| Background and ObjectiveAcute respiratory distress syndrome (ARDS) is the main reason of death in critical patients, and the incidence is high.At present, mechanical ventilation is the main therapy for ARDS, and right mode of mechanical ventilation is the key for successful rescue of ARDS. The lung tissue of ARDS patients showed a heterogeneous lung parenchyma disease--"baby lung". It means that the lung tissue of normal ventilation reduced obviously. Therefore, the reduction in normal lung volume of ARDS patients is associated with decreased lung compliance and pulmonary shunt, refractory hypoxia and ventilator-induced lung injury.In 1998, the American European Consensus Conference (AECC)recommended pressure-limited ventilation strategies for ARDS, namely the platform pressure less than 30cmH2O to 40cmH2O or the transpulmonary pressure less than 25?30 cmH2O.In 2000, the institute of heart, lung and blood in American, ARDS Network Organization (ARDS Network) published clinical research results of the 10 Center for a period of three years in the United States:low tidal volume (6mL/kg), pressure limited ventilation (platform pressure less than 30cmH2O) and conventional mechanical ventilation:tidal volume 12 mL/Kg, the effect of platform pressure less than 50cmH2O on the ALI/ARDS death rate. The study terminated ahead of the time after admission of 861 ALI/ARDS patients.The results showed that the mortality of patients in low tidal volume and pressure-limited ventilation group was significantly lower than that of conventional mechanical ventilation group (31% vs 39.8%, P=0.007). Therefore, the experts called for less than 6mL/kg of tidal volume for all patients with ARDS. However, the tidal volume less than 6 mL/kg can lead to partial atelectasis. Meanwhile, periodic opening of border area and alveolar collapse at the junction between normal ventilation and alveolar atelectasis and between atelectasis and consolidation, caused shear stress and led to lung injury. It has been reported that tidal volume decreased from 10 ml/kg to 6 ml/kg can cause lung volume significantly reduced (alveolar collapse), and it was also observed that the decreased lung volume could be reversed by high positive end expiratory pressure (PEEP) and lung recruitment maneuver(RM) (refers to the opening lung atelectasis and consolidation by increased transpulmonary pressure). Clinical trials also indicated that recruitment maneuver combined with low tidal volume ventilation could significantly improve oxygenation state, shorten ventilation time, reduce the application of sedative, and tolerance of patient was good for recruitment maneuver. The recruitment maneuver has become the conventional complementary clinical technique of samll tidal volume/limited pressure mechanical ventilation for severe ARDS.However, several foreign clinical trials have shown that RM could not improve the survival rate of the patients, and the conventional application of RM for ARDS was opposed, which leads to that RM can't became a routine treatment guide for ARDS mechanical ventilation. Therefore, this study aims to explore protective mechanism of combined RM with small tidal volume ventilation for ARDS by randomized clinical trials and animal models, and expects to provide a theoretical basis for the revision of guidelines of protective lung ventilation strategy for ARDS.This study is divided into two parts.Part I:clinical trialsMethods To select patients whose diagnosis meet standard of ARDS, and patients were randomly divided into control group (small tidal volume group) and experimental group (LM +small tidal volume group), processing procedures of two groups are as follows:The control group (small tidal volume group):according to ARDSnet protocol, tidal volume (Vt) was regulated to 6 mL/Kg (predicted body weight), control/auxiliary frequency was 12-20 times/min, the flow rate was 60-90 L/min, decreasing wave velocity, volume conversion, ratio of inspiratory time vesus expiratory time (I:E) 1:1-1:2, the oxygen concentration(FiO2) and PEEP according to the FiO2/PEEP reference table of ARDS network. Keep pressure Plateau (Pplat)?25?30 cmH2O. Above indexes were adjusted per 4 hours according to the results of blood gas analysis and oxygenation target. The target oxygenation and carbon dioxide partial pressure oxygen saturation index:oxygen saturation not less than 88?95%(using pulse oximeter detection), or arterial blood oxygen partial pressure 55`80 mmHg regardless of the value of the partial pressure of carbon dioxide, PH>7.25.In the experimental group (LM