. Twelve neonates required 4 to 14 days of mechanical ventilation and survived. Infants with PPHN may benefit from a trial of inhaled NO therapy that exceeds 30min. The variability of the response time to inhaled NO is likely to be multifactorial and dependent on the disease process associated with PPHN.     

Nitric oxide in preterm infant with pulmonary hypoplasia

Premature infants with hypoplastic lungs may have elevated pulmonary vascular resistance with right to left shunt across ductus arteriosus and/or foramen ovale. Inhaled nitric oxide (NO) being selective pulmonary vasodilator without significant effects on systemic circulation can potentially reverse this shunt. The authors herewith report a case of a premature infant with severe hypoxemic respiratory failure after preterm premature prolonged rupture of membranes leading to oligohydramnios and pulmonary hypoplasia that was treated successfully with NO and describe the neurodevelopmental outcome at 1 year of age.     

Contribution of pulmonary surfactant with inhaled nitric oxide for treatment of pulmonary hypertension

BACKGROUND: Combined therapy of inhaled nitric oxide (iNO) with pulmonary surfactant replacement was reported to improve oxygenation in patients or animal models of persistent pulmonary hypertension of the newborn with pulmonary surfactant deficiency lung. To evaluate the potential of iNO for the treatment of persistent pulmonary hypertension of the newborn, pulmonary arterial pressure (PAP) was measured during iNO before and after pulmonary surfactant replacement in an animal model of pulmonary hypertension with surfactant deficiency. METHODS: Seven newborn piglets were injected with L-nitro-arginine-methylester to produce an animal model of pulmonary hypertension. After PAP increased, iNO (30 p.p.m.) was introduced. Then iNO was stopped, and animals were subjected to lung lavage with saline. After recording the effect of iNO, all animals then received exogenous pulmonary surfactant installation. After surfactant treatment, iNO was again introduced. RESULTS: Pulmonary arterial pressure and systemic arterial pressure were increased significantly by >30% after infusion of L-nitro-arginine-methylester. During iNO only PAP was reduced significantly. Respiratory system compliance decreased significantly after lung lavage, and increased significantly after pulmonary surfactant replacement with concomitant increase of PaO2. In contrast, significant reduction of PAP with iNO before and after pulmonary surfactant replacement were also observed. The reduction ratios of PAP under each condition were 75.2 +/- 7.4%, 81.3 +/- 3.1%, and 79.1 +/- 5.3%, respectively (not significant among conditions). CONCLUSION: These results suggest that iNO is still a potent pulmonary arterial vasodilator even under pulmonary surfactant deficiency in an animal model of pulmonary hypertension.     

Nitric oxide in neonatal transposition of the great arteries

Three newborn infants with transposition of the great arteries (TGA) and intact ventricular septum (IVS) developed postnatal persistent pulmonary hypertension of the newborn (PPHN) and were successfully treated with inhaled nitric oxide (iNO). Intervention with balloon atrial septostomy (BAS) was performed in two of the infants before the iNO treatment, but they continued to be severely hypoxic with metabolic acidosis. However, the iNO immediately improved oxygenation and the clinical condition. The third neonate had a moderately large atrial communication and echocardiographic signs of PPHN. He received iNO before BAS with dramatic clinical improvement, which therefore postponed BAS.

Conclusion: Early diagnosis of PPHN and treatment with iNO may improve final outcome in neonates with TGA and IVS. In the presence of moderately large atrial communication and PPHN, treatment with iNO might be considered before BAS.     

Inhaled nitric oxide and extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) may occasionally require an invasive treatment with extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (NO) has recently been introduced as a selective pulmonary vasodilator for treatment of PPHN. We describe a case of PPHN in which neither inhaled NO nor ECMO was effective in reversing pulmonary hypertension. The clinical course of the patient suggested a potential role of NO inhalation in predicting the outcome of ECMO treatment for PPHN.     

Nitric oxide inhalation inhibits pulmonary apoptosis but not inflammatory injury in porcine meconium aspiration

To investigate the possible protective effects of nitric oxide (NO) inhalation in newborns with meconium aspiration, 18 10-12-d-old piglets were studied for 6h after an intratracheal bolus (3 ml/kg) of a 65-mg/ml mixture of human meconium. Twelve of the piglets were treated with continuous NO inhalation at a dose of 1 ppm ( n = 6) or 10 ppm ( n = 6), started 30 min before the insult. Pulmonary haemodynamics and systemic oxygenation were followed, and lung tissue samples were studied for signs of inflammation, evidence of ultrastructural injury and apoptotic cell changes. Inhalation of 10 ppm NO, in contrast to 1 ppm NO, significantly delayed the meconium-induced pulmonary pressure rise and the increase in intrapulmonary shunt fraction, and maintained better oxygenation in the piglets. Histologically and biochemically, treatment with 1 or 10 ppm NO inhalation did not protect the lungs against meconium-induced inflammatory injury. Further, ultrastructural lung tissue analysis revealed a significant amount of alveolar exudate and oedematous alveolar epithelium and endothelium after meconium instillation, also in the lungs treated with NO inhalation. However, the increase in apoptotic epithelial cell deaths, previously shown to be stimulated by intratracheal meconium, was significantly impeded after inhalation of 10 ppm. These results thus show that early continuous NO inhalation controls the rise in pulmonary artery pressure and improves the efficiency of arterial oxygenation, and further prevents the increase in epithelial apoptosis, but does not protect against early inflammatory damage caused by meconium aspiration.