高频振荡通气对急性肺损伤新生猪肺功能及病理影响的研究
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摘要
目的：用生理盐水反复灌洗新生猪肺泡的方法建立急性肺损伤(ALI)模型，研究分为两个部分：一、高频振荡通气对新生猪急性肺损伤气体交换、肺力学及血流动力学的影响：动态观察常频机械通气(CMV)、高频振荡通气(HFOV)治疗过程中损伤肺的氧合、静态顺应性及血流动力学改变，探讨HFOV对缺少肺表面活性物质引起的新生动物ALI时肺功能及循环功能的影响；二、高频振荡通气对新生猪肺组织大体及肺泡II型上皮细胞病理结构的影响：了解机械通气类型、时间与肺损伤之间的关系，探讨HFOV在治疗新生儿ALI／ARDS及减轻呼吸机相关肺损伤(VALI)发生发展中的机制及应用价值。
方法：
(一)第一部分
1、动物预处理15只出生3天内的新生猪经麻醉后气管切开插管，连接MAQUET Servo-i呼吸机，进行压力控制通气。股动咏插管连续监测动咏血压变化。预处理操作结束后通气30分钟，测量血气、动咏血压、心率、肺静态顺应性，并计算氧合指数(OI)、平均动咏压(MABP)、肺静态顺应性(Cst)，作为基础值。
2、ALI动物模型的建立所有模型建立过程均在CMV模式下进行。经气管导管向气管内注入37℃生理盐水：35ml／kg，停留约10s抽出肺内生理盐水，间隔5min后重复操作。在吸入氧浓度为1．0的条件下直至动咏血气分析Pa02< 100mmHg，并维持1h即认为模型制备成功。
3、实验动物分组将15只新生猪随机分为3组。对照组(n=3)：ALI对照组，ALI模型制备成功后不予机械通气，即处死动物。
CMV组(n=6)：动物均连接MAQUETServo-i呼吸机，进行压力控制通气。分别在常频机械通气治疗24h、48h各处死动物3只。
HFOV组(n=6)：动物模型制备成功后，转换为连接SLE5000呼吸机，进行高频振荡通气。分别在高频振荡通气治疗24h、48h各处死动物3只。
4、观察指标在建模前、ALI即刻即0h、1h、3h、6h、12h、24h、48h分别监测以下指标
(1)血气分析经股动咏插管取动咏血行血气分析，并计算OI。
(2)肺静态顺应性测定采用低流速法，CMV组通过呼吸机自带分析软件，记录第5次呼吸时的数据。HFOV组将HFOV模式转换为CMV模式，呼吸机参数设置同CMV组，记录第5次呼吸时的数据，肺顺应性测完毕后立即转换为HFOV模式。并计算Cst。
(3)动咏血压及心率记录动咏血压及心率，并计算MABP。
(二)第二部分
1、动物预处理同前
2、ALI动物模型的建立同前
3、实验动物分组同前
4、观察指标对照组动物在建模成功后即予处死，CMV组和HFOV分别在机械通气24h和48h各处死3只动物，取肺组织进行以下检测。
(1)右上肺组织光镜检测：分为重力依赖区和非重力依赖区，HE染色分别计数中性粒细胞(PMN)、巨噬细胞(AM)、红细胞(RBC)，改良Mallory’s磷钨酸苏木素法染色分别计数透明膜／水肿液(HM/E)。
(2)右下肺底组织行透射电镜检测：观察AECII超做结构改变。
结果：
(一)第一部分
1、各组的OI、Cst、HR、MABP在基础状态、ALI0h均无显著性差异。ALI0h的P/F比值<300mmHg、OI较基础值显著增加，Cst较基础值显著下降。
2、CMV组、HFOV组实验动物的OI随着治疗时间延长呈持续性下降，其中HFOV组动物的OI从第6h起至48h较CMV组动物下降的更明显(P<0．05)。
3、CMV组部分实验动物在机械通气治疗后1h及3h可见Cst下降，6h起至48h显著高于ALI0h(P<0．05)；HFOV组实验动物的Cst随着治疗时间延长呈持续性增加，从1h起就高于ALI0h(P<0．05)，从3h起就高于CMV组(P <0．05)。
4、实验过程中各组实验动物的HR、MABP均无显著改变(P>0．05)。
(二)第二部分
1、光镜观察
(1)肺组织病变重力依赖区重于非重力依赖区。
(2)PMN：CMV及HFOV各亚组各区PMN均较对照组明显增加(P< 0．01)；HFOV48h亚组的重力依赖区PMN较CMV 48h亚组明显减少(P<0．05)。
(3)AM：CMV 48h、HFOV 24h和48h亚组的AM均较对照组明显减少(P<0．05)，HFOV 24h亚组的AM较CMV 24h亚组明显减少(P< 0．01)。
(4)RBC：CMV及HFOV各亚组各区PMN均较对照组明显增加(P< 0．01)；HFOV 24h及48h亚组重力依赖区、非重力依赖区的RBC均较同时间点CMV组少(P<0．01)。
(5)HM／E：CMV及HFOV各亚组各区HM／E均较对照组明显增加(P< 0．01)；HFOV24h及48h亚组重力依赖区、非重力依赖区的HM／E均较同时间点CMV组少(P<0．01)。
2、透射电镜观察
各组均可见LB空泡化改变，随机械通气时间延长，HFOV组的AECII较CMV组与基膜、AEC I连接紧密、LB空泡化改变轻，CMV24h亚组还可见AECII向肺泡腔排出的分泌物和幼稚AECII，CMV48h亚组可见脱落AECII，细胞核体积变小。
结论：
1、HFOV治疗新生动物ALI／ARDS，不仅可以快速有效改善氧合、肺顺应性，而且对血流动力学无明显不良影响。
2、机械通气治疗新生动物ALI／ARDS时肺组织病理改变在重力依赖区重于非重力依赖区。
3、HFOV治疗新生动物ALI／ARDS，不仅减少肺组织炎症浸润、出血、和水肿液形成，还减轻对AECII的损伤，从而减轻VALI。
Ojective
