Tryptase is involved in the development of early ventilator-induced pulmonary fibrosis in sepsis-induced lung injury

IntroductionMost patients with sepsis and acute lung injury require mechanical ventilation to improve oxygenation and facilitate organ repair. Mast cells are important in response to infection and resolution of tissue injury. Since tryptase secreted from mast cells has been associated with tissue fibrosis, we hypothesized that tryptase would be involved in the early development of ventilator-induced pulmonary fibrosis in a clinically relevant model of sepsis-induced lung injury.MethodsProspective, randomized, controlled animal study using Sprague-Dawley rats. Sepsis was induced by cecal ligation and perforation. Animals were randomized to spontaneous breathing or two ventilatory strategies for 4 h: protective ventilation with tidal volume (VT) = 6 ml/kg plus 10 cmH₂O positive end-expiratory pressure (PEEP) or injurious ventilation with VT = 20 ml/kg plus 2 cmH₂O PEEP. Healthy, non-ventilated animals served as non-septic controls. We studied the following end points: histology, serum cytokine levels, hydroxyproline content, tryptase and proteinase-activated receptor-2 (PAR-2) protein level in lung homogenates, and tryptase and PAR-2 immunohistochemical localization in the lungs.ResultsAll septic animals developed acute lung injury. Animals ventilated with high VT had a significant increase of pulmonary fibrosis, hydroxyproline content, tryptase and PAR-2 protein levels compared to septic controls (P <0.0001). However, protective ventilation attenuated sepsis-induced lung injury and decreased lung tryptase and PAR-2 protein levels. Immunohistochemical staining confirmed the presence of tryptase and PAR-2 in the lungs.ConclusionsMechanical ventilation modified tryptase and PAR-2 in injured lungs. Increased levels of these proteins were associated with development of sepsis and ventilator-induced pulmonary fibrosis early in the course of sepsis-induced lung injury.     

Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury.

OBJECTIVE: To determine the impact of different protective and nonprotective mechanical ventilation strategies on the degree of pulmonary inflammation, oxidative damage, and hemodynamic stability in a saline lavage model of acute lung injury. DESIGN: A prospective, randomized, controlled, in vivo animal laboratory study. SETTING: Animal research facility of a health sciences university. SUBJECTS: Forty-six New Zealand White rabbits. INTERVENTIONS: Mature rabbits were instrumented with a tracheostomy and vascular catheters. Lavage-injured rabbits were randomized to receive conventional ventilation with either a) low peak end-expiratory pressure (PEEP; tidal volume of 10 mL/kg, PEEP of 2 cm H2O); b) high PEEP (tidal volume of 10 mL/kg, PEEP of 10 cm H2O); c) low tidal volume with PEEP above Pflex (open lung strategy, tidal volume of 6 mL/kg, PEEP set 2 cm H2O > Pflex); or d) high-frequency oscillatory ventilation. Animals were ventilated for 4 hrs. Lung lavage fluid and tissue samples were obtained immediately after animals were killed. Lung lavage fluid was assayed for measurements of total protein, elastase activity, tumor necrosis factor-alpha, and malondialdehyde. Lung tissue homogenates were assayed for measurements of myeloperoxidase activity and malondialdehyde. The need for inotropic support was recorded. MEASUREMENTS AND MAIN RESULTS: Animals that received a lung protective strategy (open lung or high-frequency oscillatory ventilation) exhibited more favorable oxygenation and lung mechanics compared with the low PEEP and high PEEP groups. Animals ventilated by a lung protective strategy also showed attenuation of inflammation (reduced tracheal fluid protein, tracheal fluid elastase, tracheal fluid tumor necrosis factor-alpha, and pulmonary leukostasis). Animals treated with high-frequency oscillatory ventilation had attenuated oxidative injury to the lung and greater hemodynamic stability compared with the other experimental groups. CONCLUSIONS: Both lung protective strategies were associated with improved oxygenation, attenuated inflammation, and decreased lung damage. However, in this small-animal model of acute lung injury, an open lung strategy with deliberate hypercapnia was associated with significant hemodynamic instability.     

The open lung during small tidal volume ventilation: concepts of recruitment and "optimal" positive end-expiratory pressure.

