臺灣博碩士論文加值系統

摘要：呼吸窘迫症後群（RDS）目前仍是造成早產兒死亡率及罹病率的主因。合併使用氣管內灌注皮質類固醇（corticosteroid）與表面張力素（surfactant）治療嚴重RDS，可不經體循環，在不增加全身性副作用的情況下，不僅可有助肺泡擴張，還可緩解肺部發炎狀況。將十二隻新生乳豬以生理食鹽水重複灌洗肺部，使肺部表面張力素耗盡以模擬新生兒RDS狀態，然後將之隨機分配至對照組（標準氣管內灌注表面張力素—Survanta 100 mg/kg）或Budesonide（Bude）組（氣管內灌注Budesonide 0.25 mg/kg與Survanta 100 mg/kg的混合懸浮液）。檢驗血液樣本，觀察期為24小時。結果顯示，與對照組相比，Bude組的血氧功能隨時間顯著較佳（p=0.016）。Bude組的發炎細胞激素（proinflammatory cytokine）介白素-1 β（interleukin-1 β）呈現下降趨勢，但與對照組之間並無顯著差異（p > 0.05）。比較兩組之間組織學的肺損傷程度，Bude組不論在仰臥時下半肺葉（dependent）或仰臥時上半肺葉（non-dependent）部位，都比對照組來的顯著較低（p < 0.05）。
結論：利用Budesonide合併表面張力素以氣管灌注法治療患有RDS的新生乳豬，似乎可持續改善24小時後其肺部預後。

Summary: Severe respiratory distress syndrome (RDS) is still a major cause of mortality and morbidity in premature infants. The combined use of intratracheal corticosteroid and surfactant in severe RDS, which bypasses the systemic circulation, may not only help recruit the lungs but also alleviates pulmonary inflammation without an increase in systemic adverse effects. Twelve newborn piglets received repeated pulmonary saline lavage to create surfactant depleted lungs that mimic neonatal RDS, and then were randomly grouped into a control group (standard intratracheal instillation of surfactant-Survanta 100 mg/kg); and a Budesonide (Bude) group (intratracheal instillation with the mixed suspension of Budesonide 0.25 mg/kg and Survanta 100 mg/kg). Blood samples were examined, and the observation period was 24 hr. The results showed that oxygenation was significantly better in Bude group compared to the control group over time (P ¼ 0.016). The proinflammatory cytokines tumor necrosis factor-a and interleukin-1 b showed a reduced trend in the Bude group, but was not significantly different from the control group (P > 0.05). Comparing the histological lung injury scores, the Bude group had a significantly lower score than the control group at both dependent and non-dependent sites (P < 0.05). In conclusion, in piglets with severe RDS, intratracheal instillation of Budesonide in addition to surfactant seems to results in a sustained improvement　in pulmonary outcome over 24 hr.

目錄
目錄……………………………………………………………………….i
表目錄………………………………………………………………..….iii
圖目錄……………………………………………………………………iv
致謝………………………………………………………………….……v
中文摘要…………………………………………………………………..vi
英文摘要……………………………………………………………..…...vii
英文縮寫………………………………………………………………....viii
第一章 緒論 .......................................1
第一節 呼吸窘迫症候群治療方式.....................2
第二節 氣管內灌注法..............................3
第三節　本實驗設計的概念和假說.....................4

第二章 研究方法................................................4
第一節 材料與方法..............................5
第二節 實驗動物的準備...........................5
第三節 生理監測................................6
第四節 引發肺部表面張力素缺乏....................6
第五節 實驗設計................................6
第六節 細胞激素分析.............................7
第七節 統計分析................................7
第三章 結果...........…………...................9
第四章 討論.. .................................11
第五章 結論....................................16


參考文獻 ..........................................25
表目錄
表一：控制組（Control）和實驗組（Bude）於誘發急性肺損傷前後之生命徵象、血液氣體分析變化和與發炎相關的細胞激素變化之比較。.....................................................19
表二：控制組（Control）和實驗組（Bude）肺損傷程度評分：肺泡發炎程度、肺泡出血程度、肺間質發炎 程度、肺間質出血程度、肺水腫、肺塌陷、和壞死程度。...............................................20
表三 :已發表之研究使用皮質類固醇氣管灌注治療急性肺損傷：以動物模式研究為主。.............................................21
圖目錄
圖一：控制組（Control）和實驗組（Ｂude）在ＰaO2、PaCO2、pH於２４小時觀察中變化之比較。................................22
圖二：控制組（Control）和實驗組（Bude）比較蘇木紫（hematoxylin）與伊紅（eosin）染色。利用光學顯微鏡檢驗放大２００倍切片,　可看出在控制組（Control）損傷變項包括肺泡與間質性發炎、肺泡與間質性出血、肺塌陷以及壞死程度均較明顯。.............................23
圖三：控制組（Control）和實驗組（Bude）比較蘇木紫（hematoxylin）與伊紅（eosin）染色。利用光學顯微鏡檢驗放大２００倍切片,　可看出在控制組（Control）損傷變項包括肺泡與間質性發炎、肺泡與間質性出血、肺塌陷以及壞死程度均較明顯。............................24

