Elevated pulmonary vascular resistance and poor ventilation-perfusion matching are commonly found in preterm infants with severe respiratory distress syndrome (RDS) and respiratory failure. Inhaled nitric oxide (iNO) can improve gas exchange and decrease pulmonary vascular resistance. This study was conducted to determine whether iNO therapy improves oxygenation in such infants.
Between July 2000 and 2006, 65 preterm infants (birth weight, <1500 g; gestational age, <31 weeks) with severe RDS and respiratory failure requiring mechanical ventilation and an oxygenation index (OI)⩾25 were randomly divided into two groups. Group A infants (n=32) received iNO therapy. iNO was started at a dose of five parts per million (p.p.m.). The maximal dose of NO was 20 p.p.m. Group B infants (n=33) did not receive iNO therapy, receive inhaled oxygen placebo only, was served as control group. Mechanical ventilation and iNO therapy were managed by neonatologists who were not involved in safety monitoring, data analysis and interpretation, or manuscript preparation. This study was randomized but not blinded.
The OI was significantly lower (P<0.01) in the iNO therapy group than in the control group at 30 min, 3, 12 and 24 h after initiating iNO therapy. Six infants in the iNO-treated group and 10 infants in the control group died. Post hoc analyses did not reveal any significant differences in the incidences of chronic lung disease (CLD), intracranial hemorrhage (ICH), patent ductus arteriosus (PDA), retinopathy of prematurity (ROP) or duration of intubation between the iNO-treated and the control groups.
We conclude that iNO therapy leads to an improvement in oxygenation without short-term side effects (such as pulmonary hemorrhage, intracranial hemorrhage, pneumothorax or acute deterioration) in premature infants with severe RDS and respiratory failure. However, iNO therapy does not significantly reduce mortality rate or the incidences of CLD, ICH, PDA or ROP.
Nitric oxide (NO) is an endogenous vasodilator that is responsible for regulating smooth muscle tone via changes in cyclic guanosine monophosphate.1 Inhaled NO (iNO) causes pulmonary vasodilation without affecting systemic vascular resistance.1 It has been reported that iNO therapy can improve oxygenation in neonates with persistent pulmonary hypertension of the newborn.2, 3 Inhaled nitric oxide (iNO) has also been used for the treatment of neonates with hypoxic respiratory failure.4, 5
Elevated pulmonary vascular resistance and poor ventilation-perfusion matching commonly exist in preterm infants with severe respiratory distress syndrome (RDS).6, 7 It has been reported that iNO therapy rapidly improves oxygenation and lowers pulmonary artery pressures in preterm infants7 and decreases the incidence of chronic lung disease (CLD) and death in premature infants with RDS.8 It has also been reported that iNO improves oxygenation in infants with severe CLD.9 Three large multicenter trials dealing with the use of iNO in preterm infants have been recently published.10, 11, 12 The National Institute of Child Health and Human Development Neonatal Network Trial showed iNO given to critically ill premature infants weighing ⩽1500 g did not decrease the mortality or the incidence of bronchopulmonary dysplasia (BPD); however, the mortality rates and incidence of BPD were reduced in infants with a birth weight ⩾1000 g.10 Ballard et al.11 reported that iNO therapy improved the pulmonary outcome in premature infants who were at risk of BPD when iNO therapy was initiated between 7 and 21 days of age. Kinsella et al.12 reported that among premature newborns with respiratory failure, low-dose iNO (5 p.p.m.) did not reduce the overall incidence of BPD, except among infants with a birth weight of at least 1000 g; however, it did reduce the overall risk of brain injury. Nevertheless, the role of iNO in preterm infants with hypoxemic respiratory failure remains controversial.13, 14 Hence, the purpose of this study was to determine the effect on oxygenation and safety of iNO therapy for preterm infants with severe RDS and respiratory failure.
