Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice

INTRODUCTION: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis. METHODS: Healthy C57Bl/6 mice (n = 66) or BALB/c mice (n = 66) were ventilated (tidal volume = 7.5 ml/kg or 15 ml/kg; positive end-expiratory pressure = 2 cmH2O; fraction of inspired oxygen = 0.5) for five hours. Normal saline or sodium bicarbonate were used to correct for hypovolaemia. Lung histopathology, lung wet-to-dry ratio, bronchoalveolar lavage fluid protein content, neutrophil influx and levels of proinflammatory cytokines and coagulation factors were measured. RESULTS: Animals remained haemodynamically stable throughout the whole experiment. Lung histopathological changes were minor, although significantly more histopathological changes were found after five hours of MV with a larger tidal volume. Lung histopathological changes were no different between the strains. In both strains and with both ventilator settings, MV caused higher wet-to-dry ratios, higher bronchoalveolar lavage fluid protein levels and more influx of neutrophils, and higher levels of proinflammatory cytokines and coagulation factors. Also, with MV higher systemic levels of cytokines were measured. All parameters were higher with larger tidal volumes. Correcting for metabolic acidosis did not alter endpoints. CONCLUSIONS: MV induces VILI, in the absence of a priming pulmonary insult and even with use of relevant (least injurious) ventilator settings. This model offers opportunities to study the pathophysiological mechanisms behind VILI and the contribution of MV to lung injury in the absence of pre-existing lung injury

Relative Tissue Factor Deficiency Attenuates Ventilator-Induced Coagulopathy but Does Not Protect against Ventilator-Induced Lung Injury in Mice

Preventing tissue-factor-(TF-) mediated systemic coagulopathy improves outcome in models of sepsis. Preventing TF-mediated pulmonary coagulopathy could attenuate ventilator-induced lung injury (VILI). We investigated the effect of relative TF deficiency on pulmonary coagulopathy and inflammation in a murine model of VILI. Heterozygous TF knockout (TF+/−) mice and their wild-type (TF+/+) littermates were sedated (controls) or sedated, tracheotomized, and mechanically ventilated with either low or high tidal volumes for 5 hours. Mechanical ventilation resulted in pulmonary coagulopathy and inflammation, with more injury after mechanical ventilation with higher tidal volumes. Compared with TF+/+ mice, TF+/− mice demonstrated significantly lower pulmonary thrombin-antithrombin complex levels in both ventilation groups. There were, however, no differences in lung wet-to-dry ratio, BALF total protein levels, neutrophil influx, and lung histopathology scores between TF+/− and TF+/+ mice. Notably, pulmonary levels of cytokines were significantly higher in TF+/− as compared to TF+/+ mice. Systemic levels of cytokines were not altered by the relative absence of TF. TF deficiency is associated with decreased pulmonary coagulation independent of the ventilation strategy. However, relative TF deficiency does not reduce VILI and actually results in higher pulmonary levels of inflammatory mediators

Mechanical ventilation with lower tidal volumes does not influence the prescription of opioids or sedatives

INTRODUCTION: We compared the effects of mechanical ventilation with a lower tidal volume (V(T)) strategy versus those of greater V(T) in patients with or without acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) on the use of opioids and sedatives. METHODS: This is a secondary analysis of a previously conducted before/after intervention study, which consisting of feedback and education on lung protective mechanical ventilation using lower V(T). We evaluated the effects of this intervention on medication prescriptions from days 0 to 28 after admission to our multidisciplinary intensive care unit. RESULTS: Medication prescriptions in 23 patients before and 38 patients after intervention were studied. Of these patients, 10 (44%) and 15 (40%) suffered from ALI/ARDS. The V(T) of ALI/ARDS patients declined from 9.7 ml/kg predicted body weight (PBW) before to 7.8 ml/kg PBW after the intervention (P = 0.007). For patients who did not have ALI/ARDS there was a trend toward a decline from 10.2 ml/kg PBW to 8.6 ml/kg PBW (P = 0.073). Arterial carbon dioxide tension was significantly greater after the intervention in ALI/ARDS patients. Neither the proportion of patients receiving opioids or sedatives, or prescriptions at individual time points differed between pre-intervention and post-intervention. Also, there were no statistically significant differences in doses of sedatives and opioids. Findings were no different between non-ALI/ARDS patients and ALI/ARDS patients. CONCLUSION: Concerns regarding sedation requirements with use of lower V(T) are unfounded and should not preclude its use in patients with ALI/ARD

Plasminogen Activator Inhibitor-Type I Gene Deficient Mice Show Reduced Influx of Neutrophils in Ventilator-Induced Lung Injury

Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes (LVT) or high tidal volumes (HVT). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with HVT as compared to LVT. In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI

Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial

Introduction: Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation. Methods: We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality. Results: One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury. Conclusions: Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation. (aut. ref.