In this study, repeated whole-lung lavage with normal saline was used to induce newborn piglets model for neonatal acute lung injury (ALI). The study holds two parts: 1、The effects of high frequency oscillatory ventilation on gas exchange、lung mechanics and hemodynamics in newborn piglets with acute lung injury: to investigate the effect of HFOV on lung function and hemodynamics in newborn piglets with acute lung injury, induced by pulmonary surfactant deficiency; 2、The effects of high frequency oscillatory ventilation on pathological structure and type II alveolar epithelium cells in newborn piglets with acute lung injury: to investigate the relationship between ventilation modes、time length and lung injury, what's more, to explore the mechanisms and applicable value of HFOV in neonatal ALI/ARDS, and in relieving and attenuating ventilator associated lung injury (VALI).
Methods
(—)Part One
1、Animal Preparation
15 no more than 3-day-old newborn piglets were intubated after anesthesia, ventilated with a MAQUET Servo-i ventilaor, using pressure control ventilation mode. Femoral artery was cannulated for arterial blood pressure monitoring and blood sampling. After surgical procedure and a stabilization period of 30 minutes, the arterial blood gas, arterial blood pressure, heart rate(HR), lung static compliance(Cst) were obtained, calculated for oxygenation index(OI), mean arterial blood pressure(MABP) and Cst as baseline parameters (baseline).
2、Induction of acute lung injury
All the piglets ALI were induced using CMV mode. To induce acute lung injury, warmed normal saline (37°C) at a volume of 35 ml/kg was instilled continuously through a endotracheal tube, the lavage procedure was repeated after each 5 minutes inteval until the PaO2 remained below 100 mmHg under the fraction of inspired oxygen being 1.0 for one hour.
3、Study Groups
After completion of lavage, piglets were randomly assigned to one of three study groups: control (n=3), conventional mechanical ventilation (CMV, n=6), or high frequency oscillatory ventilation (HFOV, n=6).Control group: piglets were killed after the completion of lavage series, no mechanical ventilation.CMV group: piglets were ventilated using a MAQUET Servo-i ventilaor with pressure control ventilation mode.Each time three piglets were killed after ventilating 24 hours and 48 hours respectively.HFOV group: piglets were ventilated using a SLE5000 ventilaor with high frequency oscillatory ventilation mode. Each time three piglets were killed after ventilating 24 hours and 48 hours respectively.
