机械通气对肺组织和全身炎症反应的影响
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摘要
创伤、感染等刺激不但可引起局部器官损伤，而且可产生大量炎性介质，引起全身或局部炎症反应，将导致多器官组织的功能障碍。机械通气对于治疗呼吸衰竭等肺部疾病具有重要作用。但机械通气亦可导致许多并发症，如呼吸机引起的肺损伤(Ventilator induced lung injury，简称VILI)。早期大都认为是气压伤(barotrauma)和容量伤(volutrauma)导致了VILI。生物伤(biotrauma)概念的提出，认为机械通气时肺泡的过度扩张、反复开放与关闭时产生的剪切力以及局部肺的塌陷能促发显著的炎症反应，进一步引起炎症级联反应。过度的炎症反应不仅可引起或加重局部肺组织损伤，而且可发展成全身炎症反应综合征(SIRS)，导致远隔部位组织器官的损伤。而保护性通气，如小潮气量通气和适当PEEP的运用对减轻或者防止VILI的发生发展有重要作用。
细胞因子是由多种细胞产生的内源性多肽，作为细胞免疫和炎性反应间的信号传递物质，它可促进炎症细胞的活化浸润，在VILI
硕士学位论文
及引mH的发生及发展中起重要作用。其中白细胞介素－6门乃）；
是一个在机体防御、急性期反应、免疫反应和造血反应等过程中起
重要作用的多功能蛋白，和 TNF－。、IL＜等在机体爆布样炎症反
应的产生和全身炎症反应的发生发展、在器官功能损伤的发生中起
重要作用；是全身炎症反应发生和发展的敏感和特异性较高的监测
指标。本实验采用不问PEEP 不同潮气量机械通气模式，观察肺
组织病理变化和血浆几乃水平的变化。
研究目的
观察不同PEEP、不同潮气量机械通气对健康小猪肺组织病理
变化和血浆IL乃水平的影响；比较不问陀P、不问潮气量机械通
气对肺局部和全身炎症反应的影响；研究机械通气对肺组织及全身
脏器功能损伤的机理；探讨小潮气量结合适当PEEP对肺的保护作
用；为临床治疗提供理论依据。
材料与方法
15只普通雄性健康小猪；体重门6．8。2．3）kg；随机等分为
3组：A组（VT－7 ml／kg，PEEP－scmH20）；B组（VT－7 ml／kg；
PEEP－16 cmH20）；C组（VT－15 ml／kg；PEEP－0）。肌注 氯胺酮
（7－8 m s／x s）；开放耳缘静脉；青汪异丙酚（2 m s／r s）、咖白月碱
3
硕士学位论文
”mg麻醉诱导；气管插管；接麻醉机机械通气，持续吸入卜2％
异氟醚及静脉问断注入芬太尼和维库澳馁维持麻醉。按不同分组要
求设定vT、PEEP；调整呼吸频率维持正常民（；，I：E为1：2。
月动脉穿刺连续有创监测血压，持续监测ECG、SPO；、直肠 温度和
尿量等。机械通气oh、lh、3h分别取其动脉血测血浆IL叶水平，
讣后放血处死；取左下肺叶作病理学检查。
会 果
A组（VT＝7 ml／kg；PEEP＝scmH20）未见明显病理学改变。B
组（VT－7 ml／kg；PEEP＝16 cmH20）和C组（VT－15 mUkg；PEEP
＊）可见肺泡问隔明显充血增厚；有大量中性粒细胞和淋巴细胞浸
润。三组血浆几 寸水平在 oh时无显著性差异（P＞0．“），A组
各时问点几寸水平亦无显著性差异（P＞0．05 L B、C两组于h
和3h时血浆1卜6水平显著高于加时血浆几乃水平卜＜0．05）；
且比A组相应时问点的血浆IL乃水平增高（P＜0．05）。
全 论
高PEEP或大潮气量的机械通气不仅可引起肺组织炎症反应；
而且使循环中IL乃水平显著升高，过度的炎症反应介导了肺组织
损伤；适当PE朋的小潮气量通气将限制肺组织局部和全身炎症反
4
硕士学位论文
应的发生和发展。
Mechanical ventilation is an important therapeutic technique for patients with respiratory failure. Whereas, it may lead to complications, such as ventilation-induced lung injury (VILI). Both clinical and basic research have demonstrated that excessive tidal volume and/or end-inspiratory lung volume is the main determinant of ventilator-induced lung injury. More recently, attention has focused on the roles and implication in the pathogenesis of ventilator-induced lung injury of inflammatory
cells and mediators that may be activated and released either in the alveolar space or in the systemic circulation because of the rupture of the alveolar-capillary barrier and on the cellular response to mechanical stress.