OBJECTIVES: To test the hypotheses that during small tidal volume ventilation (5 mL/kg) deliberate volume recruitment maneuvers allow expansion of atelectatic lung units and that a high positive end-expiratory pressure (PEEP) above the lower inflection point of the pressure/volume (PV) curve is not necessarily required to maintain recruited lung volume in acute lung injury. DESIGN: Prospective, randomized, controlled animal study. SETTING: An animal laboratory in a university setting. SUBJECTS: Adult New-Zealand rabbits. INTERVENTIONS: We studied a) the relationship of dynamic loops during intermittent positive pressure ventilation to the quasi-static PV curve, and b) the effect of lung recruitment on oxygenation, end-expiratory lung volume (EELV), and dynamic compliance in two groups (n = 4 per group) of lung-injured animals (lung lavage model): 1) the sustained inflation group, which received ventilation after a recruitment maneuver (sustained inflation); and 2) the control group, which received ventilation without any lung recruitment. MEASUREMENTS AND MAIN RESULTS: In the presence of PV hysteresis, a single sustained inflation to 30 cm H2O boosted the ventilatory cycle onto the deflation limb of the PV curve. This resulted in a significant increase in EELV, oxygenation, and dynamic compliance despite equal PEEP levels used before and after the recruitment maneuver. Furthermore, after a single sustained inflation, oxygenation remained high over 4 hrs of ventilation when a PEEP above the critical closing pressure of the lungs, defined as "optimal" PEEP, was used and was significantly higher compared with that in the control group ventilated at equal PEEP without preceding lung recruitment. CONCLUSIONS: The observation that ventilation occurs on the deflation limb of the tidal cycle-specific PV curve allows placement of the ventilatory cycle, by means of a recruitment maneuver, onto the deflation limb of the PV envelope of the optimally recruited lung. This strategy ensures sufficient lung volume recruitment to maintain the lungs during the tidal cycle while using relatively low airway pressures.     

Low positive end-expiratory pressure does not exacerbate nebulized-acid lung injury in dogs

It is not clear if low end-expiratory pressures contribute to ventilator-induced lung injury in large animals. We sought to determine whether ventilation with a low level of positive end-expiratory pressure (PEEP) worsens preexisting permeability lung injury in dogs. Lung injury was initiated in 20 mongrel dogs by ventilating with nebulized 3N hydrochloric acid until a lower inflection point (LIP) appeared on the respiratory system pressure-volume loop. One group of 10 dogs was then ventilated for 4 hours with PEEP set below the LIP (low PEEP), whereas the remaining group of dogs was ventilated for the same time period with similar tidal volumes but with PEEP set above the LIP (high PEEP). We found histologic evidence of reduced alveolar volumes in the low-PEEP animals. However, there were no differences in neutrophil infiltration, lung lobe weights, pulmonary capillary hemorrhage or congestion, or arterial endothelin-1 concentration between the 2 protocol groups. In conclusion, we were unable to demonstrate that ventilation with PEEP set below the LIP exacerbates hydrochloric acid-induced lung injury in dogs.     

A novel model of selective lung ventilation to investigate the long-term effects of ventilation-induced lung injury

Mechanical ventilation (MV) with large tidal volumes (V(T)) causes ventilator induced lung injury. Whereas immediate effects of short-term injurious ventilation are well studied, little is known about its long-term effects. We aimed to establish an animal model of selective injurious MV, permitting assessment of the long-term course of ventilation-induced lung injury. In anesthetized and instrumented rats (n = 26), laryngoscopy was performed, and one cannula for MV was placed in the left main bronchus and a second one in the trachea. Two ventilators were used to ventilate the left lung with high (20 mL/kg) and the right lung with low (4 mL/kg) V(T). In control animals, both lungs received low V(T). After 2 h of MV, animals were extubated and observed for 24 h and then killed. Left and right lungs were excised and sampled for further investigations. Survival in animals ventilated with the high V(T) was 90%. Twenty-four hours after MV, alveolar levels of humoral (tumor necrosis factor alpha, interleukin 6) and cellular (polymorphonuclear leukocytes) inflammatory markers were increased, and histological alterations were present in lungs ventilated with high V(T). A delayed decrease in PaO2 was noted 24 h after MV, with high V(T) delivered to one lung as compared with low V(T) delivered to both lungs. This animal model permits assessment of the long-term course of ventilation-induced lung injury and shows that pulmonary inflammation and histological alterations are present 24 h after unilateral injurious ventilation.     

