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Abstract

Background

Oxidative damage is important in the pathogenesis of respiratory distress syndrome (RDS). However, data on the effect of surfactant therapy on oxidative stress in vivo are limited. We aimed to evaluate the oxidant/antioxidant status in preterm infants with RDS via measurement of total antioxidant capacity (TAC) and total oxidant status (TOS), to determine the effect of surfactant on oxidant/antioxidant balance and to assess the association between TAC, TOS and clinical outcomes of the patients.

Methods

Sixty-nine infants with RDS were included. Blood samples for determining TAC and TOS were collected before and 48 h after surfactant treatment. TAC and TOS levels were analysed in serum. Patients were followed up until discharge or death.

Results

Post-surfactant TAC levels were significantly higher than pre-surfactant TAC levels (P = 0.029). TAC/TOS ratio significantly increased after surfactant treatment (P = 0.018). Infants <28 weeks of gestational age had lower levels of baseline TAC than those ≥28 weeks of gestational age (P = 0.020), whereas TOS levels were similar. Baseline TAC/TOS ratio was lower in infants who died in the study period than those who survived (P = 0.023). After controlling gestational age, baseline TAC levels were significantly and inversely correlated with the duration of total respiratory support (r = −0.343; P = 0.009) and hospitalization (r = −0.341; P = 0.009). TAC or TOS levels were not associated with the development of bronchopulmonary dysplasia or other complications as determined during the investigation period.

Conclusions

Oxidant–antioxidant balance shifts in favour of the antioxidant system after surfactant treatment. Lower TAC/TOS ratio in preterm infants may be associated with increased mortality.

Introduction

The mechanisms of tissue injury have not been completely elucidated in respiratory distress syndrome (RDS), but the involvement of oxidative damage due to reactive oxygen species (ROS) and reactive nitrogen species is important in the pathogenesis.^1,2 Preterm infants are more vulnerable to oxidative stress³ because intracellular antioxidant defense mechanisms including antioxidant enzymes increase dramatically during the last 40% of gestation and they have lower levels of plasma radical scavengers and metal-binding proteins (transferrin and ceruloplasmin), and reduced activity of antioxidant enzymes such as catalase and glutathione peroxidase. The imbalance between the oxidative forces and the antioxidant defense systems was suggested to predispose the lungs to the development of RDS.^4–8

Many studies have shown increased oxidant stress markers and/or reduced antioxidant defense in preterm infants with RDS,^9–17 although conflicting findings also exist in some studies that showed a similar oxidant and antioxidant status in preterm infants with or without RDS and full-term infants.^18–21 Lamb et al. ⁹ found increased levels of ortothyrosine, chlorotyrosine and nitrotyrosine, which are markers of oxidative damage, in bronchoalveolar fluid samples (but not in blood samples) of patients with RDS compared with normal healthy controls and ventilated controls without RDS. Huertas et al. ¹⁰ found hydroperoxide concentrations to be high in erythrocyte membranes at birth and in the initial days of life in premature infants. The erythrocyte membranes were also found to contain low levels and/or low activities of antioxidant defense mechanisms in premature newborns in comparison with full-term infants. Moison et al. ¹¹ found plasma allantoin and allantoin/uric acid ratio to be elevated in preterm infants on day 1 after birth and both markers of oxidative stress enabled early prediction of development of chronic lung disease (CLD). Boda et al. ¹² found the concentration of reduced glutathione (GSH) in the tracheal aspirate was also markedly decreased in infants with RDS. The concentration of oxidized glutathione (GSSG) and the ratio of GSSG to GSH were significantly higher in the severe cases and in those with an unfavourable prognosis.

