Mechanical ventilation drives pneumococcal pneumonia into lung injury and sepsis in mice: protection by adrenomedullin

Introduction

Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute respiratory distress syndrome (ARDS). Particularly pre-injured lungs are susceptible to VILI despite protective ventilation. In a previous study, the endogenous peptide adrenomedullin (AM) protected murine lungs from VILI. We hypothesized that mechanical ventilation (MV) contributes to lung injury and sepsis in pneumonia, and that AM may reduce lung injury and multiple organ failure in ventilated mice with pneumococcal pneumonia.

Methods

We analyzed in mice the impact of MV in established pneumonia on lung injury, inflammation, bacterial burden, hemodynamics and extrapulmonary organ injury, and assessed the therapeutic potential of AM by starting treatment at intubation.

Results

In pneumococcal pneumonia, MV increased lung permeability, and worsened lung mechanics and oxygenation failure. MV dramatically increased lung and blood cytokines but not lung leukocyte counts in pneumonia. MV induced systemic leukocytopenia and liver, gut and kidney injury in mice with pneumonia. Lung and blood bacterial burden was not affected by MV pneumonia and MV increased lung AM expression, whereas receptor activity modifying protein (RAMP) 1–3 expression was increased in pneumonia and reduced by MV. Infusion of AM protected against MV-induced lung injury (66% reduction of pulmonary permeability p < 0.01; prevention of pulmonary restriction) and against VILI-induced liver and gut injury in pneumonia (91% reduction of AST levels p < 0.05, 96% reduction of alanine aminotransaminase (ALT) levels p < 0.05, abrogation of histopathological changes and parenchymal apoptosis in liver and gut).

Conclusions

MV paved the way for the progression of pneumonia towards ARDS and sepsis by aggravating lung injury and systemic hyperinflammation leading to liver, kidney and gut injury. AM may be a promising therapeutic option to protect against development of lung injury, sepsis and extrapulmonary organ injury in mechanically ventilated individuals with severe pneumonia.     

Mechanical ventilation in acute lung injury and ARDS. Tidal volume reduction

Traditional mechanical ventilation practices used generous tidal volumes in patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). This approach may have caused overdistention of aerated lung units, thus exacerbating lung injury in some patients. Several recent clinical trials of traditional versus lower tidal volume strategies in ALI/ARDS yielded disparate results. In the largest study, the lower tidal volume approach was associated with lower mortality and more ventilator-free days. This article reviews the rationale for tidal volume reduction in ALI/ARDS and the differences between the studies. Several different interpretations of the recent clinical trial results are addressed.     

Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model

Background  

Experimental and clinical studies on sepsis have demonstrated activation of the innate immune response following the initial host–bacterial interaction. In addition, mechanical ventilation (MV) can induce a pulmonary inflammatory response. How these two responses interact when present simultaneously remains to be elucidated. We hypothesized that MV modulates innate host response during sepsis by influencing Toll-like receptor (TLR) signaling.     

Mechanical ventilation aggravates transfusion-related acute lung injury induced by MHC-I class antibodies

Purpose  

Transfusion-related acute lung injury (TRALI) occurs more often in critically ill patients than in a general hospital population, possibly due to the presence of underlying inflammatory conditions that may prime pulmonary neutrophils. Mechanical ventilation may be a risk factor for developing TRALI. We examined the influence of mechanical ventilation (MV) on the development of TRALI, combining a murine MV model causing ventilator-induced lung injury with a model of antibody-induced TRALl.     

Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation

OBJECTIVE: Although ventilation with small tidal volumes is recommended in patients with established acute lung injury, most others receive highly variable tidal volume aimed in part at normalizing arterial blood gas values. We tested the hypothesis that acute lung injury, which develops after the initiation of mechanical ventilation, is associated with known risk factors for ventilator-induced lung injury such as ventilation with large tidal volume. DESIGN: Retrospective cohort study. SETTING: Four intensive care units in a tertiary referral center. PATIENTS: Patients who received invasive mechanical ventilation for > or = 48 hrs between January and December 2001. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main outcome of interest, acute lung injury, was assessed by independent review of daily digital chest radiographs and arterial blood gases. Ventilator settings, hemodynamics, and acute lung injury risk factors were extracted from the Acute Physiology and Chronic Health Evaluation III database and the patients' medical records. Of 332 patients who did not have acute lung injury from the outset, 80 patients (24%) developed acute lung injury within the first 5 days of mechanical ventilation. When expressed per predicted body weight, women were ventilated with larger tidal volume than men (mean 11.4 vs. 10.4 mL/kg predicted body weight, p <.001) and tended to develop acute lung injury more often (29% vs. 20%, p =.068). In a multivariate analysis, the main risk factors associated with the development of acute lung injury were the use of large tidal volume (odds ratio 1.3 for each mL above 6 mL/kg predicted body weight, p <.001), transfusion of blood products (odds ratio, 3.0; p < 0.001), acidemia (pH < 7.35; odds ratio, 2.0; p =.032) and a history of restrictive lung disease (odds ratio, 3.6; p =.044). CONCLUSIONS: The association between the initial tidal volume and the development of acute lung injury suggests that ventilator-associated lung injury may be an important cause of this syndrome. Height and gender should be considered when setting up the ventilator. Strong consideration should be given to limiting large tidal volume, not only in patients with established acute lung injury but also in patients at risk for acute lung injury.     

