| Objectives:Plenty of reasons could lead to premature birth, such as premature rupture of membrane, infection, maternal diseases and uterine malformation. The lower the birth weight and gestational age of the preterm infants, the higher the mortality rate. As the neonatal intensive care unit(NICU) has been widely established for the past few years, the curative rate of preterm infants is remarkably improved. Lots of low birth weight or very low birth weight preterm infants are able to survive. Preterm infants tend to have respiratory distress syndrome because of developmental immaturity of the alveoli and low production of pulmonary surfactant, which is one of the most common causes of death in preterm infants. As a rescue therapy, mechanical ventilation could improve the gas exchange rapidly. Nevertheless, mechanical ventilation could cause plenty of complications in premature infants because of the lung imaturity, such as pneumothorax, pneumorrhagia, infection.Nasal continuous positive airway pressure(NCPAP), one mode of non-invasive ventilation, could reduce the occurrence rate of respiratory complications caused by mechanical ventilation. However, part of the preterm infants still failed to respond to NCPAP. The observation has led to efforts to find better methods of non-invasive ventilation for those infants who cannot manage with NCPAP alone. Nasal intermittent positive pressure ventilation(NIPPV) is one such technique, which has been used in several forms. NIPPV was proven to decrease extubation failure prominently, and to be more effective for the treatment of apnea in preterm infants in precious literature.Helium-oxygen mixture(heliox) has been proposed as a medical therapy for pulmonary obstructive diseases. The physical properties of heliox have been reported to be beneficial in different pediatric diseases, such as athma, bronchiolitis and croup. Some animal experiments showed that helium had protective effects on heart and brain during ischemia-reperfusion injury. In addition, helium also exerts effects in the lungs, the immune system, and the blood vessels. Heliox has complementary effects with used with non-invasive ventilation. Indeed, the combination of heliox and non-invasive ventilation can even be considered synergistic. The aim of our study was to assess the effectiveness of NIPPV with heliox on length of ventilation(Lo V), lung inflammation cytokines and myocardial enzymes in preterm infants with RDS.Methods:1. ParticipantsInclusion criteriaInfants with a gestational age of <37 weeks with a diagnosis of RDS and required a fraction of inspired oxygen(Fi O2) ≧0.3 to maintain Pa O2 >50 mm Hg and oxygen saturation >88% in the first hour after birth were eligible for the study. The diagnosis of RDS was based on clinical manifestations and chest radiograph findings.Exclusion criteriaInfants were excluded from this study if met any of the following criteria: pneumonia, meconium aspiration, major congenital anomalies, intubation in the delivery room, transient tachypnea without evidence of RDS, consent not provided or refused and severe respiratory failure or frequent apnea requiring endotracheal intubation.The clinical trial has got the approval of the institutional ethical committee of Daping Hospital, Third Military Medical University, China. The informed consent form was signed by parents before enrollment.2. InterventionAll eligible participants were randomly assigned to receive heliox or air oxygen mixture(airox) according to random number table by blinded personnel, using a closed-envelope method. All infants were supported with NIPPV using Fabian neonatal ventilator. The control group received NIPPV with airox(30% oxygen) provided by the central wall supply. Heliox group was treated with NIPPV for 3 hours with heliox delivered from 40-L cylinders containing a mixture of 70% helium and 30% oxygen, followed by airox until ventilation support was no longer needed.Clinical characteristics such as birth weight, gestational age, gender, maternal pregnancy diseases, antenatal steroids, cesarean section, gravidity, parity and Apgar score were recorded. The main outcome was the length of ventilation(Lo V) to wean from the ventilator successfully with minimal work of breath. The secondary outcomes were changes in transcutaneous pressure of oxygen and carbon dioxide(Tc PO2 and Tc PCO2), lung inflammation cytokines(interleukin-6, tumor necrosis factor-α, myeloperoxidase, malonyldialdehyde and inducible nitric oxide synthase), myocardial