Interleukin-6 (IL-6) is a pleiotropic cytokine that is commonly produced at local tissue sites and released into circulation in almost all situations of homeostatic perturbation typically including trauma, endotoxic lung, and acute infections. IL-6 is induced often together with the proinflammatory cytokines (TNF-a and IL-1) in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions.
Objective
The purpose of this study was to investigate the effect of different mechanical ventilation strategies on pulmonary and systemic inflammatory responses.
Materials and Methods
Fifteen healthy pigs (male, mean weight is 26.2 ?1.0 kg)
were randomly divided into three groups: group A (VT=7 ml/kg, PEEP=8cmH2O); group B (VT=7 ml/kg, PEEP=16cm H20), and
group C (VT=15 ml/kg, PEEP=0).
General anesthesia was induced with IV diprivan, 2 mg/kg; fentanyl, 0.05mg/kg; scoline, 50mg. The trachea was intubated with a 7.5-8mm inner-diameter tube, and mechanical ventilation was started. Anesthesia was maintained by continuous inhalation isoflurane. Additional fentanyl and vecuronium were administered if needed. ECG, SpO2, ABP, PETCO2, et al were recorded continually.
Peripheral blood were drawn at 0h,1h,3h following ventilation. After 3hrs' ventilation, the pigs were killed and lung biopsy specimens were obtained. Plasma levels of IL-6 were determined using ELISA. The alteration of pulmonary histopathology were observed as well.
Results
There is a significant histological change (alveolar congestion, thickness of the alveolar wall, and leukocyte infiltration) in group B (VT=7 ml/kg, PEEP-16cm H2O) and C (VT=15 ml/kg, PEEP=0), whereas no significant alteration in group A (VT=7 ml/kg, PEEP=8cmH2O). The plasma levels of IL-6 in group B
and C increased significantly at 1h and 3h following ventilation compared to the baseline. However, there is no significant elevation of plasma IL-6 concentration in group A following ventilation.
Conclusions
Mechanical ventilation either with high PEEP or with large volume strategy would induce local and systemic inflammatory responses, overwhelming inflammation may play an important role in the VILI.
细胞因子是由多种细胞产生的内源性多肽，作为细胞免疫和炎性反应间的信号传递物质，它可促进炎症细胞的活化浸润，在VILI
硕士学位论文
及引mH的发生及发展中起重要作用。其中白细胞介素－6门乃）；
是一个在机体防御、急性期反应、免疫反应和造血反应等过程中起
重要作用的多功能蛋白，和 TNF－。、IL＜等在机体爆布样炎症反
应的产生和全身炎症反应的发生发展、在器官功能损伤的发生中起
重要作用；是全身炎症反应发生和发展的敏感和特异性较高的监测
指标。本实验采用不问PEEP 不同潮气量机械通气模式，观察肺
组织病理变化和血浆几乃水平的变化。
研究目的
观察不同PEEP、不同潮气量机械通气对健康小猪肺组织病理
变化和血浆IL乃水平的影响；比较不问陀P、不问潮气量机械通
气对肺局部和全身炎症反应的影响；研究机械通气对肺组织及全身
脏器功能损伤的机理；探讨小潮气量结合适当PEEP对肺的保护作
用；为临床治疗提供理论依据。
材料与方法
15只普通雄性健康小猪；体重门6．8。2．3）kg；随机等分为
3组：A组（VT－7 ml／kg，PEEP－scmH20）；B组（VT－7 ml／kg；
PEEP－16 cmH20）；C组（VT－15 ml／kg；PEEP－0）。肌注 氯胺酮
（7－8 m s／x s）；开放耳缘静脉；青汪异丙酚（2 m s／r s）、咖白月碱
3
硕士学位论文
”mg麻醉诱导；气管插管；接麻醉机机械通气，持续吸入卜2％
异氟醚及静脉问断注入芬太尼和维库澳馁维持麻醉。按不同分组要
求设定vT、PEEP；调整呼吸频率维持正常民（；，I：E为1：2。
月动脉穿刺连续有创监测血压，持续监测ECG、SPO；、直肠 温度和
尿量等。机械通气oh、lh、3h分别取其动脉血测血浆IL叶水平，
讣后放血处死；取左下肺叶作病理学检查。
会 果
A组（VT＝7 ml／kg；PEEP＝scmH20）未见明显病理学改变。B
组（VT－7 ml／kg；PEEP＝16 cmH20）和C组（VT－15 mUkg；PEEP
＊）可见肺泡问隔明显充血增厚；有大量中性粒细胞和淋巴细胞浸
润。三组血浆几 寸水平在 oh时无显著性差异（P＞0．“），A组