Mechanical ventilation and lung infection in the genesis of air-space enlargement

Introduction  

Air-space enlargement may result from mechanical ventilation and/or lung infection. The aim of this study was to assess how mechanical ventilation and lung infection influence the genesis of bronchiolar and alveolar distention.     

Quantification of lung injury using ventilation and perfusion distributions obtained from gamma scintigraphy

This paper explores the potential of isotope V/Q lung scans to quantify lung disease. Areas of restricted perfusion in subjects with a pulmonary embolus (PE) were identified in 3D reconstructions of V/Q images achieved using anatomical data from the Visible Human Project. From these, the extent of lung damage was quantified. Significant differences in the values of both LogSD V and LogSD Q (p > 0.05) obtained from plots of V and Q against Log(V/Q) were found between normal subjects and subjects with a PE, but no correlation was found between either of these parameters and the degree of lung damage in subjects with a PE (p > 0.05). Whilst V/Q values were log normally distributed, the V/Q distributions from the subjects with a PE failed to show the bimodal distribution predicted from theoretical considerations and MIGET measurements previously reported. There was a statistically significant difference in the mean and standard deviation values of the V/Q distributions between normal subject and subjects with a PE (p < 0.05) but not in the median values (p > 0.05). There was no correlation between the mean, median and standard deviation of the distributions from the subjects with a PE and the percentage of damage present (p > 0.05).     

Ventilator-related causes of lung injury: the mechanical power

Purpose

We hypothesized that the ventilator-related causes of lung injury may be unified in a single variable: the mechanical power. We assessed whether the mechanical power measured by the pressure–volume loops can be computed from its components: tidal volume (TV)/driving pressure (?P _aw), flow, positive end-expiratory pressure (PEEP), and respiratory rate (RR). If so, the relative contributions of each variable to the mechanical power can be estimated.

Methods

We computed the mechanical power by multiplying each component of the equation of motion by the variation of volume and RR:

$${\text{Power}}_{\text{rs}} = {\text{RR}} \cdot \left\{ {\Delta V^{2} \cdot \left[ {\frac{1}{2} \cdot {\text{EL}}_{\text{rs}} + {\text{RR}} \cdot \frac{{\left( {1 + I:E} \right)}}{60 \cdot I:E} \cdot R_{\text{aw}} } \right] + \Delta V \cdot {\text{PEEP}}} \right\},$$

where ?V is the tidal volume, EL_rs is the elastance of the respiratory system, I:E is the inspiratory-to-expiratory time ratio, and R _aw is the airway resistance. In 30 patients with normal lungs and in 50 ARDS patients, mechanical power was computed via the power equation and measured from the dynamic pressure–volume curve at 5 and 15 cmH₂O PEEP and 6, 8, 10, and 12 ml/kg TV. We then computed the effects of the individual component variables on the mechanical power.

Results

Computed and measured mechanical powers were similar at 5 and 15 cmH₂O PEEP both in normal subjects and in ARDS patients (slopes = 0.96, 1.06, 1.01, 1.12 respectively, R ² > 0.96 and p < 0.0001 for all). The mechanical power increases exponentially with TV, ?P _aw, and flow (exponent = 2) as well as with RR (exponent = 1.4) and linearly with PEEP.

Conclusions

The mechanical power equation may help estimate the contribution of the different ventilator-related causes of lung injury and of their variations. The equation can be easily implemented in every ventilator’s software.

     

Mechanical ventilation alters the immune response in children without lung pathology

OBJECTIVE: This study was undertaken to examine the hypothesis that mechanical ventilation in association with anesthesia would alter the cytokine profile in infants without preexisting lung pathology. DESIGN AND SETTING: Prospective observational study in pediatric intensive care unit in a university hospital. PATIENTS: Twelve infants who were subjected to an uncomplicated diagnostic cardiac catheterization procedure were studied. All subjects were ventilated with a volume control mode, 0.3 FIO(2), 4 cmH(2)O PEEP, and 10 ml/kg tidal volume. Volatile (servoflurane) anesthetics were given. MEASUREMENTS AND RESULTS: Tracheal aspirates and blood samples were obtained before and after 2 h of mechanical ventilation. In tracheal aspirates and in supernatants of stimulated whole-blood cultures cytokine concentrations were measured. In the tracheal aspirates the immune balance was characterized by a proinflammatory response pattern, with a significant increase in TNF-alpha and IL-6 concentrations; concentrations of anti-inflammatory mediators remained very low. The functional capacity of peripheral blood leukocytes to produce INF-gamma, TNF-alpha, and IL-6 in vitro was significantly decreased. This was accompanied by a significant decrease in the killing activity of natural killer cells. CONCLUSIONS: Two hours of servoflurane and mechanical ventilation using a tidal volume of 10 ml/kg is associated with remarkable changes in the immune response in infants without preexisting lung pathology undergoing cardiac catheterization. In the lungs the immune balance favors a proinflammatory response pattern without detectable concentrations of anti-inflammatory mediators. The Th1 immune response by peripheral blood leukocytes was decreased. The observed change in Th1/Th2 balance in favor of Th2 cytokine activity may be a systemic adaptation to the proinflammatory milieu in the lung.     

