Oxygen Toxicity to the Immature Lung—Part II: The Unmet Clinical Need for Causal Therapy
Abstract
:1. The Global Disease Burden of Bronchopulmonary Dysplasia after Preterm Delivery
2. Oxygen Requirements of the Preterm Infant
3. ROS-Induced Injury to the Immature Lung as a Key Driver of BPD
3.1. Underdeveloped ROS Defense Mechanisms
3.2. Cell Death Induction
3.3. Inflammation
3.4. Epigenetic Modifications
4. Clinical Approaches to Prevent ROS-Induced Lung Injury and BPD
4.1. Antioxidants
4.2. Enzymatic Therapy
4.3. Trace Elements as Enzyme Cofactors
4.4. Anti-Inflammatory Drugs
5. Unmet Needs and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Intervention | Study Design | Study Population | Primary Outcome | Effect on BPD/Lung Injury | Reference |
---|---|---|---|---|---|
Vitamin A (supplementation vs. control, placebo, or no supplementation) | Cochrane Database Syst Rev. included trials (RCTs): 11 | n = 1580 BW ≤ 1500 g or GA ≤ 32 | death (at 28 days and at hospital discharge) chronic lung disease (defined as oxygen use at 28 days or 36 weeks PMA) death or chronic lung disease | small benefit in reducing the risk of chronic lung disease (RR 0.87; 95% CI 0.77–0.99) | [56] |
Vitamin E (supplementation vs. either placebo, no treatment, or another type, dose, or route of administration | Cochrane Database Syst Rev. included trials (RCTs): 26 | n = 2028 GA < 37 or BW < 2500 g | mortality, combined outcome at 18 months including mortality | no effect on BPD (RR 0.91; 95% CI 0.73–1.14) or mortality until discharge (RR 0.97; 95% CI 0.83–1.14) | [63] |
DHA | RCT | n = 1273 GA ≤ 27 | BPD (physiological basis, oxygen-saturation monitoring at 36 weeks PMA or discharge) | no effect on BPD (RR 1.13; 95% CI 1.02–1.25; p = 0.02) | [67] |
NAC (supplementation vs. placebo) | RCT | n = 391 BW 500–999 g | death or BPD (supplementary oxygen requirement at 36 weeks PMA) | no difference in the combined incidence of death or BPD (OR 1.0; 95% CI 0.7–1.6) | [65] |
Caffeine (high vs. low dose) | Meta-analysis Included trials (RCTs): 6 | n = 816 GA < 34 | mortality during the first admission, BPD (at 36 weeks CA), cerebral palsy | fewer cases of BPD (RR 0.76; 95% CI 0.60–0.96); quality of the evidence was low due to imprecision of the estimates | [69] |
iNO (supplementation vs. control with or without placebo) | Cochrane Database Syst Rev. included trials (RCTs): 17 | n = 4062 | death before hospital discharge BPD (oxygen dependence at 36 weeks PMA) death or BPD (at 36 weeks PMA) IVH (any grade and more severe, grades 3 and 4) | early routine use of iNO in preterm infants with respiratory disease does not improve survival without BPD (RR 0.89; 95% CI 0.76–1.04) later use of iNO to prevent BPD could be effective, but the current 95% CI included no effect; the effect size is likely small (RR 0.92; CI 0.85–1.01) and requires further study | [70] |
Intervention | Study Design | Study Population | Primary Outcome | Effect on BPD/Lung Injury | Reference |
---|---|---|---|---|---|
r-h CuZnSOD (supplementation vs. placebo) | RCT | n = 302 BW 600–1200g GA ≥ 24 | death or BPD (oxygen dependency at 28 days of life, with a chest radiograph with an Edwards score ≥3) at 28 days of life | no differences in BPD or death incidence (p = 0.11), treatment at birth may reduce early pulmonary injury, with improved clinical status when measured at 1-year corrected age | [71] |
Surfactant (animal-derived treatment vs. control treatment in RDS infants) | Cochrane Database Syst Rev. included trials (RCTs): 13 | GA < 37 | neonatal mortality (mortality <28 days of age) from any cause mortality prior to hospital discharge (from any cause) BPD (oxygen requirement at 28 to 30 days of age) BPD or death prior to 28 days of age chronic lung disease (use of supplemental oxygen at 36 weeks PMA) chronic lung disease (use of supplemental oxygen at 36 weeks PMA) or death prior to 36 weeks PMA | significant decrease in BPD or death at 28 days of age (RR 0.83; 95% CI 0.77–0.90) no significant impact on BPD alone (RR 0.95; 95% CI 0.84–1.08) | [6] |