Lung recruitment during small tidal volume ventilation allows minimal positive end-expiratory pressure without augmenting lung injury.

OBJECTIVES: Ventilation with positive end-expiratory pressure (PEEP) above the inflection point (P(inf)) has been shown to reduce lung injury by recruiting previously closed alveolar regions; however, it carries the risk of hyperinflating the lungs. The present study examined the hypothesis that a new strategy of recruiting the lung with a sustained inflation (SI), followed by ventilation with small tidal volumes, would allow the maintenance of low PEEP levels ( P(inf). MEASUREMENTS AND MAIN RESULTS: In groups 2 and 4, static compliance decreased after ventilation (p < .01). Histologically, group 2 (PEEP < P(inf) without SI) showed significantly greater injury of small airways, but not of terminal respiratory units, compared with group 1. Group 3 (PEEP < P(inf) after a SI), but not group 4, showed significantly less injury of small airways and terminal respiratory units compared with group 2. CONCLUSIONS: We conclude that small tidal volume ventilation after a recruitment maneuver allows ventilation on the deflation limb of the pressure/volume curve of the lungs at a PEEP < P(inf). This strategy a) minimizes lung injury as well as, or better than, use of PEEP > P(inf), and b) ensures a lower PEEP, which may minimize the detrimental consequences of high lung volume ventilation.     

Using pressure-volume curves to set proper PEEP in acute lung injury

The evolution of respiratory care on patients with acute respiratory distress syndrome (ARDS) has been focused on preventing the deleterious effects of mechanical ventilation, termed ventilator-induced lung injury (VILI). Currently, reduced tidal volume is the standard of ventilatory care for patients with ARDS. The current focus, however, has shifted to the proper setting of positive end-expiratory pressure (PEEP). The whole lung pressure-volume (P/V) curve has been used to individualize setting proper PEEP in patients with ARDS, although the physiologic interpretation of the curve remains under debate. The purpose of this review is to present the pros and cons of using P/V curves to set PEEP in patients with ARDS. A systematic analysis of recent and relevant literature was conducted. It has been hypothesized that proper PEEP can be determined by identifying P/V curve inflection points. Acquiring a dynamic curve presents the key to the curve's bedside application. The lower inflection point of the inflation limb has been shown to be the point of massive alveolar recruitment and therefore an option for setting PEEP. However, it is becoming widely accepted that the upper inflection point (UIP) of the deflation limb of the P/V curve represents the point of optimal PEEP. New methods used to identify optimal PEEP, including tomography and active compliance measurements, are currently being investigated. In conclusion, we believe that the most promising method for determining proper PEEP settings is use of the UIP of the deflation limb. However, tomography and dynamic compliance may offer superior bedside availability.     

Positive end-expiratory pressure above lower inflection point minimizes influx of activated neutrophils into lung

OBJECTIVES: To compare the effects of low vs. high tidal volume (Vt) with three positive end-expiratory pressure (PEEP) strategies on activated neutrophil influx into the lung. DESIGN: Prospective, randomized controlled animal study. SETTING: Animal laboratory in a university hospital. SUBJECTS: Newborn piglets. INTERVENTIONS: Surfactant-depleted piglets were randomized in littermate pairs; to PEEP of either 0 (zero end-expiratory pressure [ZEEP]; n = 6), 8 cm H2O (PEEP 8; n = 5), or 1 cm H2O above the lower inflection point (LIP) (PEEP>LIP; n = 6). Within each pair piglets were randomized to a low VT (5-7 mL/kg) or high VT strategy (17-19 mL/kg). After 4 hrs of mechanical ventilation, 18-fluorodeoxyglucose (18FDG) was injected and positron emission tomography scanning was performed. MEASUREMENTS AND MAIN RESULTS: VT and PEEP changes on influx constants of 18FDG were assessed by analysis of variance. A within-litter comparison of Vt was nonsignificant (p = .50). A between-litter comparison, ordered in linear trend rank, from ZEEP, to PEEP 8, to PEEP>LIP, showed a strong effect of PEEP on influx constant (p = .019). CONCLUSIONS: PEEP set above the LIP on the inspiratory limb of the pressure-volume curve affords a stronger lung protection than VT strategy.     

