| 摘要: | 早產兒的Chronic Lung Disease (CLD) 目前仍是Respiratory Distress Syndrome (RDS)治療後最主要的complication，此病發生後，對整個家庭及社會的精神及經濟負擔非常的大。雖然發生的真正mechanism 尚未完全清楚，許多研究證明發炎(inflammation)在CLD 的早期機轉中，占有很重要地位。同時有許多研究告訴我們，此發炎現象，在早產兒生下不久，用了呼吸器之後，很快就發生。所以要預防CLD，任何治療皆須要很早就開始。我們幾年來的研究，告訴我們，早期靜脈注射dexamethasone 四星期，可有效的抑制發炎現象，可減少CLD 的發生。(PEDIATRICS 1997., 100, No 4 and J. of ped. 1990.,171,No 2),(Appendix I-Ⅱ)。然而，早期使用 dexamethasone，亦帶來許多副作用，其中，感染及敗血病是最主要的合併症，也會造成死亡率的增加。同時我們亦作了長期追蹤研究(Pediatrics, 1998,101:917,and New Eng J. Med 2004,36:1304), (Appendix Ⅲ-Ⅳ)。在早期Dexamethasone 治療的小孩，Psychomotor delay(輕中度)的發生率比較高，同時對身高及體重亦有影響，因此，我們在此提一種新的治療方式。 Budesonide 是一種inhaled glucocorticoid,有很強的局部抗發炎效果，Budesonide 為水溶性，與Surfactant 混合後，在一定範圍的比例，不會影響Surfactant 的Surface tension reducing property，因此，Budesonide 用Surfactant 當Vehicle不會影响surfactant的功能，同時可容易達到肺部的周邊單位(peripheral units)， Budesonide 吸收後，很快被肝臟代謝掉。因此，此新的治療方法，對肺部的局部抗炎性(local anti-inflammatory effect)會增強，而全身性的副作用(Systemic side effects)會比較小。我們先期的研究(pilot study) (Pediatrics,May 2008),(AppendixⅤ)，發現用surfactant當引導(vehicle)，Budesonide注入肺部後、呼吸功能及血中的氧氣(PO2) 及二氧化碳(PCO2) 皆顯著的改善。容易拔掉氣管，CLD及死亡率都降低，同時副作用少。然而，因為我們的病人數目不多，統計學上，尚無法完全肯定效果及證明完全沒有副作用。因此，提出一個全國性多中心的合作研究計劃（National Collaborative Study）。我們以500-1500 公克的早產兒，有嚴重的Respiratory Distress Syndrome (RDS)，並生下4 小時內須用呼吸器者，且FIO2 > 0.6的早產兒，作為研究的對象。病人將雙盲的分二組，第一組為治療組(treated group) ─ 接受Surfactant (survanta Abbott, 100 mg/kg/dose) 及 Budesonide (0.25 mg/kg) ； 第二組為對照組(control group) ─ 接受Surfactant (survanta Abbott, 100 mg/kg/dose)及空氣，每一組都每8小時治療一次，直到小孩的FIO2小於0.3或不須使用呼吸器。本研究最終的目的，在評估懷孕後36 週(36 weeks postconceptional age)，有沒有CLD 或死亡的發生率。目前在台灣，合乎本研究對象的早產兒，CLD 或死亡的頻率約為60%，如果我們預期經過治療後，發生的頻率減少到40%，同時準予5% Type I error 及10% Type II error，則每組約需130 case，我們暫定每組須150人，二組共300人，因此須要多中心合作研究，時間約4年。研究當中，我們會觀察所有可能發生的合併症。我們亦測定tracheal aspirate 內的發炎物質以及CLD 及死亡的發生頻率，同時作2-3年的神經及智力追蹤。本研究預估在4年內完成，我們預期，利用此新的治療方法，Budesonide 可以很均勻的分佈到整個肺部的周邊單位，就如注入 Surfactant 一樣。同時可以用比較少的surfactant及glucocorticoid的劑量，比較少的治療時間，達到局部抗炎效果，並且減少短期及長期的副作用。
KEYWORD: Premature infant, Chronic Lung Disease, Surfactant, Budesonide, Respiratory Distress Syndrome (RDS) Growing evidences suggest that pulmonary inflammation plays an important role in the early development of chronic lung disease (CLD) in preterm infants on mechanical ventilation. There are also evidences suggesting that this inflammation occurs very early in postnatal life or even in intrauterine life. Thus, any therapy to be beneficial in preventing CLD, it should be started very early, e.g. shortly after birth. Our previous double-blind study showed that early (< 12 hours) postnatal use of intravenous dexamethasone therapy for 4 weeks significantly suppress pulmonary inflammatory reaction and significantly reduced the incidence of CLD (PEDIATRICS, 1997; 100, No 4. and J. of Ped.1990; 171:No2) (appendixⅠ-Ⅱ). However, the use of dexamethasone was associated with increased incidence of infection and sepsis that may affect immediate outcome and contribute significantly to increased mortality. Our follow-up study (Pediatrics,1998;101:917 and New Eng J Med. 104;35:1304) (appendix Ⅲ-Ⅳ) also suggested an increase in incidence of psychomotor delay (mild to moderate degree) associated with dexamethasone therapy. In view of these results, we would like to propose a new therapeutic regimen. We hypothesize that