enzymes(creatine kinase and creatine kinase-isoenzyme MB), intubation rate. Tc PO2 and Tc PCO2 were measured at baseline, 1h, 2h and 3h of the treatment. Interleukin-6 and myocardial enzymes were collected at baseline and 3 hours of the administration. The other laboratory test data were collected at 3 hours.The occurrence of patent ductus arteriosus, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia were also recorded.3. Statistical analysisAll the data were analyzed with an alpha level set at 0.05 using SPSS 17 software. The independent-samples t test was used to analyze the measurement data. As for categorical data, Chi-squared test was used to detect the difference between heliox group and airox group. 2-way analysis of variance with repeated measures was used to analyze repeated measurement data. Multiple linear regression and correlation analysis was used to correlation test. The difference was considered to be of statistical significance when P<0.05.Results:1. Participant flow303 infants of RDS were admitted to NICU from December 2012 to August 2013. During the period, 64 infants were diagnosed with RDS. 28 were not fit for inclusion criteria and excluded based on the exclusion criteria. The remaining 36 neonates were allocated to the treatment and randomly assigned to heliox group(n=19) and control group(n=17).2. Baseline characteristicsClinical characteristics such as birth weight, gestational age, gender, maternal pregnancy diseases, antenatal steroids, cesarean section, gravidity, parity and Apgar score were not statistically significant. The two groups had comparable clinical characteristics at birth and prenatal conditions(P>0.05).3. Length of ventilationHeliox administration significantly decreased Lo V of the patients(39.29 hours vs 57.8 hours,P=0.02).4. Intubation rateThree infants had to receive MV in the control group(17%) because of respiratory failure 24 hours after weaning from NIPPV successfully, while there’s none in the heliox group(P=0.10).5. Transcutaneous blood gas analysisBoth Tc PO2 and Tc PCO2 improved after 3 hours in each group(P<0.001).The difference of Tc PO2 and Tc PCO2 was not statistically significant at each time point(P>0.05). Carbon dioxide elimination was better in the heliox group than in control group(10.39 mm Hg vs 6.0mm Hg, P=0.03).6. Interleukin-6There were no statistical significance between heliox and airox group in the analysis of interleukin-6(P>0.05), but the values of interleukin-6 showed a prominent reduction in the heliox group after 3 hours(P=0.001).7. Lung inflammation cytokines and myocardial enzymesAlthough the values of myocardial enzymes in the heliox group showed a notable reduction after 3 hours, analysis of creatine kinase and creatine kinase-isoenzyme MB were not statistically significant between heliox and airox group(P>0.05).8. Correlation analysisLo V was found to be significantly and positively correlated with interleukin-6 at baseline(r=0.474, P=0.006), but the difference is not statistically significant in heliox group and airox group separately(r=0.362, P=0.128 vs r=0.452, P=0.069).9. Complications and adverse effect7 patients in the heliox group(36.8%) and 5 patients in the control group(29.4%) were diagnosed with patent ductus arteriosus, while 3 patients in the heliox group(15.8%) and 1 patients in the control group(5.9%) were diagnosed with necrotizing enterocolitis. There were no statistically significant differences in both groups(P>0.05). There were no cases of retinopathy of prematurity, intraventricular hemorrhage, periventricular leukomalacia and bronchopulmonary dysplasia in both groups.The infants were well tolerated and vital signs were stable in the whole study. No side effects were found in the whole study.Conclusions:Either airox or heliox combined with NIPPV could improve hypoxemia and hypercapnia of preterm infants with RDS. Meanwhile, the pulmonary ventilation functions and gas exchange of the patients were also improved. NIPPV combined with heliox had been more advantageous in shortening Lo V of preterm infants of RDS, and the Lo V was found to be positively correlated with IL-6 at baseline. Heliox inhalation could improve the efficiency of carbon dioxide clearance and correct the retention of carbon dioxide prominently. No further cardiac and pulmonary protection was demonstrated during the heliox inhalation. Heliox was well tolerated during the study and proved to be safe for the infants. |
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