Surfactant is the primary treatment for neonatal RDS. Surfactant was shown to reduce hyperoxia-induced lung damage in animal models.^22–24 In vitro studies have shown surfactant protein (SP)-A and SP-D to have potent, direct antioxidant properties. The surfactant proteins protect unsaturated phospholipids and growing cells from oxidative injury at physiological concentrations.²⁵ Dani et al. ²⁶ demonstrated superoxide dismutase (SOD) and catalase activities in four natural surfactants, as well as scavenger activity against hydrogen peroxide. However, data on the in vivo effect of surfactant on oxidant–antioxidant balance and association with clinical outcomes is limited. One previous study showed a decrease in both the GSSG concentration and in the GSSG/GSH ratio in the tracheal aspirate of newborns with RDS after surfactant treatment.¹² The primary aim of our study was to evaluate the oxidant/antioxidant status in preterm infants with RDS via measurement of total antioxidant capacity (TAC) and total oxidant status (TOS) and to determine the effect of surfactant on oxidant/antioxidant balance. The secondary outcome was to assess the association between TAC, TOS and clinical outcomes of the patients. Because the measurement of different oxidants and antioxidants separately is not practical, and their oxidant and antioxidant effects are additive, the TAC and TOS of the samples were measured as a reliable, sensitive and inexpensive direct measurement method. A new-generation, more stable, coloured 2,2′–azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS) was employed for the measurement of TAC. The relative antioxidant activities of individual antioxidants and their estimated contributions to TAC were reduced glutathione (52.9%), uric acid (33.1%), vitamin C (4.7%), total bilirubin (2.4%), vitamin E (1.7%) and others (5.2%).²⁷ The main components of serum TOS were hydrogen peroxide and lipid hydroperoxide.²⁸

Patients and methods

This study was performed in Zekai Tahir Burak Maternity and Teaching Hospital Neonatal Intensive Care Unit. Infants eligible for the study were those <37 weeks of gestational age and with the diagnosis of RDS clinically and radiologically. Infants with congenital heart disease and other lung diseases were excluded. Patient characteristics including gestational age, gender, birth weight, route of delivery, Apgar scores and pre-surfactant fraction of inspired oxygen levels were recorded. All the infants with RDS were treated with poractant-alfa (200 mg/kg for the initial dose, 100 mg/kg for the following doses if needed) within 12 h after birth as soon as RDS was diagnosed. Blood samples (1 mL) for determining the oxidant status were collected from the infants both before and 48 h after surfactant treatment. Serum samples were centrifuged and stored at −80°C until analysis.

Patients were followed up until discharge or death. The duration of intubation, nasal continuous positive airway pressure (CPAP), supplemental O₂ support with or without hood and total respiratory support (the sum of mechanical ventilation days + nasal CPAP days + O₂ support days with or without hood) were recorded, as well as the duration of hospitalization. The following complications were also assessed on follow-up: patent ductus arteriosus (PDA), intraventricular haemorrhage, pulmonary haemorrhage, bronchopulmonary dysplasia (BPD) and death.

RDS was diagnosed on the presence of typical clinical and radiological signs of the disease in the preterm infants. Babies were considered to have RDS if they had tachypnea, grunting and cyanosis within several hours of birth, required mechanical ventilation including CPAP and oxygen in the first hours of life, and typical radiographic findings on the chest X-ray.²⁹ BPD was diagnosed by using the US National Institutes of Health diagnostic criteria for BPD.³⁰ PDA diagnosis required an echocardiogram with Doppler verification and cardiology recommendation of ibuprofen therapy based on significance of flow.

TAC levels were measured by Erel's TAC method, which is based on the bleaching of the characteristic colour of a more stable ABTS by antioxidants. The results were expressed in mmol Trolox equiv./L. Serum thiol (total – SH group) content was measured by using dithionitrobenzoic acid.²⁷ ABTS was decolourized by antioxidants according to their concentrations and capacities. The change in colour was measured as a change in absorbance at 660 nm. TOS serum concentrations were measured using Erel's TOS method, which is based on the oxidation of ferrous ion to ferric ion in the presence of various oxidative species in acidic medium and the measurement of the ferric ion by xylenol orange.²⁸ Oxidants present in the sample oxidize the ferrous ion-o-dianisidine complex to ferric ion. The oxidation reaction is enhanced by glycerol molecules, which are abundantly present in the reaction medium. The ferric ion makes a coloured complex with xylenol orange in an acidic medium. The colour intensity, which can be measured spectrophotometrically, is related to the total amount of oxidant molecules present in the sample. The assay is calibrated with hydrogen peroxide and the results are expressed in terms of micromolar hydrogen peroxide equivalent per litre (μmol H₂O₂ Equiv./L). Erel's TAC and TOS methods are colourimetric and automated and the precision of this assay is lower than 3%.