各时问点几寸水平亦无显著性差异（P＞0．05 L B、C两组于h
和3h时血浆1卜6水平显著高于加时血浆几乃水平卜＜0．05）；
且比A组相应时问点的血浆IL乃水平增高（P＜0．05）。
全 论
高PEEP或大潮气量的机械通气不仅可引起肺组织炎症反应；
而且使循环中IL乃水平显著升高，过度的炎症反应介导了肺组织
损伤；适当PE朋的小潮气量通气将限制肺组织局部和全身炎症反
4
硕士学位论文
应的发生和发展。
Mechanical ventilation is an important therapeutic technique for patients with respiratory failure. Whereas, it may lead to complications, such as ventilation-induced lung injury (VILI). Both clinical and basic research have demonstrated that excessive tidal volume and/or end-inspiratory lung volume is the main determinant of ventilator-induced lung injury. More recently, attention has focused on the roles and implication in the pathogenesis of ventilator-induced lung injury of inflammatory
cells and mediators that may be activated and released either in the alveolar space or in the systemic circulation because of the rupture of the alveolar-capillary barrier and on the cellular response to mechanical stress.
Interleukin-6 (IL-6) is a pleiotropic cytokine that is commonly produced at local tissue sites and released into circulation in almost all situations of homeostatic perturbation typically including trauma, endotoxic lung, and acute infections. IL-6 is induced often together with the proinflammatory cytokines (TNF-a and IL-1) in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions.
Objective
The purpose of this study was to investigate the effect of different mechanical ventilation strategies on pulmonary and systemic inflammatory responses.
Materials and Methods
Fifteen healthy pigs (male, mean weight is 26.2 ?1.0 kg)
were randomly divided into three groups: group A (VT=7 ml/kg, PEEP=8cmH2O); group B (VT=7 ml/kg, PEEP=16cm H20), and
group C (VT=15 ml/kg, PEEP=0).
General anesthesia was induced with IV diprivan, 2 mg/kg; fentanyl, 0.05mg/kg; scoline, 50mg. The trachea was intubated with a 7.5-8mm inner-diameter tube, and mechanical ventilation was started. Anesthesia was maintained by continuous inhalation isoflurane. Additional fentanyl and vecuronium were administered if needed. ECG, SpO2, ABP, PETCO2, et al were recorded continually.
Peripheral blood were drawn at 0h,1h,3h following ventilation. After 3hrs' ventilation, the pigs were killed and lung biopsy specimens were obtained. Plasma levels of IL-6 were determined using ELISA. The alteration of pulmonary histopathology were observed as well.
Results
There is a significant histological change (alveolar congestion, thickness of the alveolar wall, and leukocyte infiltration) in group B (VT=7 ml/kg, PEEP-16cm H2O) and C (VT=15 ml/kg, PEEP=0), whereas no significant alteration in group A (VT=7 ml/kg, PEEP=8cmH2O). The plasma levels of IL-6 in group B
and C increased significantly at 1h and 3h following ventilation compared to the baseline. However, there is no significant elevation of plasma IL-6 concentration in group A following ventilation.
Conclusions
Mechanical ventilation either with high PEEP or with large volume strategy would induce local and systemic inflammatory responses, overwhelming inflammation may play an important role in the VILI.