Our goal was to evaluate the short-term effect of iNO on gas exchange over a 24-h time period in critically ill preterm neonates. Therefore, premature infants with RDS and respiratory failure (oxygenation index ⩾25) who were admitted to the neonatal intensive care unit (NICU) of our university hospital, were born at 31 weeks' gestational age or less, had a birth weight ⩽1500 g, and who required mechanical ventilation were eligible for inclusion.
Our primary outcome variable was the mean oxygenation index (OI) 24 h after randomization. We estimated that 32 patients were required in each group to have a 90% chance of detecting a 25% reduction in the mean OI (from 25 to 20), assuming a standard deviation of 6 for both groups, at the 5% level of significance using Student's t-test. Other secondary outcome variables, such as mortality rate, CLD, intracranial hemorrhage (ICH), patent ductus arteriosus (PDA) and retinopathy of prematurity (ROP) were also measured and analyzed on a post hoc basis. Between July 2000 and 2006, 65 preterm infants were enrolled and randomly divided according to a permuted-block design into two groups: one receive iNO and the other received placebo. Table 1 shows the baseline characteristics of both groups.
Infants with evidence of uncorrectable bleeding disorders, cerebral ultrasonographic evidence of severe ICH (Papile grades III or IV),15 severe congenital abnormalities or lethal chromosomal anomalies, were excluded from this study.
RDS was diagnosed clinically based on the presence of signs of respiratory distress, such as intercostal retractions, nasal alar flaring and expiratory grunting, as well as by chest X-rays showing severe diffuse reticulogranular infiltrates with low lung volumes. In our NICU, only premature infants with RDS who have chest X-ray findings of diffuse reticulogranular infiltrates, air bronchograms and a blurred diaphragm or heart during the first 24 h of life receive surfactant replacement therapy. Overall, 24 infants in the iNO-treated group and 23 infants in the control group received surfactant (Survanta, Ross Laboratories, Columbus, OH, USA) replacement therapy. Eight patients in the iNO-treated group and 10 patients in the control group whose chest X-rays showed a reticulogranular pattern without a blurred diaphragm or heart during the first 24 h of life subsequently worsened did not receive surfactant replacement therapy. All 65 of the studied infants with severe RDS and respiratory failure had an OI>25 at the beginning of this study. The OI was calculated as follows:
Inhaled nitric oxide dose and delivery
iNO was delivered into the inspiratory flow of the ventilator circuit using an iNO delivery system (Servo Ventilator 300 with NO, Siemens, Life Support System, Solna, Sweden). The device continuously sampled gas from the endotracheal side-port adapter and measured the NO and nitrogen dioxide levels using electrochemical monitors. iNO was started at a dose of 5 p.p.m. and was then weaned based on the response achieved within the first 6 h of treatment. A ‘positive’ oxygenation response consisted of a decrease in the OI by 25% or more, or a reduction in the FiO2 of 0.1 or more, while the PaO2 level was maintained above 50 mm Hg and the pH was >7.25. If a positive response occurred at 6 h, the dose of iNO was decreased by 1 p.p.m.; if this was tolerated, iNO dose reduction was continued in 1 p.p.m. steps every 6 h to a minimum dose of 1 p.p.m. If an infant had a small or no response, the dose of iNO was increased by 5 p.p.m. every 6 h to a maximum dose of 20 p.p.m. Patients in the control group were treated using synchronized intermittent mandatory ventilation (Servo Ventilator 300, Siemens, Life Support System, Solna, Sweden). All study infants received conventional mechanical ventilation; high-frequency oscillatory ventilation or high-frequency flow interruption was not used in this study. Arterial blood gas concentrations were measured before and 0.5, 3, 12, 24, 48, 72, 96 and 120 h after the start of iNO therapy. Serum methemoglobin levels were measured every 24 h while patients were receiving iNO therapy. If the concentration of NO2 exceeded 3 p.p.m. or the concentration of methemoglobin exceeded 5%, the iNO concentration was decreased. Mechanical ventilation and iNO therapy were managed by the neonatologists of our NICU who were aware of the treatment assignment; however, they were not involved in safety monitoring, data analysis and interpretation, or manuscript preparation.