Informed parental consent was obtained for all study infants and the study protocol has been approved by the institute's committee on human research.

Statistical analysis

Descriptive analysis was performed for demographic and clinical characteristics of the patients. A student's t-test or Mann − Whitney U test was used for comparison of numeric variables between two groups and Wilcoxon test for dependent variables. A Chi-square test was used for comparison of ratios between the groups. A Spearman's test was used for correlation analysis. Partial correlation analysis was used to control for confounding factors in correlation analysis. Statistical analysis was performed with SPSS 13.0 (Chicago, IL, USA) and statistical significance was set at P less than 0.05.

Results

Between August 2008 and June 2009, 69 preterm infants with RDS were included in the study. Patient characteristics are shown in Table 1.

Table 1

Patient characteristics (n = 69)

Gender (male/female), n (%)	43 (62)/26 (38)
Gestational week (median, range)	29 (25–36)
Birth weight (g) (median, range)	1165 (620–2750)
Maternal age (median, range)	28 (19–40)
1st minute Apgar score (median, range)	5 (1–7)
5th minute Apgar score (median, range)	7 (3–9)
Pre-surfactant FiO₂ (median, range)	76 (40–100)
Route of delivery
(Caesarean section/vaginal), n (%)	54 (78)/15(22)
Multiple pregnancy, n (%)	31 (45)
Surfactant administration, n (%)
Once	52 (75)
Twice	14 (20)
Three times	3 (5)
Antenatal steroid use, n (%)	41 (59)
Pre-eclampsia, n (%)	5 (7)
Chorioamnionitis, n (%)	0
Early membrane rupture, n (%)	7 (10)

FiO_2, fraction of inspired oxygen

All the patients were intubated and surfactant was applied within the first 12 h after birth. Pre-surfactant TAC and TOS levels were also obtained in this period and post-surfactant levels 48 h thereafter; both are shown in Table 2. Post-treatment TAC levels were significantly higher than pre-treatment TAC levels (P = 0.029). Post-treatment TOS levels were similar with pre-treatment TOS levels. TAC/TOS ratio also significantly increased after surfactant treatment (Table 2).

Table 2

Pre- and post-surfactant TAC and TOS levels and TAC/TOS ratios of infants with RDS

	Pre-surfactant	Post-surfactant	P
TAC mmol Trolox equiv./L (mean ± SD)	1.834 ± 0.28	1.972 ± 0.17	0.029
TOS μmol H₂O₂/L (mean ± SD)	49.087 ± 29.01	42.254 ± 26.56	0.282
TAC/TOS (mean ± SD)	0.051 ± 0.029	0.073 ± 0.055	0.018

TAC, total antioxidant capacity; TOS, total oxidant status; RDS, respiratory distress syndrome; SD, standard deviation

Infants <28 weeks of gestational age (n = 18) had lower levels of baseline TAC than those ≥28 weeks of gestational age (1.68 ± 0.34 versus 1.89 ± 0.29, P = 0.020). TOS levels (54.2 versus 53.3, P = 0.926) and TAC/TOS ratio (0.050 versus 0.045, P = 0.527) were similar between the groups. Baseline TAC and TOS levels were not correlated with gender, route of delivery, birth weight or Apgar scores.

Among all patients, the median duration of mechanical ventilation was three days (range 1–26 d), total respiratory support was 11 d (range 1–86 d) and hospitalization was 31 days (range 1–130 d). After controlling for gestational age, baseline TAC levels were significantly and inversely correlated with duration of total respiratory support (partial correlation analysis, r = −0.343; P = 0.009) and with duration of hospitalization (partial correlation analysis, r = −0.341; P = 0.009).

Regarding the complications observed on follow-up, baseline TAC and TOS levels were not associated with subsequent rates of BPD, intraventricular haemorrhage, pulmonary haemorrhage or PDA. Thirteen patients developed BPD and 11 patients died on follow-up. Baseline TAC/TOS ratio was lower in infants who died in the study period than those who survived (median TAC/TOS ratio 0.028 versus 0.043, respectively, P = 0.023). TAC/TOS ratio was not associated with development of BPD, IVH, pulmonary haemorrhage or PDA.