iNO+surfactant vs. iNO alone | RCT | n = 511 GA < 28 | survival at 36 weeks PMA without BPD (evaluated by physiological oxygen/flow reduction) | no differences on BPD at 36 weeks PMA (95% CI 0.75–1.28; p = 0.89) | [79] |
Selenium (supplementation vs. control) | RCT | n = 534 BW < 1500g | oxygen dependency at 28 days and total days oxygen dependency | no data on BPD no effect on O2 dependency at 28 days (RR 0.97; 95% CI 0.80–1.18) | [80] |
Intervention | Study Design | Study Population | Primary Outcome | Effect on BPD/Lung Injury | Reference |
---|---|---|---|---|---|
Postnatal corticosteroids (early, <8 d) (supplementation vs. placebo or control) | Cochrane Database Syst Rev. included trials (RCTs): 32 | n = 4445 GA < 37 | mortality BPD (at 28 days of life, at 36 weeks PMA, and at 36 weeks PMA in survivors) death or BPD (at 28 days of life and at 36 weeks PMA) long-term outcomes | early corticosteroids reduced the incidence of BPD at 28 days of life (RR 0.87; 95% CI 0.81-0.93) and at 36 weeks PMA (RR 0.79; 95% CI 0.72–0.87) | [82] |
Postnatal corticosteroids (late, >7 d) (supplementation vs. placebo or control) | Cochrane Database Syst Rev. included trials (RCTs): 21 | n = 1424 | chronic lung diesease (mortality and/or BPD at 36 weeks PMA) | reduction of BPD (RR 0.77; 95% CI 0.67–0.88) and combined outcome death or BPD (RR 0.77; 95% CI 0.70–0.86) | [83] |
early (within 24 h after birth) inhaled budesonide (supplementation vs. placebo) | RCT | n = 863 GA > 23 < 28 | death or BPD (confirmed by means of standardized oxygen-saturation monitoring at a 36 weeks PMA) | death or BPD was lower in the budesonide group, but the advantage may have been gained at the expense of increased mortality (RR 0.86; 95% CI 0.75–1.00; p = 0.05; OR 0.71; 95% CI 0.53–0.97) | [85] |
intratracheal administration of surfactant/budesonide vs. surfactant alone | Clinical trial | n = 265 BW < 1500 g | death or BPD (supplemental oxygen at 36 weeks PMA) | lower incidence of BPD or death in intervention group (RR 0.58; 95% CI 0.44–0.77; p < 0.01) | [87] |
Vitamin D (birth levels in BPD infants vs. control) | Meta-analysis, included trials: 8 | n= 909 | BPD (oxygen dependency at either 28 days of age or 36 weeks PMA) | BPD was associated with vitamin D deficiency at birth (OR 2.405; 95% CI 1.269–4.560; p = 0.007) and low levels at birth (standardized mean difference −1.463; 95% CI −2.900–0.027; p = 0.046) | [88] |
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Behnke, J.; Dippel, C.M.; Choi, Y.; Rekers, L.; Schmidt, A.; Lauer, T.; Dong, Y.; Behnke, J.; Zimmer, K.-P.; Bellusci, S.; et al. Oxygen Toxicity to the Immature Lung—Part II: The Unmet Clinical Need for Causal Therapy. Int. J. Mol. Sci. 2021, 22, 10694. https://doi.org/10.3390/ijms221910694
Behnke J, Dippel CM, Choi Y, Rekers L, Schmidt A, Lauer T, Dong Y, Behnke J, Zimmer K-P, Bellusci S, et al. Oxygen Toxicity to the Immature Lung—Part II: The Unmet Clinical Need for Causal Therapy. International Journal of Molecular Sciences. 2021; 22(19):10694. https://doi.org/10.3390/ijms221910694
Chicago/Turabian StyleBehnke, Judith, Constanze M. Dippel, Yesi Choi, Lisa Rekers, Annesuse Schmidt, Tina Lauer, Ying Dong, Jonas Behnke, Klaus-Peter Zimmer, Saverio Bellusci, and et al. 2021. "Oxygen Toxicity to the Immature Lung—Part II: The Unmet Clinical Need for Causal Therapy" International Journal of Molecular Sciences 22, no. 19: 10694. https://doi.org/10.3390/ijms221910694