1. Engle WA, American Academy of Pediatrics Committee on Fetus and Newborn. Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics 2008;121:419-432.
2. American Academy of Pediatrics, Committee on Fetus and Newborn. Surfactant replacement therapy for respiratory distress syndrome. Pediatrics 1999;103:684–685.
3. Soll R, Ozek E. Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2010;(1):CD001079.
4. Soll RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2000;(2):CD000511.
5. Corbet A, Bucciarelli R, Goldman S, Mammel M, Wold D, Long W. Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: a multicenter controlled trial. American Exosurf Pediatric Study Group I. J Pediatr 1991;118:277–284.
6. Pierce MR, Bancalari E. The role of inflammation in the pathogenesis of bronchopulmonary dysplasia. Pediatr Pulmonol 1995;19:371–378.
7. Henderson-Smart DJ, Cools F, Bhuta T, Offringa M. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev 2007;(3):CD000104.
8. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97:210-215.
9. Nimmo AJ, Carstairs JR, Patole SK, Whitehall J, Davidson K, Vink R. Intratracheal administration of glucocorticoids using surfactant as a vehicle. Clin Exper Pharmcol Physiology 2002;29:661-665.
10. Chen CM, Fang CL, Chang CH. Surfactant and corticosteroid effects on lung function in a rat model of acute lung injury. Crit Care Med 2001;29:2169-2175.
11. Yang CF, Jeng MJ, Soong WJ, Lee YS, Tsao PC, Tang RB. Acute pathophysiological effects of intratracheal instillation of budesonide and exogenous surfactant in a neonatal surfactant-depleted piglet model. Pediatr Neonatal 2010;51:219-226.
12. Shah V, Ohlsson A, Halliday HL, Dunn MS. Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database Syst Rev 2007;(4):CD001969.
13. Askin DF, Diehl-Jones W. Pathogenesis and prevention of chronic lung disease in the neonate. Crit Care Nurs Clin North Am 2009;21:11-25.
14. Stevens TP, Blennow M, Myers EH, Soll R. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev 2007;(4):CD003063.
15. Kuo HT, Lin HC, Tsai CH, Chouc IC, Yeh TF. A Follow-up Study of Preterm Infants Given Budesonide Using Surfactant as a Vehicle to Prevent Chronic Lung Disease in Preterm Infants. J Pediatr 2010;156:537-541.
16. Rademaker KJ, de Vries LS, Uiterwaal CS, Groenendaal F, Grobbee DE, van Bel F. Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up. Arch Dis Child Fetal Neonatal Ed 2008;93: 58-63.
17. Yeh TF, Lin HC, Chang CH, Wu TS, Su BH, Li TC, Pyati S, Tsai CH. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics 2008;121:e1310-e1318.
18. Schulzke SM, Pillow JJ. The management of evolving bronchopulmonary dysplasia. Paediatr Respir Rev 2010;11:143-148.
19. Vermont Oxford Network Steroid Study Group. Early postnatal dexamethasone therapy for the prevention of chronic lung disease. Pediatrics 2001;108:741-748.
20. Buimer M, van Wassenaer AG, Kok JH. Postnatal administration of dexamethasone for weaning off the ventilator affects thyroid function. Neonatology 2008;94:164-169.
21. Shah SS, Ohlsson A, Halliday H, Shah VS. Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants. Cochrane Database Syst Rev 2007;(4):CD002057.
22. Dani C, Corsini I, Burchielli S, Cangiamila V, Longini M, Paternostro F, Buonocore G, Rubaltelli FF Natural surfactant combined with beclomethasone decreases oxidative lung injury in the preterm lamb. Pediatr Pulmonol 2009;44:1159-1167.
23. van 't Veen A, Gommers D, Mouton JW, Kluytmans JA, Krijt EJ, Lachmann B. Exogenous pulmonary surfactant as a drug delivering agent: influence of antibiotics on surfactant activity. Br J Pharmacol 1996;118: 593-598.
24. Haitsma JJ, Lachmann U, Lachmann B. Exogenous surfactant as a drug delivery agent. Adv Drug Deliv Rev 2001:47:197-207.
25.Jeng MJ, Lee YS, Soong WJ. Effects of perfluorochemicals for intrapulmonary vancomycin administration and partial liquid ventilation in an animal model of meconium-injured lungs. Pediatr Neonatal 2007;48:309-316.