4、Observing Markers and MethodsObserving markers were monitoring at preinjury、ALI 0h、1h、3h、6h、12h、24 h、48 h respectively.
(1) Blood Gas Analysis: arterial blood samples were analyzed and calculated for OI.
(2) Lung Static Compliance: fifth datum of respiration were recorded using low flow technique. In HFOV group, HFOV mode was changed into CMV mode before monitoring, ventilator parameters were set as those in CMV group, after monitoring completed, ventilator mode was changed back into HFOV mode immediatly.Cst was calculated.
(3) Arterial Blood Pressure and Heart Rate: MABP was calculated.
(二) Part Two
1、Animal Preparation It is same as part one.
2、Induction of acute lung injury It is same as part one.
3、Study Groups It is same as part one.
4、Observing Markers and Methods
(1) light Microscopy (LM): right upper lung tissues were divided into gravitational dependent region and gravitational nondependent region. The numbers of polymorphonuclear leukocyte (PMN)、alveolar macrophage (AM)、red blood cell (RBC) were counted respectively using Hematoxylin-Eosine staining. The numbers of hyaline membrane/edema(HM/E) were counted using modified Mallory's phosphotungstic acid-hematoxylin (PTAH) staining.
(2) Transmission Electron Microscope (TEM): the ultrastructure of type II alveolar epithelium cells(AEC II ) in right down-backside lung tissue was observed.
Results
(—) Part One
1、No differences were found in OI、Cst、HR、MABP at baseline、ALI Oh between groups. At ALI 0h, P/F ratio was below 300 mmHg, apart from this, OI was significantly higher and Cst was significantly lower than those at baseline.
2、As the extension of ventilation time, OI was continuously decreased in CMV group and HFOV group, however, from sixth hour to forty-eighth hour, OI in HFOV group was significantly lower than that in CMV group (P<0.05).
3、In CMV group, it was observed that Cst was decreased in some piglets at the first and third hour, Cst was significantly higher than that at ALI Oh (P< 0.05). In HFOV group, Cst was continuously increased as the extension of ventilation time,it was significantly higher than that at ALI Oh from the first hour to forty-eighth hour (P<0.05), and it was significantly higher than that in CMV group from third hour to forty-eighth hour (P<0.05). 4、No differences were found in HR、MABP at each time point between groups (P>0.05).
(二) Part Two
1、TM
(1) It presented a greater degree of histopathologic lung damage in the gravitational dependent region than that in gravitational nondependent region.
(2) PMN: PMNs in gravitational dependent and nondependent region of both CMV and HFOV group were significantly more than in control group (P< 0.01). PMNs in gravitational dependent region of HFOV 48h group were significantly less than in CMV 48h group (P<0.05).
(3) AM: AMs in CMV 48h group、HFOV 24h group and HFOV 48h group were significantly less than in control group (P<0.05). AMs in HFOV 24h group were significantly less than in CMV 24h group (P<0.01).
(4) RBC: RBCs in gravitational dependent and nondependent region of both CMV and HFOV group were significantly more than in control group (P< 0.01). RBCs in gravitational dependent and nondependent region of all HFOV groups were significantly less than in CMV group respectively (P< 0.01).
(5) HM/E: HM/Es in gravitational dependent and nondependent region of both CMV and HFOV group were significantly more than in control group (P< 0.01). HM/Es in gravitational dependent and nondependent region of all HFOV groups were significantly less than in CMV group respectively (P< 0.01).
2、TEM
It was found that lamellar body (LB) with vacuole-like deformity was occurred in each group. As the extension of ventilation time, comparing with CMV group, the juxtaposition of AECII to basal membrane and AEC I in HFOV group was closer and the electron density of LB in HFOV group decreased less. In CMV 24h group, the secretion of AECII discharged into alveolar space and naive AECII were observed. In CMV 48h group, some AEC II s were dislodged from basal membrane, and the volume of some nuclei became shrank.
Conclusions
1、Treating neonatal ALI/ARDS with HFOV, it can more rapidly andeffectively improve gas exchange and lung mechanics, and have no adverse effect on hemodynamics.