Cranial ultrasound examinations were performed at the beginning of the study and at 12-h intervals during the intervention period. The echoencephalograms were graded according to the classification of Papile et al.15 CLD was defined as continued oxygen dependency for at least 28 days and beyond 36 weeks' postmenstrual age in patients whose chest X-rays showed persistent parenchymal lung disease.16 Pulmonary hemorrhage was defined as clinically significant, bloody tracheal secretions associated with a new pulmonary infiltrate and worsening pulmonary function. ROP was classified using the international classification scheme.17 Patent ductus arteriosus was diagnosed using color Doppler echocardiography (Sonos 1000, Hewlett-Packard, Andover, MA, USA) with 5.0 and 7.5 MHz transducers. A diagnosis of significant PDA was made based on echocardiographic evidence of a ductal left to right shunt with a left atrium to aortic root ratio ⩾1.3 or a ductal size ⩾1.5 mm. Necrotizing enterocolitis (NEC) was diagnosed based on the presence of characteristic clinical features (abdominal distension and gastrointestinal hemorrhage) with pneumatosis intestinalis, hepatobiliary gas or free intraperitoneal air on X-ray.
The values are expressed as the mean±s.d. Two-way analysis of variance was used to determine the main effect of treatment and time. If there was an interaction between treatment and time, Student's t-test with a Bonferroni correction was used to compare the mean difference in the OI between the two groups at each time point. The χ2-test was used to compare the incidence of complications between the iNO-treated and the control groups. SPSS 13.0 was used for all statistical analyses. The study was approved by the hospital ethics committee, and written informed consents were obtained from the parents of all of the infants.
Table 2 shows the OI changes in both the iNO-treated and the control infants, as well as the concentration of iNO delivered. At the beginning of the study, there was no significant difference in the OI between the iNO-treated (30.3±3.5) and the control groups (30.5±4.7). Thirty minutes after iNO therapy was initiated, the OI decreased significantly (P<0.01) in the iNO-treated group; however, there was no significant change in the control group. The OI values in the iNO-treated group were significantly lower (P<0.01) than in the control group 0.5, 3, 12 and 24 h after iNO therapy.
Table 3 shows the infants' outcomes. There were no significant differences in the duration of mechanical ventilation between the iNO-treated and the control groups. Six infants in the iNO-treated group and 10 infants in the control group died during the study. During the first 24 h, one patient died of severe ICH and one patient died of respiratory failure in iNO-treated group, whereas, two patients died of severe ICH and four patients died of respiratory failure in control group. During the 24 to 48 h period, one patient died of severe ICH and one patient died of respiratory failure in each group. One patient in each group died of respiratory failure during the 48 to 72 h period and 72 to 96 h period. On post hoc analysis, there were no significant differences (P>0.05) in the incidence of the secondary outcomes (CLD, ICH, PDA, ROP, pneumothorax, pulmonary hemorrhage, NEC, sepsis or periventricular leukomalacia) between the iNO-treated and the control groups.
During the study period, all infants in the iNO-treated group had serum methemoglobin levels that were less than 2.5% and NO2 concentrations that were less than 2 p.p.m.
