探討高濃度氧氣及呼吸器對早產兒之影響

蔡文暉

doi:10.6844/NCKU.2014.02007

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探討高濃度氧氣及呼吸器對早產兒之影響

Effect of hyperoxia and mechanical ventilation on premature infants

蔡文暉 , Ph.D　　Advisor：林秀娟;張文粲　　

英文 DOI： 10.6844/NCKU.2014.02007

自噬作用；肺支氣管發育不全；高濃度氧氣；機械式呼吸；神經發展預後；早產兒； autophagy ； bronchopulmonary dysplasia ； hyperoxia ； mechanical ventilation ； neurodevelopmental outcome ； premature infant

Abstract │ Reference (144) │ Altmetrics

Abstract 〈TOP〉

機械式呼吸合併使用高濃度氧氣常常用來治療有不成熟肺部的早產兒。然而，機械式呼吸不可避免的會傷害肺部並且可能造成早產兒的肺支氣管發育不全。肺支氣管發育不全的特徵是肺部發育受損導致肺泡較大而數目較少，並且常常需要長期的呼吸支持。造成肺支氣管發育不全的因素包括:高濃度氧氣造成的氧氣毒性，機械式呼吸，周產期感染/發炎，和肺部不成熟。
    為了研究氧氣毒性對肺支氣管發育不全的貢獻，第一個研究分析高濃度氧氣造成肺部傷害的致病機轉。我們發現高濃度氧氣會抑制A549肺上皮細胞的增殖並且導致細胞周期停滯，有趣的是，高濃度氧氣不止會導致A549細胞壞死並且會引發細胞的自噬作用。高濃度氧氣會增加細胞內的反應性氧族並且改變粒線體的膜電位。抗氧化劑N-乙醯-L-半胱胺酸可以減輕高濃度氧氣造成的A549細胞死亡。最後我們證實在新生鼠動物模式中高濃度氧氣也可以觀察到細胞的自噬作用。如果自噬作用是細胞在壓力下趨向存活的一種反應，我們的研究在臨床上有機會可以發展成對發育中的肺部受到高濃度氧氣傷害時的保護策略，例如，早產兒的肺支氣管發育不全。
    很多研究指出肺支氣管發育不全與較差的神經發展預後有相關，為了進一步探討造成肺支氣管發育不全的因素對早產兒神經發展預後的影響，第二個研究使用一個全國性的大型資料庫並且回溯追踪10年來研究使用機械式呼吸的天數與1998到2001年間出生的超低出生體重早產兒(出生體重<1,000公克)各種發展性疾病的關係。在此期間共有728位在第一次住院期間沒有被診斷為腦損傷或局部性的腦部疾患的超低出生體重早產兒，分成三組(使用呼吸器的天數：≦ 2, 3-14, ≧ 15天)。經過醫療資料的校正後，使用機械式呼吸 ≧ 15天的超低出生體重早產兒比使用機械式呼吸 ≦ 2天者有較高的機會得到腦性麻痺(校正風險比: 2.66; 95%信賴區間: 1.50 - 4.59; p < 0.001)及注意力不足過動症(校正風險比: 1.95; 95%信賴區間: 1.02 - 3.76; p < 0.05) 。然而，自閉症以及智能不足的風險在3組間則沒有明顯的差異。我們的結論是超低出生體重早產兒，即使沒有明顯的腦部損傷，使用機械式呼吸 ≧ 15天，就會增加腦性麻痺以及注意力不足過動症的機會。因此，發展出一個可以即時因應大腦的血液動力學以及氧氣變化的呼吸支持策略，有機會可以進一步改善超低出生體重早產兒的神經發展預後。

Parallel Abstract 〈TOP〉

Mechanical ventilation with hyperoxia is often needed to treat premature infants with immature lungs. However, mechanical ventilation inevitably damages the lungs and causes bronchopulmonary dysplasia (BPD) in some premature infants. BPD is characterized by larger and fewer alveoli due to impaired lung development and usually requires prolonged respiratory support. The possible contributing factors of BPD include oxygen toxicity, mechanical ventilation, perinatal infection/inflammation, and immaturity of the lungs.
To investigate the contribution of oxygen toxicity to BPD, the first study was to analyze the mechanism underlying hyperoxia-induced lung injury. We found that hyperoxia inhibited proliferation and induced cell cycle arrest in A549 pulmonary epithelial cells. Interestingly, hyperoxia induced not only necrotic cell death but also an autophagic response in A549 cells. Moreover, hyperoxia increased intracellular reactive oxygen species and altered mitochondrial membrane potential. The antioxidant N-acetyl-L-cysteine attenuated hyperoxia-induced cell death in A549 cells. Finally, the hyperoxia-induced autophagic response was confirmed in a neonatal rat model of acute lung injury. If autophagy is a prosurvival response of cells under stress, our findings may have clinical implications for the development of protective strategies against hyperoxia-induced injury in the developing lung, such as BPD in the premature infants.
Many studies have pointed out that BPD is associated with poorer neurodevelopmental outcomes. To explore the underlying mechanism of BPD that may contribute to the neurodevelopmental impairment in premature infants, the second study, which used a large nationwide database, investigated in a 10-year retrospective follow-up the association between the duration of mechanical ventilation and the risk for various developmental disorders in extremely low birth weight (ELBW) (< 1,000 g) infants born between 1998 and 2001. Seven hundred twenty-eight ELBW infants without diagnoses of brain insults or focal brain lesions in the initial hospital stay were identified and divided into three groups (days on ventilator: ≦ 2, 3-14, ≧ 15 days). After adjusting for demographic and medical factors, the infants in the ≧ 15 days group had higher risks for cerebral palsy (CP) (adjusted hazard ratio: 2.66; 95% confidence interval: 1.50-4.59; p < 0.001) and attention-deficit/hyperactivity disorder (ADHD) (adjusted hazard ratio: 1.95; 95% confidence interval: 1.02-3.76; p < 0.05), than did infants in the ≦ 2 days group. The risk for autism spectrum disorder (ASD) or intellectual disability (ID) was not significantly different between the three groups. We conclude that mechanical ventilation for ≧ 15 days increased the risk for CP and ADHD in ELBW infants even without significant neonatal brain damage. Developing a brain-protective respiratory support strategy in response to real-time cerebral hemodynamic and oxygenation changes has the potential to improve neurodevelopmental outcomes in ELBW infants.

Reference ( 144 ) 〈TOP〉

Albertine, K.H., Jones, G.P., Starcher, B.C., Bohnsack, J.F., Davis, P.L., Cho, S.C., Carlton, D.P., and Bland, R.D. (1999). Chronic lung injury in preterm lambs. Disordered respiratory tract development. American Journal of Respiratory and Critical Care Medicine 159, 945-958.
連結：
Alexandrou, G., Martensson, G., Skiold, B., Blennow, M., Aden, U., and Vollmer, B. (2014). White matter microstructure is influenced by extremely preterm birth and neonatal respiratory factors. Acta Paediatrica 103, 48-56.
連結：
Anderson, P.J., and Doyle, L.W. (2006). Neurodevelopmental outcome of bronchopulmonary dysplasia. Seminars in Perinatology 30, 227-232.
連結：
Aruoma, O.I., Halliwell, B., Hoey, B.M., and Butler, J. (1989). The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biology and Medicine 6, 593-597.
連結：
Asikainen, T.M., and White, C.W. (2004). Pulmonary antioxidant defenses in the preterm newborn with respiratory distress and bronchopulmonary dysplasia in evolution: implications for antioxidant therapy. Antioxidants & Redox Signaling 6, 155-167.
連結：

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