with small tidal volume group):FiO2100% for patients for 1 to 2 minutes firstly, and then the lung recruitment maneuver (RM):40cmH2O CPAP ventilation for 60 seconds; then BIPAP (Bi-level positive airway pressure) mode for ventilation, parameters as follows:adjustment of low pressure level was same to PEEP in control group, according to FiO2/PEEP ratio table of ARDS network; high level could be maintained in a tidal volume of 6 ml/Kg (PBW), while the driving pressure (high pressure and low pressure difference) was less than 20 cmH20 and high pressure was less than 30cmH2O. If Vt was ?4 mL/Kg. driving pressure could be? 20 cmH2O, the control frequency was 12-20 times/min. Above indexes were adjusted per 4 hours according to the results of blood gas analysis and oxygenation target. Oxygen partial pressure and carbon dioxide pressure were same to those in the control group.To collect blood samples at 0,24,48 and 72 hours after enrollment, and took them into the refrigerator at -80 ?.The primary outcome was dead number of patients in every group, then calculated mortality. Other indicators including oxygenation index changes with time, ventilation time, the damage number of extrapulmonary organs, ICU hospitalization time and sedative drugs and dosage of vasoactive drugs.Result1. General situation:In 179 ARDS patients,21 patients died due to severe illness in 72 hours,5 patients automatically discharged with various reasons in 72 hours,12 patients refused to participate in the study group due to relatives'disagreement, and 26 patients didn't meet standard of enrollment due to complications or mechanical ventilation more than 36 hours. Finally,115 patients who met the study criteria and signed informed consent,58 patients were randomly selected in control group,57 patients in experimental group.2.Mortality:8 patients in the experimental group died (26.60%) at day 28,11 patients died in the control group (35.48%), and the difference was statistically significant (P<0.05).3.Oxygenation index:There was no difference between the two groups at Oh, and the oxygenation index in the experimental group was significantly better than the control group after 24 hours(P< 0.01).4.Cumulative damage number of extrapulmonary organs:Compared with the control group, the damage number of extrapulmonary organs in the experimental group was significantly decreased (2.06±0.34 vs 2.87±0.4,P< 0.05).5.Ventilation days:Survival patients in experimental group shorten the average ventilation time (12±1.5 days vs 15±2.3 days, P<0.05).6. VWF and TNF-a levels in the blood:The levels of blood TNF-a in two groups rose gradually from 24 to 48 h, and began to decrease after 72 h, but TNF-a levels in the experimental group was lower than those in the control group at each time point (P<0.05 at 48 h, P<0.01 at 72 h).The activity of vWF in the control group showed gradually upward trend with time (0h-24h-48h-72h), and reached the highest value at 72 h; the experimental group showed gradually downward trend with time from 0 hours to 48 h, and decreased at 72 h. vWF levels in experimental group were lower than those in the control group (P<0.05 or <0.01 respectively).7. MMP-9 levels in bronchoalveolar lavage fluid:MMP-9 levels in bronchoalveolar lavage fluid significantly increased in patients treated with both simple tidal volume and combined RM with low tidal volume in the early stage of onset, reached the peak at 24-48 h, and began to fall back at 72 h. MMP-9 levels in the experimental group were lower than those in control group after 48 h (P<0.05), and decreased more significantly at 72 h (P<0.01).S. The total cell number and classification of bronchoalveolar lavage fluid sediment:The total number of cells in bronchoalveolar lavage fluid and percentage of neutrophils in both experimental and control groups rose significantly at 0 h, reached the peak at 24-48 h; total cell and neutrophil percentage were decreased at 72h, but vWF levels decreased more significantly than those in the control group.9.The correlation between MMP-9 and the percentage of neutrophils in the lavage fluid: MMP-9 levels in the bronchoalveolar lavage fluid were positive proportional to the total number of inflammatory cells and the number of granulocyte, and showed the linear correlation (r=0.9107,P<0.01).Part II:Animal experimentMethods 40 healthy rabbits were randomly divided into four groups: ? control group (sham operation group), ? ARDS model group (ARDS group); ? ARDS+small tidal volume group (SVt group) ? ARDS+LM+samll tidal volume group (LM+SVt group),10 rats in each