2、Treating neonatal ALI/ARDS with mechanical ventilation,histopathologic lung damage in the gravitational dependent region was more intense than that in gravitational nondependent region.
3、HFOV can reduce and attenuate VALI through reducing pulmonaryinflammation、haemorrhage and alveolar edema and hyaline membrane formation, and attenuating the damage to AEC II.QIN Xiaofei (Pediatrics) Directed by professor FU Wanhai
方法：
(一)第一部分
1、动物预处理15只出生3天内的新生猪经麻醉后气管切开插管，连接MAQUET Servo-i呼吸机，进行压力控制通气。股动咏插管连续监测动咏血压变化。预处理操作结束后通气30分钟，测量血气、动咏血压、心率、肺静态顺应性，并计算氧合指数(OI)、平均动咏压(MABP)、肺静态顺应性(Cst)，作为基础值。
2、ALI动物模型的建立所有模型建立过程均在CMV模式下进行。经气管导管向气管内注入37℃生理盐水：35ml／kg，停留约10s抽出肺内生理盐水，间隔5min后重复操作。在吸入氧浓度为1．0的条件下直至动咏血气分析Pa02< 100mmHg，并维持1h即认为模型制备成功。
3、实验动物分组将15只新生猪随机分为3组。对照组(n=3)：ALI对照组，ALI模型制备成功后不予机械通气，即处死动物。
CMV组(n=6)：动物均连接MAQUETServo-i呼吸机，进行压力控制通气。分别在常频机械通气治疗24h、48h各处死动物3只。
HFOV组(n=6)：动物模型制备成功后，转换为连接SLE5000呼吸机，进行高频振荡通气。分别在高频振荡通气治疗24h、48h各处死动物3只。
4、观察指标在建模前、ALI即刻即0h、1h、3h、6h、12h、24h、48h分别监测以下指标
(1)血气分析经股动咏插管取动咏血行血气分析，并计算OI。
(2)肺静态顺应性测定采用低流速法，CMV组通过呼吸机自带分析软件，记录第5次呼吸时的数据。HFOV组将HFOV模式转换为CMV模式，呼吸机参数设置同CMV组，记录第5次呼吸时的数据，肺顺应性测完毕后立即转换为HFOV模式。并计算Cst。
(3)动咏血压及心率记录动咏血压及心率，并计算MABP。
(二)第二部分
1、动物预处理同前
2、ALI动物模型的建立同前
3、实验动物分组同前
4、观察指标对照组动物在建模成功后即予处死，CMV组和HFOV分别在机械通气24h和48h各处死3只动物，取肺组织进行以下检测。
(1)右上肺组织光镜检测：分为重力依赖区和非重力依赖区，HE染色分别计数中性粒细胞(PMN)、巨噬细胞(AM)、红细胞(RBC)，改良Mallory’s磷钨酸苏木素法染色分别计数透明膜／水肿液(HM/E)。
(2)右下肺底组织行透射电镜检测：观察AECII超做结构改变。
结果：
(一)第一部分
1、各组的OI、Cst、HR、MABP在基础状态、ALI0h均无显著性差异。ALI0h的P/F比值<300mmHg、OI较基础值显著增加，Cst较基础值显著下降。
2、CMV组、HFOV组实验动物的OI随着治疗时间延长呈持续性下降，其中HFOV组动物的OI从第6h起至48h较CMV组动物下降的更明显(P<0．05)。
3、CMV组部分实验动物在机械通气治疗后1h及3h可见Cst下降，6h起至48h显著高于ALI0h(P<0．05)；HFOV组实验动物的Cst随着治疗时间延长呈持续性增加，从1h起就高于ALI0h(P<0．05)，从3h起就高于CMV组(P <0．05)。
4、实验过程中各组实验动物的HR、MABP均无显著改变(P>0．05)。
(二)第二部分
1、光镜观察
(1)肺组织病变重力依赖区重于非重力依赖区。
(2)PMN：CMV及HFOV各亚组各区PMN均较对照组明显增加(P< 0．01)；HFOV48h亚组的重力依赖区PMN较CMV 48h亚组明显减少(P<0．05)。
(3)AM：CMV 48h、HFOV 24h和48h亚组的AM均较对照组明显减少(P<0．05)，HFOV 24h亚组的AM较CMV 24h亚组明显减少(P< 0．01)。
(4)RBC：CMV及HFOV各亚组各区PMN均较对照组明显增加(P< 0．01)；HFOV 24h及48h亚组重力依赖区、非重力依赖区的RBC均较同时间点CMV组少(P<0．01)。
(5)HM／E：CMV及HFOV各亚组各区HM／E均较对照组明显增加(P< 0．01)；HFOV24h及48h亚组重力依赖区、非重力依赖区的HM／E均较同时间点CMV组少(P<0．01)。
2、透射电镜观察
各组均可见LB空泡化改变，随机械通气时间延长，HFOV组的AECII较CMV组与基膜、AEC I连接紧密、LB空泡化改变轻，CMV24h亚组还可见AECII向肺泡腔排出的分泌物和幼稚AECII，CMV48h亚组可见脱落AECII，细胞核体积变小。
结论：
1、HFOV治疗新生动物ALI／ARDS，不仅可以快速有效改善氧合、肺顺应性，而且对血流动力学无明显不良影响。
2、机械通气治疗新生动物ALI／ARDS时肺组织病理改变在重力依赖区重于非重力依赖区。
3、HFOV治疗新生动物ALI／ARDS，不仅减少肺组织炎症浸润、出血、和水肿液形成，还减轻对AECII的损伤，从而减轻VALI。
Ojective