Discussion

In this study, we have assessed the oxidant/antioxidant status of preterm infants with RDS. We have found lower levels of TAC in younger infants, and a significant increase in TAC levels and TAC/TOS ratio after surfactant treatment. Lower baseline TAC levels were associated with longer duration of respiratory support and hospitalization. A lower baseline TAC/TOS ratio was associated with a higher rate of death.

The rapid transition of the fetus from a relatively hypoxic to a relatively hyperoxic environment at birth gives rise to oxidative stress. However, oxidant defense mechanisms are induced late in gestation.^7,31 Antioxidant enzyme systems are upregulated primarily during the latter part of gestation. Non-enzymatic antioxidants cross the placenta in increasing quantities during the same timeframe, as reviewed previously.³ The exposure of the preterm lung to increased oxygen, which is often necessary for survival, contributes to excessive production of ROS in the respiratory system. Thus, premature infants are more vulnerable to this oxidative stress. We have found lower levels of TAC in infants <28 weeks of age compared with those ≥28 weeks of age, showing the immaturity of the antioxidant defense system in younger infants. We found TOS levels to be similar between the groups. Although this finding is in conflict with the majority of the previous studies, comparable studies also exist. In one study, cord blood antioxidant enzyme activities were found to be lower in preterm infants than in full-term infants whereas lipid peroxidation markers were similar.³² The differences in results might be secondary to the site and timing of the measurement and the component assessed.

The highly reactive oxidant species led to damage to cellular macromolecules including proteins, carbohydrates, lipids and nucleic acid as well as surfactant. The resulting damage promotes inflammation. ROS also have important effects on different lung cells as regulators of signal transduction, activators of key transcription factors and modulators of gene expression and apoptosis, resulting in a number of inflammatory pulmonary diseases including RDS.¹ TAC and TOS indicate a shift in anti-oxidant balance without detailing which oxidant or antioxidant is involved. TOS may reflect increased inflammation as toxic oxygen and nitrogen radicals are formed by activated phagocytes such as neutrophils. One of the defenses against these radicals is the intracellular enzyme SOD, which dismutates the extremely toxic superoxide radical into potentially less toxic hydrogen peroxide. Catalase and glutathione reductase then convert the H₂O₂ to H₂O. Pulmonary surfactant normally contains significant amounts of SOD and catalase. We have not assessed levels of catalase and SOD in our study but both probably contribute to TAC and TOS levels.

The toxic oxygen and nitrogen derivatives produced during oxidant stress have high chemical reactivity and damage cellular macromolecules including surfactant. If exogenous surfactant is given, this may also be destroyed.³³ However, data on the effect of surfactant treatment on oxidant/antioxidant status in neonatal RDS are limited. We have found a significant increase in serum TAC levels and TAC/TOS ratio after surfactant treatment. Surfactant improves gas exchange and oxygenation and subsequently decreases the need for oxygen supplementation, thus reducing oxidant insult. Decreased oxygen support after surfactant may have alleviated the deleterious effects of oxygen on the oxidant/antioxidant balance. Dani et al. ²⁶ have demonstrated that commercial natural surfactants showed measurable SOD and catalase activities, which differed between surfactants, likely due to their different origins and preparation procedures. All studied surfactants exhibited scavenger activity against H₂O₂ with poractant, which was used in this study, and beractant having the highest antioxidant effect. Poractant is a modified natural surfactant from porcine origin and contains the highest amount of plasmalogens, which are antioxidant phospholipids and may offer protection against oxidative stress.³⁴ Therefore, an antioxidant shift in our study might also be secondary to endogenous antioxidant activity of the surfactant itself.