group. the simple samll tidal volume group (SVt), a tidal volume (Vt) for 6 mL/Kg, the control/auxiliary frequency was 30 times/min, decreasing wave velocity, inspiratory and expiratory time ratio (I:E) 1:1-1:2, time conversion, oxygen concentration (FiO2) and PEEP according to the reference ratio of FiO2/PEEP adjustment table of ARDS network. To keep the platform pressure (Pplat)?25?30 cmH2O. Rats were killed at 6 hours after the successful model. In RM with small tidal volume group (LM+SVt), the initial set was same to simple low tidal volume group, and peformed RM every 1 hour after ventilation, using 40 cmH2OŚ30 seconds RM, a total of 6 times, and killed the animal after successful model. ARDS model group and the control group performed the tracheotomy and didn't performed mechanical ventilation. Rats were sacrificed after 6 hours. Dynamically monitored blood gas and the changes of TNF-a, vWF and MMP-9, and observed the neutrophil counts in bronchoalveolar lavage fluid in lung tissue, the wet/dry ratio and lung tissue pathology change.Result1.Changes of oxygenation index:Oxygenation index in untreated model group decreased gradually with time, was lower than that in the mechanical ventilation group at each time point, oxygenation improved significantly in simple small tidal volume (SVt) group animal; Oxygenation improved significantly in lung recruitment+samll tidal volume group (LM+ SVt).2.Blood vWF, TNF-a and MMP-9 changes in every group:Blood TNF-? and MMP-9 decreased gradually with treatment in simple low tidal volume group; TNF-a and MMP-9 decreased more significantly under the treatment of RM with small tidal volume. vWF levels in serum in the model group (regardless of mechanical ventilation) was significantly higher than those in control group. There were no obvious changes until the animal were sacrificed, and the differences between the groups were not statistically significant.3.The changes of vWF, TNF-a and MMP-9 levels in bronchoalveolar lavage fluid of every group:Similar to the changes in blood, vWF, TNF-a and MMP-9 levels in ARDS model group were higher than those in sham group, but TNF-a and MMP-9 levels in small tidal volume ventilation were significantly lower than those in ARDS model group, while TNF-a and MMP-9 levels in the RM with small tidal volume ventilation group were lower than those in small tidal volume ventilation.VWF had no statistical difference in the three model groups.4.The total cell number and classification of bronchoalveolar lavage fluid sediment: White blood cell count in control group BALF decreased, and macrophages(M)cell accounted for about 88%. White blood cell count in BALF rose after 6 hours, rose more than 10 times compared with those in the control group. Neutrophil (N) accounted for about 80%. The small tidal volume mechanical ventilation could reduce the recruitment of leukocytes and neutrophil infiltration, The treatment of combined lung recruitment with low tidal volume more significantly reduced white cell aggregation in lung, but white cell aggregation in lung was more obvious than those in control group.5.Lung wet/dry ratio (W/D) in every group:Lung tissue W/D ratio in all ARDS animals were increased compared with sham control group. Small tidal volume ventilation could reduce the W/D ratio, but RM with small tidal volume group reduced more significantly (4.8±0.24 vs 5.86±0.38, p< 0.05).6.Pathological changes:Lung tissues in control group rabbit showed the clear structure under light microscope, few inflammatory cells in pulmonary interstitial, intact alveolar wall, no alveolar fluid and alveolar collapse. Model group showed thick alveolar septum, significant interstitial pulmonary edema, a large number of neutrophil infiltration, part alveolar atrophy collapse, airway secretions. Small tidal volume ventilation group showed reduced alveolar collapse, the reduced inflammatory exudatation. Lung tissue in RM with small tidal volume group showed lighter inflammatory exudation and interstitial edema than small tidal volume mechanical ventilation group.Conclusion1. RM with small tidal volume ventilation can improve oxygenation, and shorten the ventilation time, reduce the damage number of extrapulmonary organ, and reduce 28-day mortality.2. RM with small tidal volume ventilation can reduce lung tissue neutrophil aggregation, the release of inflammatory cytokines, pulmonary edema and the pathological injury.3. RM with small tidal volume ventilation can reduce repeated lung collapse and open, and prevent the excessive pulmonary stretch. |
PDF Full Text Request