引文
1 俞森洋主编．现代机械通气的理论和实践．北京：中国协和医科大学出版社，2000，442～458
2 Kacmarek RM. Ventilator-associated lung injury. Iht Anesthesiol Clin. 1999, 37(3):47-64
3 Kawano T, Mori S, Cybulsky M, et al. Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol. 1987, 62: 27-33.
4 Lentsch AB, Czermak B J, Bless NM, et al. Essential role of alveolar macrophages in intrapulmonary activation of NF-kappaB. Am J Respir Cell Miol. 2000, 20: 692-698.
5 Vlahakis NE, Schroeder MA, Limper AH, et al. Stretch induces cytokine release by alveolar epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol. 1999, 277:L167-L173.
6 Chernoff AE, Granowitz EV, Shapiro L, et al. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995, 154(10):5492-9.
7 Lorraine Tremblay, Franco Valenza, Sergio P, et al. Injurious ventilatory strategies increase cytokines and c-fos m-RNA
expression in an isolated rat lung model. J Clin Invest. 1997, 99: 944-52.
8 Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma. Proc Assoc Am Physicians, 1998, 110: 482-488.
9 Slutsky AS. Lung injury caused by mechanical ventilation. Chest, 1999, 116: 9s-15s
10 黄文起，陈秉学，何东升等．呼气末正压对血栓素和前列环素的影响．临床麻醉学杂志．1997，13：259-261．
11 Chiumello D, Pristine G, Slutsky AS. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999,160:109-116.
12 Tauno K, Minra K, Takeya M, et al. Histopathologic pulmonary changes from mechanical ventilation at high peak airway pressures. Am Rev Respir Dis. 1991, 143:1115-1120.
13 Webb HH, Tierney DF. Experimental pulmonary edema due to intermittent positive pressure ventilation wih high inflation pressures. Protection by positive end espiratory pressure. Am Rev Respir Dis. 1974, 110; 556-565.
14 Dreyfuss D, Basset G, Soler P, et al. Intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary
microvascular injury in rats. Am Rev Respir Dis. 1985, 132; 880-884.
15 Ricard JD, Dreyfuss D, Sanmon G, et al. Ventilator-induced lung injury. Curr Opin Crit Care. 2002, 8; 12-20.
16 Marc J, Bonten, Albert H, et al. The systemic inflammatory response in the development of ventilator-associated pneumonia. Am J Respir Crit Care Med. 1997, 156; 1105-1113.
17 Arthur S, Slutsky, Lorraine N, et al. Multiple System Organ Failure. Is Mechanical Ventilation a Contributing Factor? Am J Respir Crit Care Med. 1998, 157; 1721-1725.
18 Verbrugge SJ, Sorm V, Lachmann B. Mechanisms of acute respiratory distress syndrome: role of surfactant changes and mechanical ventilation. J Physiol Pharmacol. 1997, 48; 537-57.
19 Imai, Kawano T, Miyasaka K, et al. Inflammatory chemical mediators during conventional ventilation and during high frequency oscillatory ventilation. Crit Care Med. 1994; 1550-1554.
20 Chiumello D, Pristine G, Slutsky AS. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999, 160:109-16.
21 Meduri G, Kohler S, Headley E, et al. Inflammatory cytokines in the BAL of patients with ARDS. Chest. 1995, 108; 1303-1314.
22 Bhatia M, Brady M, Shokuhi S, et al. Inflammatory mediators in acute pancreatitis. J Pathol, 2000, 190:117-25.
23 Simons Rk, Junger WG, Loomis WH, et al. Acute lung injury in endotoxemic rats is associated with sustained circulating IL-6 levels and intrapulmonary CINC activity and neutrophil recruiment-role of circulating TNF-alpha and IL-beta? Shock. 1996, 6:39-45.
24 Multlu Gm, Factor PC. Complications of mechanical ventilation. Respir Care Clin N Am, 2000, 6:213-52.
25 Xing Z, Gauldie J, Cox G, et al. IL-6 is an anti-inflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest, 1998, 101:311-20.
26 Karzaiw, Oberhoffer M, Meier-Hellmann A, et al. Procalcitonin-a new indicator of the systemic response to severe infections. infection. 1997, 25: 329-34.