26. Jeng MJ, Soong WJ, Lee YS, Chang HL, Shen CM, Wang CH, Yang SS, Hwang B. Effects of therapeutic broncho-alveolar lavage and partial liquid ventilation on meconium aspirated newborn piglets. Crit Care Med 2006;34:1099-1105.
27. Jeng MJ, Soong WJ, Lee YS. Effective lavage volume of diluted surfactant improves the outcome of meconium aspiration syndrome in newborn piglets. Pediatr Res 2009;66:107-112.
28. Jeng MJ, Kou YR, Sheu CC, Hwang B. Effects of exogenous surfactant supplementation and partial liquid ventilation on acute lung injury induced by wood smoke inhalation in newborn piglets. Crit Care Med 2003;31:1166-1174.
29. Jian MY, Koizumi T, Tsushima K, Yokoyama T, Kubo K, Baba A. Exogenous surfactant instillation attenuates inflammatory response to acid-induced lung injury in rat. Pulm Pharmacol Ther 2010;23:43-47.
30. Halliday HL, Ehrenkranz RA, Doyle LW. Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 2009;(1):CD001145.
31. Leite-Junior JH, Garcia CS, Souza-Fernandes AB, Silva PL, Ornellas DS, Larangeira AP, Castro-Faria-Neto HC, Morales MM, Negri EM, Capelozzi VL, Zin WA, Pelosi P, Bozza PT, Rocco PR. Methylprednisolone improves lung mechanics and reduces the inflammatory response in pulmonary but not in extrapulmonary mild acute lung injury in mice. Crit Care Med 2008;36:2621-2628.
32. Meduri G, Golden E, Freire A. Methylprednisolone infusion in early severe ARDS. Chest 2007;131:954-963.
33. Steinberg K, Hudson L, Goodman R. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-1684.
34. Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2009;(1):CD001146.
35. Todd DA, Marsh MJ, George A, Henderson NG, Barr H, Sebastian S, Clark GT, Koster G, Clark HW, Postle AD. Surfactant phospholipids, surfactant proteins, and inflammatory markers during acute lung injury in children. Pediatr Crit Care Med 2010;11:82-91.
36. Mokra D, Mokry J. Glucocorticoids in the treatment of neonatal meconium aspiration syndrome. Eur J Pediatr 2011;170:1495-505.
37. Cullen AB, Cox CA, Hipp SJ, Wolfson MR, Shaffer TH. Intracheal delivery of gentamicin with partial liquid ventilation. Respir Med 1999;93:770-778.
38. Mokra D, Mokry J, Drgova A, Petraskova M, Bulikova J, Calkovska A. Intratracheally administered corticosteroids improve lung function in meconium-instilled rabbits. J Physiol Pharmacol 2007;58:389-398.
39. Jeng MJ, Soong WJ, Chiou SY, Wu YT, Tsai TH, Lin CC, Yang CF, Tsao PC, Lee YS. Efficacy of intratracheal instillation of a meropenem/perfluorochemical suspension in acute lung injury. Pediatr Pulmonol 2011 Aug 3. doi: 10.1002/ppul.21523. [Epub ahead of print].
40. Mokra D, Drgova A, Mokry J, Bulikova J, Pullmann R, Durdik P, Petraskova M, Calkovska A. Combination of budesonide and aminophylline diminished acute lung injury in animal model of meconium aspiration syndrome. J Physiol Pharmacol 2008;59:461-471.
41. Mokra D, Mokry J, Drgova A, Bulikova J, Petraskova M, Calkovska A. Single-dose versus two-dose dexamethasone effects on lung inflammation and airway reactivity in meconium-instilled rabbits. J Physiol Pharmacol 2007;58:379-387.
42. Fajardo C, Levin D, Garcia M, Adrams D, Adamson I. Surfactant versus saline as a vehicle for corticosteroid delivery to the lungs of ventilated rabbits. Pediatr Res 1998;43:542-547.
43. Pan NY, Hui WS, Tipoe GL, Taylor GW, Leung RY, Lam WK, Tsang KW, Mak JC. Inhibition of pyocyanin-potentiated IL-8 release by steroids in bronchial epithelial cells. Respir Med 2006; 100:1614-1622.
44. Borchard G, Cassara ML, Roemele, PEH, Florea BI, Junginer HE. Transport and local metabolism of budesonide and fluticasone propionate in a human bronchial epithelial cell line (calu-3). J Pharm Sci 2002;91:1561- 1566.
45. Miller-Larsson A, Mattsson H, Hjertberg E, Dahlbäck M, Tunke A, Brattsand R. Reversible fatty acid conjugation of budesonide: novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998;26:623- 630.
46. Roubliova XI, Van der Biest AM, Vaast P, Lu H, Jani JC, Lewi PJ, Verbeken EK, Tibboel D, Deprest JA. Effect of maternal administration of betamethasone on peripheral arterial development in fetal rabbit lungs. Neonatology 2008;93:64-72.