NO is a colorless gas that is an endothelial-derived relaxing factor.18 iNO relaxes preconstricted pulmonary blood vessels without causing concomitant systemic hypotension. The selectivity of NO for pulmonary vasorelaxation relates to its direct action on pulmonary vascular smooth muscle and its rapid inactivation by hemoglobin.19
RDS is the most common cause of respiratory failure in preterm infants and is characterized by atelectasis due to surfactant deficiency.20 Several previous studies have reported elevated pulmonary vascular resistance in preterm in infants with severe RDS, and there is a correlation between pulmonary hypertension and poor outcome.21, 22, 23 Hypoxemia in RDS is predominantly the result of intrapulmonary shunting and poor ventilation-perfusion matching.7 In this study, we found that iNO facilitates an acute and sustained significant improvement in oxygenation in very low birth weight (VLBW) infants with severe respiratory failure without short-term side effects (such as pulmonary hemorrhage, ICH, pneumothorax or acute deterioration). Similar findings have been previously reported.7, 13 Taylor et al.24 have also reported that iNO at a dose of 5 p.p.m. in patients with acute respiratory distress syndrome results in significant improvements in oxygenation during the initial 24 h, with resolution by 48 h. It has been suggested that the improvement in oxygenation with iNO for premature infants with severe RDS and respiratory failure occurs by lowering pulmonary vascular resistance, reversing extrapulmonary shunting through selective pulmonary vasodilation and by a redistribution of pulmonary blood flow with enhanced ventilation-perfusion matching.25, 26 In premature lambs with RDS, iNO has been shown to improve gas exchange and reduce lung inflammation.27
In 2003, Schreiber et al.8 reported that iNO therapy in premature infants with mild RDS decreased the incidence of CLD and death. In this study, we did not find a significant difference in CLD between the iNO-treated and the control groups. Similar findings have been reported by others.6, 7 Treatment with iNO soon after birth and less severe RDS (median OI of 7.3) as reported by Schreiber et al.8 may account for the lower incidence of CLD in the iNO-treated than control groups. Field et al.,28 in the INNOVO trial, reported that iNO may prolong the duration of intensive care, costs were higher when using iNO as rescue therapy, and did not account for benefits in long-term morbidity or quality of life. They did not recommend iNO therapy for preterm infants with severe hypoxic respiratory failure. However, in their study, most of the patients were very ill with severe hypoxic respiratory failure, and iNO therapy was initiated relatively late in comparison to our study and most other similar studies; this may explain their patients' poor outcomes. It has been reported that iNO may cause platelet dysfunction.29 In this study, we did not find a significant difference (P<0.05) in ICH or pulmonary hemorrhage between the iNO-treated and the control groups. The same findings have also been reported elsewhere.6, 7 Other major safety concerns regarding the use of iNO therapy are methemoglobinemia and elevated NO2 levels. In this study, using low-dose NO (<20 p.p.m.) therapy, serum methemoglobin values were less than 2.5% and NO2 concentrations were less than 2 p.p.m. in all infants. The use of higher NO concentrations (80 p.p.m.) may result in methemoglobin and NO2 levels in excess of 5% and 3 p.p.m., respectively.2 When this occurs, the iNO concentration should be reduced, or iNO therapy should be discontinued.
This study was designed as a rescue therapy for premature infants with respiratory failure, not for prophylaxis of RDS or for the treatment of established BPD. The limitations of the present study include the small sample size, the involvement of a single center and the lack of long-term follow-up to assess pulmonary and neurodevelopmental outcomes. Although the mortality rates did not differ significantly (P>0.05) between the iNO-treated and the control groups in this study, there was a trend of fewer patients dying in the iNO-treated group (6 infants in the iNO-treated group and 10 infants in the control group). Elevated pulmonary vascular resistance and poor ventilation-perfusion matching are commonly found in VLBW infants with severe RDS and respiratory failure.21, 22, 23 Moreover, Mestan et al.30 have reported that premature infants treated with iNO have improved neurodevelopment outcomes at 2 years of age. We think that iNO therapy may play a role in the treatment of VLBW infants with progressive respiratory failure shortly after birth. We conclude that iNO therapy can result in short-term improvements in oxygenation in VLBW infant with severe RDS and respiratory failure. Post hoc analyses did not reveal any differences in mortality rate, CLD, ICH, PDA or ROP between the iNO-treated and the control groups in this study. Further research is needed to confirm the efficiency and safety of iNO given to VLBW infants with respiratory failure and long-term follow-up for neurodevelopmental outcomes are also needed.
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Cite this article
Su, P., Chen, J. Inhaled nitric oxide in the management of preterm infants with severe respiratory failure. J Perinatol 28, 112–116 (2008). https://doi.org/10.1038/sj.jp.7211881
- inhaled nitric oxide
- preterm infant
- respiratory distress syndrome
- oxygenation index
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