Static and dynamic pressure-volume curves reflect different aspects of respiratory system mechanics in experimental acute respiratory distress syndrome.

INTRODUCTION: A lower inflection point, an upper inflection (or deflection) point, and respiratory system compliance can be estimated from an inspiratory static pressure-volume (SPV) curve of the respiratory system. Such data are often used to guide selection of positive end-expiratory pressure (PEEP)/tidal volume combinations. Dynamic pressure-volume (DPV) curves obtained during tidal ventilation are effortlessly displayed on modern mechanical ventilator monitors and bear a theoretical but unproven relationship to the more labor-intensive SPV curves. OBJECTIVE: Attempting to relate the SPV and DPV curves, we assessed both curves under a range of conditions in a canine oleic acid lung injury model. METHODS: Five mongrel dogs were anesthetized, paralyzed, and monitored to assure a stable preparation. Acute lung injury was induced by infusing oleic acid. SPV curves were constructed by the super-syringe method. DPV curves were constructed for a range of PEEP and inspiratory constant flow settings while ventilating at a frequency of 15 breaths/min and tidal volume of 350 mL. Functional residual capacity at PEEP = 0 cm H2O was measured by helium dilution. The change in lung volume by PEEP at 8, 16, and 24 cm H2O was measured by respiratory inductance plethysmography. RESULTS: The slope of the second portion of the DPV curve did not parallel the corresponding slope of the SPV curve. The mean lower inflection point of the SPV curve was 13.2 cm H2O, whereas the lower inflection point of the DPV curve was related to the prevailing flow and PEEP settings. The absolute lung volume during the DPV recordings exceeded (p < 0.05) that anticipated from the SPV curves by (values are mean +/- SEM) 267 +/- 86 mL, 425 +/- 129 mL, and 494 +/- 129 mL at end expiration for PEEP = 8, 16, and 24 cm H2O, respectively. CONCLUSIONS: The contours of the SPV curve are not reflected by those of the DPV curve in this model of acute lung injury. Therefore, this study indicates that DPV curve should not be used to guide the selection of PEEP/tidal volume combinations. Furthermore, an increase in end-expiratory lung volume occurs during tidal ventilation that is not reflected by the classical SPV curve, suggesting a stable component of lung volume recruitment attributable to tidal ventilation, independent of PEEP.     

Inspiratory vs. expiratory pressure-volume curves to set end-expiratory pressure in acute lung injury

Objective To study the effects of two levels of positive end-expiratory pressure (PEEP), 2 cmH₂O above the lower inflection point of the inspiratory limb and equal to the point of maximum curvature on the expiratory limb of the pressure-volume curve, in gas exchange, respiratory mechanics, and lung aeration.Design and setting Prospective clinical study in the intensive care unit and computed tomography ward of a university hospital.Patients Eight patients with early acute lung injury.Interventions Both limbs of the static pressure-volume curve were traced and inflection points calculated using a sigmoid model. During ventilation with a tidal volume of 6 ml/kg we sequentially applied a PEEP 2 cmH₂O above the inspiratory lower inflection point (15.5±3.1 cmH₂O) and a PEEP equal to the expiratory point of maximum curvature (23.5±4.1 cmH₂O).Measurements and results Arterial blood gases, respiratory system compliance and resistance and changes in lung aeration (measured on three computed tomography slices during end-expiratory and end-inspiratory pauses) were measured at each PEEP level. PEEP according to the expiratory point of maximum curvature was related to an improvement in oxygenation, increase in normally aerated, decrease in nonaerated lung volumes, and greater alveolar stability. There was also an increase in PaCO₂, airway pressures, and hyperaerated lung volume.Conclusions High PEEP levels according to the point of maximum curvature of the deflation limb of the pressure-volume curve have both benefits and drawbacks.This work was supported by a grant from Fondo de Investigación Sanitaria (PI03/0833) and Red GIRA (G03/063)     