27 Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999,282; 54-61
2 Kacmarek RM. Ventilator-associated lung injury. Iht Anesthesiol Clin. 1999, 37(3):47-64
3 Kawano T, Mori S, Cybulsky M, et al. Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol. 1987, 62: 27-33.
4 Lentsch AB, Czermak B J, Bless NM, et al. Essential role of alveolar macrophages in intrapulmonary activation of NF-kappaB. Am J Respir Cell Miol. 2000, 20: 692-698.
5 Vlahakis NE, Schroeder MA, Limper AH, et al. Stretch induces cytokine release by alveolar epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol. 1999, 277:L167-L173.
6 Chernoff AE, Granowitz EV, Shapiro L, et al. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995, 154(10):5492-9.
7 Lorraine Tremblay, Franco Valenza, Sergio P, et al. Injurious ventilatory strategies increase cytokines and c-fos m-RNA
expression in an isolated rat lung model. J Clin Invest. 1997, 99: 944-52.
8 Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma. Proc Assoc Am Physicians, 1998, 110: 482-488.
9 Slutsky AS. Lung injury caused by mechanical ventilation. Chest, 1999, 116: 9s-15s
10 黄文起，陈秉学，何东升等．呼气末正压对血栓素和前列环素的影响．临床麻醉学杂志．1997，13：259-261．
11 Chiumello D, Pristine G, Slutsky AS. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999,160:109-116.
12 Tauno K, Minra K, Takeya M, et al. Histopathologic pulmonary changes from mechanical ventilation at high peak airway pressures. Am Rev Respir Dis. 1991, 143:1115-1120.
13 Webb HH, Tierney DF. Experimental pulmonary edema due to intermittent positive pressure ventilation wih high inflation pressures. Protection by positive end espiratory pressure. Am Rev Respir Dis. 1974, 110; 556-565.
14 Dreyfuss D, Basset G, Soler P, et al. Intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary
microvascular injury in rats. Am Rev Respir Dis. 1985, 132; 880-884.
15 Ricard JD, Dreyfuss D, Sanmon G, et al. Ventilator-induced lung injury. Curr Opin Crit Care. 2002, 8; 12-20.
16 Marc J, Bonten, Albert H, et al. The systemic inflammatory response in the development of ventilator-associated pneumonia. Am J Respir Crit Care Med. 1997, 156; 1105-1113.
17 Arthur S, Slutsky, Lorraine N, et al. Multiple System Organ Failure. Is Mechanical Ventilation a Contributing Factor? Am J Respir Crit Care Med. 1998, 157; 1721-1725.
18 Verbrugge SJ, Sorm V, Lachmann B. Mechanisms of acute respiratory distress syndrome: role of surfactant changes and mechanical ventilation. J Physiol Pharmacol. 1997, 48; 537-57.
19 Imai, Kawano T, Miyasaka K, et al. Inflammatory chemical mediators during conventional ventilation and during high frequency oscillatory ventilation. Crit Care Med. 1994; 1550-1554.
20 Chiumello D, Pristine G, Slutsky AS. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999, 160:109-16.
21 Meduri G, Kohler S, Headley E, et al. Inflammatory cytokines in the BAL of patients with ARDS. Chest. 1995, 108; 1303-1314.
22 Bhatia M, Brady M, Shokuhi S, et al. Inflammatory mediators in acute pancreatitis. J Pathol, 2000, 190:117-25.
23 Simons Rk, Junger WG, Loomis WH, et al. Acute lung injury in endotoxemic rats is associated with sustained circulating IL-6 levels and intrapulmonary CINC activity and neutrophil recruiment-role of circulating TNF-alpha and IL-beta? Shock. 1996, 6:39-45.
24 Multlu Gm, Factor PC. Complications of mechanical ventilation. Respir Care Clin N Am, 2000, 6:213-52.
25 Xing Z, Gauldie J, Cox G, et al. IL-6 is an anti-inflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest, 1998, 101:311-20.
26 Karzaiw, Oberhoffer M, Meier-Hellmann A, et al. Procalcitonin-a new indicator of the systemic response to severe infections. infection. 1997, 25: 329-34.
27 Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999,282; 54-61