In this study, repeated whole-lung lavage with normal saline was used to induce newborn piglets model for neonatal acute lung injury (ALI). The study holds two parts: 1、The effects of high frequency oscillatory ventilation on gas exchange、lung mechanics and hemodynamics in newborn piglets with acute lung injury: to investigate the effect of HFOV on lung function and hemodynamics in newborn piglets with acute lung injury, induced by pulmonary surfactant deficiency; 2、The effects of high frequency oscillatory ventilation on pathological structure and type II alveolar epithelium cells in newborn piglets with acute lung injury: to investigate the relationship between ventilation modes、time length and lung injury, what's more, to explore the mechanisms and applicable value of HFOV in neonatal ALI/ARDS, and in relieving and attenuating ventilator associated lung injury (VALI).
Methods
(—)Part One
1、Animal Preparation
15 no more than 3-day-old newborn piglets were intubated after anesthesia, ventilated with a MAQUET Servo-i ventilaor, using pressure control ventilation mode. Femoral artery was cannulated for arterial blood pressure monitoring and blood sampling. After surgical procedure and a stabilization period of 30 minutes, the arterial blood gas, arterial blood pressure, heart rate(HR), lung static compliance(Cst) were obtained, calculated for oxygenation index(OI), mean arterial blood pressure(MABP) and Cst as baseline parameters (baseline).
2、Induction of acute lung injury
All the piglets ALI were induced using CMV mode. To induce acute lung injury, warmed normal saline (37°C) at a volume of 35 ml/kg was instilled continuously through a endotracheal tube, the lavage procedure was repeated after each 5 minutes inteval until the PaO2 remained below 100 mmHg under the fraction of inspired oxygen being 1.0 for one hour.
3、Study Groups
After completion of lavage, piglets were randomly assigned to one of three study groups: control (n=3), conventional mechanical ventilation (CMV, n=6), or high frequency oscillatory ventilation (HFOV, n=6).Control group: piglets were killed after the completion of lavage series, no mechanical ventilation.CMV group: piglets were ventilated using a MAQUET Servo-i ventilaor with pressure control ventilation mode.Each time three piglets were killed after ventilating 24 hours and 48 hours respectively.HFOV group: piglets were ventilated using a SLE5000 ventilaor with high frequency oscillatory ventilation mode. Each time three piglets were killed after ventilating 24 hours and 48 hours respectively.
4、Observing Markers and MethodsObserving markers were monitoring at preinjury、ALI 0h、1h、3h、6h、12h、24 h、48 h respectively.
(1) Blood Gas Analysis: arterial blood samples were analyzed and calculated for OI.