根据压力-容积曲线选择理想潮气量对呼吸机护理的指导

目的探讨使用呼吸机时,不同的潮气量对急性肺损伤患者血流动力学、肺通气和肺机械力学的影响及护理要点。方法对ICU急性肺损伤16例患者采取自身对照的方法,利用压力-容积（P．v）曲线下曲点＋0．196kPa确定呼气末正压（PEEP）后,再根据P—V曲线的上拐点（VUIP）,分别取上拐点对应的潮气量100％Vt、85％Vt和70％Vt分为3组,以相同的分钟通气量和吸入氧浓度分别给予定容机械通气,监测肺机械力学、血流动力学、血气改变及P—V曲线的变化。结果85％Vt组在心率、中心静脉压、动脉血氧分压、气道峰值压、气道平均压及系统静态顺应性等对患者的综合影响优于100％Vt组和70％Vt组。结论以呼吸系统P-V曲线的下曲点（Pinf）确定PEEP值,以上拐点压力对应的潮气量的85％调节潮气量符合个体化保护性通气策略,对改善肺的顺应性、降低肺病理性损伤效果最好。护理时应注重P—V曲线的变化。     

PEEP has beneficial effects on inflammation in the injured and no deleterious effects on the noninjured lung after unilateral lung acid instillation

Objective In clinical lung injury areas of inflammation and structural alveolar alteration are unevenly distributed and interspaced between healthy or less injured lung areas. Positive end-expiratory pressure (PEEP) applied with mechanical ventilation (MV) may affect injured and healthy lung areas differently. We compared the effects of PEEP on the inflammatory response in injured and noninjured regions of the lung in an animal model of unilateral lung acid instillation.Subjects Anesthetized, paralyzed, and ventilated rats.Interventions Rats underwent left-endobronchial instillation with either hydrochloric acid or isotonic saline and were randomized 24 h later to MV using constant tidal volume (16 ml/kg) with either ZEEP, PEEP at 5 mmHg, or PEEP at 10 mmHg. After 4 h of MV the animals (n = 9 or 10 per group) were killed and inflammatory markers assessed in left- and right-lung lavage fluid samples. In four additional animals per group differential lung perfusion was assessed.Results Unilateral acid injury alone worsened oxygenation, decreased left-lung perfusion, and increased left-lung lavage neutrophil and macrophage counts and cytokine levels. MV with ZEEP further impaired oxygenation and further decreased left-lung perfusion in acid-injured animals. MV with high PEEP preserved oxygenation and significantly decreased left-lung lavage protein content and cell counts in acid-injured animals and had no deleterious effect on the right (noninjured) lung.Conclusion In this model of unilateral lung acid injury high PEEP attenuates the inflammatory cell response in the acid-injured lung, preserved oxygenation and has no deleterious effects in the opposite lung.Electronic supplementary material The electronic reference of this article is . The online full-text version of this article includes electronic supplementary material. This material is available to authorised users and can be accessed by means of the ESM button beneath the abstract or in the structured full-text article. To cite or link to this article you can use the above reference.     

Respective effects of end-expiratory and end-inspiratory pressures on alveolar recruitment in acute lung injury

OBJECTIVE: A low tidal volume can induce alveolar derecruitment in patients with acute lung injury. This study was undertaken to evaluate whether this resulted mainly from the decrease in tidal volume or from the reduction in end-inspiratory plateau pressure and whether there is any benefit in raising the level of positive end-expiratory pressure (PEEP) while plateau pressure is kept constant. DESIGN: Prospective crossover study. SETTING: Medical intensive care unit of a university teaching hospital. PATIENTS: Fifteen adult patients ventilated for acute lung injury (PaO2/FiO2, 158 +/- 34 mm Hg; lung injury score, 2.7 +/- 0.6). INTERVENTIONS: Three combinations were tested: PEEP at the lower inflection point with 6 mL/kg tidal volume, PEEP at the lower inflection point with 10 mL/kg tidal volume, and high PEEP with tidal volume at 6 mL/kg, keeping the plateau pressure similar to the preceding condition. MEASUREMENTS AND MAIN RESULTS: Pressure-volume curves at zero PEEP and at set PEEP were recorded, and recruitment was calculated as the volume difference between both curves for pressures ranging from 15 to 30 cm H2O. Arterial blood gases were measured for all patients. For a similar PEEP at the lower inflection point (10 +/- 3 cm H2O), tidal volume reduction (10 to 6 mL/kg) led to a significant derecruitment. A low tidal volume (6 mL/kg) with high PEEP (14 +/- 3 cm H2O), however, induced a significantly greater recruitment and a higher Pao than the two other strategies. CONCLUSION: At a given plateau pressure (i.e., similar end-inspiratory distension), lowering tidal volume and increasing PEEP increase recruitment and PaO2.     