Adoption of lower tidal volume ventilation improves with feedback and education

OBJECTIVE: To determine whether feedback and education improve adoption of lung-protective mechanical ventilation (ie, with lower tidal volume [V(T)]). METHODS: We conducted a retrospective study of ventilator settings; we used data from 3 consecutive studies of patients with acute lung injury and/or acute respiratory distress syndrome, in the intensive care units of 2 university hospitals in the Netherlands. At site 1 we conducted a time series study of before and after education and feedback about lung-protective mechanical ventilation, and we compared the results from site 1 to the ventilation strategies used at site 2, which did not undergo the education and feedback intervention. Feedback and education consisted of presentations of actual ventilator settings, advised ventilator settings, and discussions on potential reasons for not using lower V(T). RESULTS: Two studies were performed at site 1, in 1999-2000 (Study 1, n = 22) and in 2002 (Study 2, n = 12). In 2003-2004, Study 3 was performed simultaneously at site 1 (n = 8) and site 2 (n = 17). At site 1, the mean +/- SD V(T) was 10.9 mL/kg predicted body weight (PBW) (95% CI 10.3-11.6) in Study 1 and 9.9 mL/kg PBW (95% CI 9.0-10.8) in Study 2 (difference not significant). After the feedback and education intervention at site 1, V(T) declined to 7.6 mL/kg PBW (95% CI 6.5-8.7) in Study 3 (p = 0.003). At site 2, where no feedback or education were given, V(T) was 10.3 mL/kg PBW (95% CI 9.5-11.0) in Study 3 (p < 0.001 vs Site 1). CONCLUSIONS: Adoption of a lower-V(T) ventilation strategy in patients with acute lung injury or acute respiratory distress syndrome is far from complete in the Netherlands. Adoption of a lower-V(T) strategy improves after feedback and educatio

Lung epithelial injury markers are not influenced by use of lower tidal volumes during elective surgery in patients without preexisting lung injury

Clara cell protein levels are elevated in plasma of individuals with mild or subclinical lung injury. We studied the influence of two mechanical ventilation strategies on local and systemic levels of Clara cell protein (CC16) and compared them with levels of soluble receptor for advanced glycation end products (sRAGE) and surfactant proteins (SP)-A and -D in patients undergoing elective surgery. Saved samples from a previously reported investigation were used for the study. Forty patients planned for elective surgery were randomized to mechanical ventilation with either a conventional tidal volume (V(T)) of 12 ml/kg without positive end-expiratory pressure (PEEP) or low V(T) of 6 ml/kg and 10 cmH(2)O PEEP. Plasma and bronchoalveolar lavage fluid (BALF) was collected directly after intubation and after 5 h of mechanical ventilation. While systemic levels of SP-A and SP-D remained unchanged, systemic levels of CC16 and sRAGE increased significantly in both groups after 5 h (P < 0.001 for both). BALF levels of SP-A, SP-D, CC16, and sRAGE remained unaffected. No differences were found between the two mechanical ventilation strategies regarding any of the measured biological markers. In conclusion, systemic levels of CC16 and sRAGE rise after 5 h in patients receiving mechanical ventilation for elective surgery. Mechanical ventilation with lower tidal volumes and PEEP did not have a different effect on levels of biomarkers of lung epithelial injury compared with conventional mechanical ventilatio

Feedback and education improve physician compliance in use of lung-protective mechanical ventilation

Objective: Use of lung-protective mechanical ventilation (MV) by applying lower tidal volumes is recommended in patients suffering from acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Recent data suggest that lung-protective MV may benefit non-ALI/ARDS patients as well. This study analyzed tidal volume settings in three ICUs in The Netherlands to determine the effect of feedback and education concerning use of lung-protective MV. Design and setting: Observational study in one academic and two nonacademic "closed format" ICUs. Patients: Intubated mechanically ventilated subjects. Interventions: Feedback and education concerning lung-protective MV with special attention to the importance of closely adjusting tidal volumes to predicted body weight (PBW). Results: Tidal volumes declined significantly within 6 months after intervention (from 9.8 +/- 2.0 at baseline to 8.1 +/- 1.7 ml/kg PBW) as the percentage of undesirable ventilation data points, defined as tidal volumes greater than 8 ml/kg PBW (84% vs. 48%). There were no differences between patients meeting the international definition criteria for ALI/ARDS and those not. Only four patients received tidal volumes less than 6 ml/kg PBW. Lower tidal volumes were still used after 12 months. Tidal volumes in patients on mandatory MV and patients breathing on spontaneous modes were similar. Conclusions: Feedback and education improve physician compliance in use of lung-protective M