(2) Lung Static Compliance: fifth datum of respiration were recorded using low flow technique. In HFOV group, HFOV mode was changed into CMV mode before monitoring, ventilator parameters were set as those in CMV group, after monitoring completed, ventilator mode was changed back into HFOV mode immediatly.Cst was calculated.
(3) Arterial Blood Pressure and Heart Rate: MABP was calculated.
(二) Part Two
1、Animal Preparation It is same as part one.
2、Induction of acute lung injury It is same as part one.
3、Study Groups It is same as part one.
4、Observing Markers and Methods
(1) light Microscopy (LM): right upper lung tissues were divided into gravitational dependent region and gravitational nondependent region. The numbers of polymorphonuclear leukocyte (PMN)、alveolar macrophage (AM)、red blood cell (RBC) were counted respectively using Hematoxylin-Eosine staining. The numbers of hyaline membrane/edema(HM/E) were counted using modified Mallory's phosphotungstic acid-hematoxylin (PTAH) staining.
(2) Transmission Electron Microscope (TEM): the ultrastructure of type II alveolar epithelium cells(AEC II ) in right down-backside lung tissue was observed.
Results
(—) Part One
1、No differences were found in OI、Cst、HR、MABP at baseline、ALI Oh between groups. At ALI 0h, P/F ratio was below 300 mmHg, apart from this, OI was significantly higher and Cst was significantly lower than those at baseline.
2、As the extension of ventilation time, OI was continuously decreased in CMV group and HFOV group, however, from sixth hour to forty-eighth hour, OI in HFOV group was significantly lower than that in CMV group (P<0.05).
3、In CMV group, it was observed that Cst was decreased in some piglets at the first and third hour, Cst was significantly higher than that at ALI Oh (P< 0.05). In HFOV group, Cst was continuously increased as the extension of ventilation time,it was significantly higher than that at ALI Oh from the first hour to forty-eighth hour (P<0.05), and it was significantly higher than that in CMV group from third hour to forty-eighth hour (P<0.05). 4、No differences were found in HR、MABP at each time point between groups (P>0.05).
(二) Part Two
1、TM
(1) It presented a greater degree of histopathologic lung damage in the gravitational dependent region than that in gravitational nondependent region.
(2) PMN: PMNs in gravitational dependent and nondependent region of both CMV and HFOV group were significantly more than in control group (P< 0.01). PMNs in gravitational dependent region of HFOV 48h group were significantly less than in CMV 48h group (P<0.05).
(3) AM: AMs in CMV 48h group、HFOV 24h group and HFOV 48h group were significantly less than in control group (P<0.05). AMs in HFOV 24h group were significantly less than in CMV 24h group (P<0.01).
(4) RBC: RBCs in gravitational dependent and nondependent region of both CMV and HFOV group were significantly more than in control group (P< 0.01). RBCs in gravitational dependent and nondependent region of all HFOV groups were significantly less than in CMV group respectively (P< 0.01).
(5) HM/E: HM/Es in gravitational dependent and nondependent region of both CMV and HFOV group were significantly more than in control group (P< 0.01). HM/Es in gravitational dependent and nondependent region of all HFOV groups were significantly less than in CMV group respectively (P< 0.01).
2、TEM
It was found that lamellar body (LB) with vacuole-like deformity was occurred in each group. As the extension of ventilation time, comparing with CMV group, the juxtaposition of AECII to basal membrane and AEC I in HFOV group was closer and the electron density of LB in HFOV group decreased less. In CMV 24h group, the secretion of AECII discharged into alveolar space and naive AECII were observed. In CMV 48h group, some AEC II s were dislodged from basal membrane, and the volume of some nuclei became shrank.
Conclusions
1、Treating neonatal ALI/ARDS with HFOV, it can more rapidly andeffectively improve gas exchange and lung mechanics, and have no adverse effect on hemodynamics.
2、Treating neonatal ALI/ARDS with mechanical ventilation,histopathologic lung damage in the gravitational dependent region was more intense than that in gravitational nondependent region.
3、HFOV can reduce and attenuate VALI through reducing pulmonaryinflammation、haemorrhage and alveolar edema and hyaline membrane formation, and attenuating the damage to AEC II.QIN Xiaofei (Pediatrics) Directed by professor FU Wanhai
引文
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