Effects of positive end-expiratory pressure on hyaline membrane formation in a rabbit model of the neonatal respiratory distress syndrome

Sixteen rabbits were anaesthetized and subjected to saline lavage of the lungs to produce surfactant deficiency. This resulted in an arterial oxygen tension of less than 12 kPa on 100% inspired oxygen and an inflection point on the pressure-volume curve at a pressure of 8–12 mmHg. After lavage the animals were randomly assigned to receive either conventional mechanical ventilation (CMV) with a positive end-expiratory pressure (PEEP) of 1–2 mmHg (group I —low PEEP) or CMV with PEEP equal to the inflection point pressure (group II — high PEEP). Mean airway pressures were kept at 14–16 mmHg in both groups by increasing the inspiratory: expiratory time ratios in the low PEEP group. The 5-h protocol was completed by 4 animals in group I and 6 animals in group II, early death usually being associated with a metabolic acidosis. On 100% oxygen, the mean PaO₂ at 2-h post-lavage was 15.2±8.3 kPa in group I and 39.6±21.8 kPa in group II. Group I had much lower end-expiratory lung volumes (3.0±1.5 ml above FRC) than group II (34.9±12.2 ml above FRC). Histological examination of the lungs revealed significantly less hyaline membrane formation in group II (p=0.001). Thus, the prevention of alveolar collapse by the use of high PEEP levels appears to reduce lung damage in this preparation.     

Lung collapse during low tidal volume ventilation in acute respiratory distress syndrome

BACKGROUND: Current ventilator management for acute respiratory distress syndrome (ARDS) incorporates low tidal volume (V(T)) ventilation in order to limit ventilator-induced lung injury. Low V(T) ventilation in supine patients, without the use of intermittent hyperinflations, may cause small airway closure, progressive atelectasis, and secretion retention. Use of high positive end-expiratory pressure (PEEP) levels with low V(T) ventilation may not counter this effect, because regional differences in intra-abdominal hydrostatic pressure may diminish the volume-stabilizing effects of PEEP. CASE SUMMARY: A 35-year-old man with abdominal compartment syndrome (intra-abdominal pressure > 48 cm H2O developed ARDS and was treated with V(T) of 4.5 mL/kg and PEEP of 20 cm H2O. Despite aggressive fluid therapy, appropriate airway humidification and tracheal suctioning, the patient developed complete bronchial obstruction, involving the entire right lung and left upper lobe. After bronchoscopy the patient was placed on a higher V(T) (7.0 mL/kg). Intermittent PEEP was instituted at 30 cm H2O for 2 breaths every 3 minutes. This intermittently raised the end-inspiratory plateau pressure from 38 cm H2O to 50 cm H2O. With the same airway humidity and tracheal suctioning practices bronchial obstruction did not reoccur. CONCLUSION: Low V(T) ventilation in ARDS may increase the risk of small airway closure and retained secretions. This adverse effect highlights the importance of pulmonary hygiene measures in ARDS during lung-protective ventilation.     

Approaches to conventional mechanical ventilation of the patient with acute respiratory distress syndrome

To minimize ventilator-induced lung injury, attention should be directed toward avoidance of alveolar over-distention and cyclical opening and closure of alveoli. The most impressive study of mechanical ventilation to date is the Acute Respiratory Distress Syndrome (ARDS) Network study of higher versus lower tidal volume (V(T)), which reported a reduction in mortality from 39.8% to 31.0% with 6 mL/kg ideal body weight rather than 12 mL/kg ideal body weight (number-needed-to-treat of 12 patients). To achieve optimal lung protection, the lowest plateau pressure and V(T) possible should be selected. What is most important is limitation of V(T) and alveolar distending pressure, regardless of the mode set on the ventilator. Accumulating observational evidence suggests that V(T) should be limited in all mechanically ventilated patients-even those who do not have ALI/ARDS. Evidence does not support the use of pressure controlled inverse-ratio ventilation. Although zero PEEP is probably injurious, an area of considerable controversy is the optimal setting of PEEP. Available evidence does not support the use of higher PEEP, compared to lower PEEP, in unselected patients with acute lung injury (ALI)/ARDS. However, results of a meta-analysis using individual patients from 3 randomized controlled trials suggest that higher PEEP should be used for ARDS, whereas lower PEEP may be more appropriate in patients with ALI. PEEP should be set to maximize alveolar recruitment while avoiding over-distention. Many approaches for setting PEEP have been described, but evidence is lacking that any one approach is superior to any other. In most, if not all, cases of ALI/ARDS, conventional ventilation strategies can be used effectively to provide lung-protective ventilation strategies.     