Budesonide, a strong local anti-inflammatory glucocorticoid, can be directly instill into the lungs through endotracheal tube, using surfactant as “vehicle”. Budesonide, following absorption, undergoes an extensive biotranformation during the first pass metabobism in the liver to metabolites of low glucocorticoid activity. As compared to intravenous administration, this therapeutic regimen will provide more local anti-inflammatory effect and less systemic side effects. Since Budesonide is water soluble, it would not affect much on the surface tension property of surfactant once it is mixed with surfactant, as demonstrated from our invitro study. The results of our pilot study indicated that, following this new therapeutic regimen, the blood gases and acid- base balance improved, and more infants were extubated in the treated group as compared to control (PEDIATRICS 2008)(appendix Ⅴ). The incidence of CLD and/or death was also lower in the treatment group. There was no immediate side effects noted. However our sample size was not large enough to rule out all side effects. Further more, the hypothetical successful rate in this pilot study was too high to be realistic. More infants is needed. To include more infants for the study, a national collaborative study is therefore proposed. Infants will be eligible for the study if their birth weight are between 500-1500 gm and if they have severe respiratory distress syndrome requiring mechanical ventilation shortly after birth (< 4 hours). After informed consent is obtained, infant will be randomly assigned to two groups based on a double-blind design. Group I (treated) will received surfactant (survanta® Abbott, 100 mg/kg/dose), and Budesonide (0.25 mg/kg/dose) and group II (control) will receive surfactant (Survanta® Abbott, 100 mg/kg/dose) and similar volume of air. Therapy will be given every 8 hrs until the infants require FIO2 < 0.3 or are extubated. In order to deliver surfactant and Budesonide together, the surfactant and Budesonide will be gently mixed before endotracheal instillation. The end point of assessment is the combined incidence of CLD and death judged at 36 weeks postconceptional age and the long term neurological and cognitive outcome at 2-3 years. The incidence of CLD and death in the selective group of infants is about 60%. Using this 60% incidence in the placebo group and an expected 40%(33% improvement) in the treated group, 130 infants in each group is needed to detect a difference, permitting 5% chance of type I error and 10% of type II error. The safe target number in each group will be 150(total 300 infants). This would require 10 years study period in our hospital. A multicenters collaborative study is therefore proposed. All infants will be observed for possible side effects and for long term neurological and cognitive outcome at 2-3 years of age. Tracheal aspirates for various inflammatory mediators will also be assessed. We expect that, by using this therapeutic regimen, Budesonide can be effectively administered to the lungs, and just like surfactant, it will uniformely distribute to the peripheral lung units. The local lung inflammation can be suppressed and CLD can be prevented. The systemic side effects, should be minimal and be less than systemic administration. |