The aetiology of BPD is unknown, but a growing body of evidence denotes the importance of the oxidant/antioxidant system in the pathogenesis, as reviewed previously.³⁵ Even low oxygen concentrations may result in significant oxidant stress in preterm infants with underdeveloped antioxidant defenses. We have found no association between baseline TAC or TOS levels and BPD risk. A number of studies have shown markers of increased peroxidation in tracheal lavage fluid and urine of infants who later developed BPD.^36,37 Ogihara et al. ¹⁵ have found increased levels of allantoin, which is an oxidant molecule and a marker of free radical generation, and increased allantoin/urate ratio in infants with severe RDS who later developed CLD compared with those who did not. Another study showed that while infants developing BPD typically exhibited increased concentrations of including elastase, myeloperoxidase, xanthine oxidase and catalase enzyme activities in the epithelial lining fluid during the first week of life, those infants with simple RDS displayed low, uniform or decreasing values of these oxyradical inflammation markers over this interval.¹⁷ However, controversial results are also present on the prediction of BPD risk by using oxidative markers in the pertinent literature. Ballard et al. ³⁸ found an association between the development of BPD and baseline protein carbonyl concentration but not 3-nitrotyrosine concentration in preterm infants. However, the same investigators had previously found elevated levels of 3-nitrotyrosine in infants who developed BPD.³⁹ Winterbourn et al. ⁴⁰ could not find a correlation between plasma carbonyl concentrations and CLD development. Hamon et al. ²⁰ also could not find a significant relationship between spot levels of early oxidative stress markers and post-natal clinical outcome but malondialdehyde evolution over a 24-h period was significantly correlated with respiratory outcome. The measurement of oxidative biomarkers was performed in different timepoints (within 12 h after birth in our study versus 14 h to 21 d in various studies^20,38,41,42), which may also account for the different results as the levels of these markers may increase or decrease over time.²⁰ Ahola et al. ⁴³ showed that erythrocyte-glutathione concentration decreased during the first week of life whereas erythrocyte-cysteine concentration increased significantly from day 3 to day 7 in preterm infants with a birthweight of 500–1500 g. Farkas et al. ¹⁶ found an eight-fold increase in haeme oxygenase-1 gene expression in the preterm infants with RDS on the fifth day as compared with the first day after birth. May et al. ⁴² showed that end tidal carbon monoxide levels on day 14, but not on day 3, significantly predicted BPD development. In summary, blood/tracheobronchial fluid levels of various oxidants/antioxidants seem to be altered compared with controls but probably the site and timing of measurements, type of the assays used and extremely reactive and transient nature of the ROS measured account for the different results obtained in these studies.⁹ Finally, the factors involved in CLD development are numerous, complex and interactive, including immature lung structure, deficient antioxidant defenses, infections, nutrition, treatment procedures, etc.^44,45 Therefore, it is unlikely that one spot measurement of any mediator can predict BPD development but serial measurements, particularly in tracheobronchial samples, may be helpful in discriminating a high-risk group.

We have assessed the association of TAC and TOS levels with clinical outcomes of the patients and found that lower baseline TAC levels were associated with longer duration of respiratory support and hospitalization. Lower baseline TAC/TOS ratio was associated with higher rate of death. Gestational age, birth weight, severity of initial disease as reflected by Apgar scores and lowest pH in the first 12 h are well-recognized prognostic indicators in newborns with RDS. Various additional factors were determined in clinical studies, including immediate response to surfactant in terms of change in the arterial:alveolar ratio before and after surfactant,⁴⁶ ventilator parameters and⁴⁷ improvement of pulmonary aeration in chest X-rays.⁴⁸ Our results suggest that baseline TAC of preterm infants might also serve as a prognostic factor. Partial correlation analysis showed that association between the duration of respiratory support/hospitalization and TAC levels was independent from gestational age.

In conclusion, surfactant treatment increases antioxidant status of newborns with RDS. TAC level and TAC/TOS ratio might have prognostic value in preterm infants with RDS and might help distinguish high-risk infants. Whether these parameters have an independent prognostic value in combined analysis with other variables or whether they might be predictive for treatment response to antioxidant therapies remain to be elucidated. Further, more detailed studies of the effect of surfactant therapy on oxidant–antioxidant balance in various stages of the post-natal period may lead to development of new treatment strategies.

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: The ethics committee of Zekai Tahir Burak Maternity Teaching Hospital approved this study (Reference number: 24.03.2009/40).

Guarantor: None.

Contributorship: EAD, NU, SO researched literature and conceived the study. EAD, FNS, OE and UD were involved in protocol development, gaining ethical approval, patient recruitment and interpretation data analysis. EAD wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Acknowledgements: None.

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Total antioxidant capacity and total oxidant status after surfactant treatment in preterm infants with respiratory distress syndrome

Abstract

Background

Methods

Results

Conclusions

Introduction

Patients and methods

Statistical analysis

Results

Discussion

DECLARATIONS

References