根据压力-容积曲线选择理想潮气量对呼吸机护理的指导

目的 探讨使用呼吸机时,不同的潮气量对急性肺损伤患者血流动力学、肺通气和肺机械力学的影响及护理要点.方法 对ICU急性肺损伤16例患者采取自身对照的方法,利用压力-容积(P-V)曲线下曲点+0.196 kPa确定呼气末正压(PEEP)后,再根据P-V曲线的上拐点(VUIP),分别取上拐点对应的潮气量100%Vt、85%Vt和70%Vt分为3组,以相同的分钟通气量和吸入氧浓度分别给予定容机械通气,监测肺机械力学、血流动力学、血气改变及P-V曲线的变化.结果 85%Vt组在心率、中心静脉压、动脉血氧分压、气道峰值压、气道平均压及系统静态顺应性等对患者的综合影响优于100%Vt组和70%Vt组.结论 以呼吸系统P-V曲线的下曲点(Pinf)确定PEEP值,以上拐点压力对应的潮气量的85%调节潮气量符合个体化保护性通气策略,对改善肺的顺应性、降低肺病理性损伤效果最好.护理时应注重P-V曲线的变化.     

Recruitment maneuvers attenuate repeated derecruitment-associated lung injury

OBJECTIVE: Repeated derecruitments of previously recruited lungs can exacerbate lung injuries during mechanical ventilation. The aim of this study was to assess lung injury associated with repeated derecruitments and to assess whether this type of injury could be attenuated by recruitment maneuvers. DESIGN: Prospective, randomized, experimental animal study. SETTING: University laboratory. SUBJECTS: New Zealand White rabbits. INTERVENTIONS: Twenty-one rabbits were ventilated in pressure-controlled mode with constant tidal volume (10 mL/kg). After lung injury was induced by repeated saline lavage, positive end-expiratory pressure (PEEP) at a lower inflection point was applied for 3 hrs. The control group (n = 7) received ventilation with the same PEEP for 3 hrs without derecruitments. In the derecruitment group (n = 7), derecruitment was repeatedly induced by intentional disconnection of the ventilatory circuit for 1 min every 10 mins for 3 hrs. In the recruitment maneuver group (n = 7), continuous positive airway pressure of 30 cm H2O was applied for 30 secs after each derecruitment. MEASUREMENTS AND MAIN RESULTS: After PEEP levels were increased to lower the inflection point value, Pao2 increased to >500 mm Hg in all groups. Increased Pao2 persisted at >450 mm Hg in the control and recruitment maneuver groups, whereas progressive declines in arterial oxygen levels were observed in the derecruitment group (median, 381.1 mm Hg [interquartile range, 350.1-466.7 mm Hg] at 2 hrs and 318.2 mm Hg [214.3-414.9 mm Hg] at 3 hrs, p < .05 compared with other groups). Histologically, there was significantly increased hyaline membrane formation in alveolar ducts in the derecruitment group compared with the control group (p = .005). Also, significantly more membranous and respiratory bronchiolar injuries were observed in the derecruitment group compared with the control and recruitment maneuver group (p < .005). CONCLUSIONS: These findings suggest that repeated derecruitments could induce lung injuries during mechanical ventilation, and recruitment maneuvers may attenuate derecruitment-associated lung injuries.     

Cyclin-dependent kinase inhibition reduces lung damage in a mouse model of ventilator-induced lung injury

Mechanical ventilation (MV) has the potential to induce lung damage in healthy lungs or aggravate existing lung injury. Polymorphonuclear neutrophil (PMN) recruitment plays an important role in driving the inflammatory response in ventilator-induced lung injury (VILI). The cyclin-dependent kinase inhibitor r-roscovitine has been shown to induce apoptosis in PMNs. In this study, we investigated the potential of r-roscovitine treatment in reducing lung damage in a mouse model of VILI. Mice were tracheotomized and subjected to lung-protective MV with lower (～7.5 mL/kg) or lung-injurious MV with higher (～15 mL/kg) tidal volume (VT). R-roscovitine treatment enhanced apoptosis in PMNs in vitro. Ventilator-induced lung injury was associated with pulmonary PMN influx in low and high VT MV. During lung-injurious MV, r-roscovitine treatment reduced the number of PMNs and lowered levels of the lung damage markers RAGE (receptor for advanced glycation end products) and total immunoglobulin M in bronchoalveolar lavage fluid. R-roscovitine did not affect cytokine or chemokine levels in the bronchoalveolar space, neither during lung-protective nor lung-injurious MV. Thus, r-roscovitine treatment reduces lung damage in VILI, possibly dependent on increased apoptosis of PMNs.     

高呼气末正压通气结合小潮气量对急性肺损伤/急性呼吸窘迫综合征患者预后影响的荟萃分析

目的 系统评价高呼气末正压(PEEP)与低PEEP机械通气对急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)患者预后的影响.方法 通过检索美国<医学索引>、荷兰<医学文摘>、Cochrane临床试验数据库、中国生物医学文献数据库(CBM)和中国期刊网全文数据库(CNKI)等文献数据库,全面收集全世界范围内高PEEP与低PEEP治疗ALI/ARDS患者的随机对照试验(RCT),提取文献中的相关资料和评估方法学质量,而后采用Cochrane协作网RevMan 5.0软件对资料进行荟萃分析(Meta分析).结果 最终纳入6个RCT共2484例ALI/ARDS患者.A亚组的3个RCT中试验组采用了高PEEP(相对于对照组),对照组采用了低PEEP(相对于试验组),两组均采用了小潮气量(6 ml/kg)通气;B亚组的3个RCT中试验组采用了高PEEP加小潮气量,对照组采用了低PEEP加传统潮气量通气.合并结果显示,B亚组中高PEEP加小潮气量通气策略可以降低患者的28 d病死率[Peto比值比(OR)=0.40,95%可信区间(95%CI)0.22～0.72,P=0.003]和气压伤发生率(OR=0.20,95%CI 0.05～0.82,P=0.02);A亚组中,两组患者的28 d病死率(OR=0.86,95%CI 0.72～1.02,P=0.08)和气压伤发生率(OR=1.19,95%CI 0.89～1.58,P=0.25)差异无统计学意义.结论 高PEEP加小潮气量通气可以改善ALI/ARDS患者的28 d病死率和气压伤发生率,单独高PEEP的作用需要进一步评价.

Abstract：

Objective To compare the effects of high and low positive end-expiratory pressure (PEEP) levels on prognosis of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Methods The data in PubMed, EMbase, Cochrane Library, CBM and CNKI were retrieved. All randomized controlled trials (RCTs) of treatment of ALI/ARDS with PEEP with high or low level were included. Study selection and assessment, data collection and analyses were undertaken by two independent reviewers. Meta-analyses were done using Cochrane Collaboration's RevMan 5.0 software.Results Six RCTs, involving a total of 2 484 patients of ALI/ARDS were included in the review. According to ventilation strategy, all trials were divided into subgroup A (high PEEP+low tidal volume of 6 ml/kg vs.low PEEP+low tidal volume) and subgroup B (high PEEP+low tidal volume vs. low PEEP+traditional tidal volume). In subgroup B, there were three RCTs, and high PEEP was found to be associated with a lower 28-day mortality [odds ratio (OR)=0. 40, 95% confidence interval (95%CI) 0.22 -0.72, P=0.003]and a lower barotraumas (OR = 0.20,95%CI 0.05 - 0.82, P = 0.02) in patients with ALI/ARDS. In subgroup A, there were three RCTs, and it was found that the differences in 28-day mortality (OR=0.86,95%CI 0.72 - 1.02, P = 0.08) and barotraumas (OR = 1.19, 95%CI 0.89 - 1.58, P= 0.25) were not significant. Conclusion As compared with conventional ventilation, high PEEP and low tidal volume ventilation are associated with improved survival and a lower rate of barotrauma in patients with ALI/ARDS.It is necessary to further confirm the role of high PEEP only in the ventilation strategy in patients with ALI/ARDS.