Increasing the inspiratory time and I:E ratio during mechanical ventilation aggravates ventilator-induced lung injury in mice

IntroductionLung-protective ventilation reduced acute respiratory distress syndrome (ARDS) mortality. To minimize ventilator-induced lung injury (VILI), tidal volume is limited, high plateau pressures are avoided, and positive end-expiratory pressure (PEEP) is applied. However, the impact of specific ventilatory patterns on VILI is not well defined. Increasing inspiratory time and thereby the inspiratory/expiratory ratio (I:E ratio) may improve oxygenation, but may also be harmful as the absolute stress and strain over time increase. We thus hypothesized that increasing inspiratory time and I:E ratio aggravates VILI.MethodsVILI was induced in mice by high tidal-volume ventilation (HV_T 34 ml/kg). Low tidal-volume ventilation (LV_T 9 ml/kg) was used in control groups. PEEP was set to 2 cm H₂O, FiO₂ was 0.5 in all groups. HV_T and LV_T mice were ventilated with either I:E of 1:2 (LV_T 1:2, HV_T 1:2) or 1:1 (LV_T 1:1, HV_T 1:1) for 4 hours or until an alternative end point, defined as mean arterial blood pressure below 40 mm Hg. Dynamic hyperinflation due to the increased I:E ratio was excluded in a separate group of animals. Survival, lung compliance, oxygenation, pulmonary permeability, markers of pulmonary and systemic inflammation (leukocyte differentiation in lung and blood, analyses of pulmonary interleukin-6, interleukin-1β, keratinocyte-derived chemokine, monocyte chemoattractant protein-1), and histopathologic pulmonary changes were analyzed.ResultsLV_T 1:2 or LV_T 1:1 did not result in VILI, and all individuals survived the ventilation period. HV_T 1:2 decreased lung compliance, increased pulmonary neutrophils and cytokine expression, and evoked marked histologic signs of lung injury. All animals survived. HV_T 1:1 caused further significant worsening of oxygenation, compliance and increased pulmonary proinflammatory cytokine expression, and pulmonary and blood neutrophils. In the HV_T 1:1 group, significant mortality during mechanical ventilation was observed.ConclusionAccording to the “baby lung” concept, mechanical ventilation-associated stress and strain in overinflated regions of ARDS lungs was simulated by using high tidal-volume ventilation. Increase of inspiratory time and I:E ratio significantly aggravated VILI in mice, suggesting an impact of a “stress/strain × time product” for the pathogenesis of VILI. Thus increasing the inspiratory time and I:E ratio should be critically considered.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0759-2) contains supplementary material, which is available to authorized users.     

Pressure support ventilation in patients with acute lung injury

OBJECTIVES: To assess the success rate of pressure support ventilation (PSV) in acute lung injury patients undergoing continuous positive pressure ventilation (CPPV), to study physiologic changes after the transition from CPPV to PSV, and to investigate differences between patients who succeed and patients who fail PSV according to predetermined criteria. DESIGN: Observational study. SETTING: General intensive care unit in a teaching hospital. SUBJECTS: We studied 48 patients having acute lung injury, as defined by a PaO2/F(IO2) <300 mm Hg and the presence of bilateral infiltrates on chest radiograph, and ventilated with CPPV. We included patients with PaO2 >80 mm Hg, at positive end-expiratory pressure of <15 cm H2O and with F(IO2) up to 1.0. INTERVENTIONS: After enrollment, PSV was instituted and patients were strictly monitored during the following 48 hrs. Subjects who met any of the predefined PSV failure criteria during this period were returned to CPPV (Group F). PSV was continued in the remaining patients (Group S). MEASUREMENTS AND MAIN RESULTS: Gas exchange, respiratory mechanics, and hemodynamics measurements were collected before switching from CPPV to PSV and were repeated at 24 hrs after beginning PSV, or immediately before return to CPPV in Group F patients. The physiologic deadspace volume to tidal volume ratio (V(D)/V(T)) was obtained by the Enghoff's equation from the measurement of the mixed expired CO2 fraction. PSV resulted in a significant PaCO2 decrease (49.2+/-10.9 mm Hg to 44.4+/-7.2 mm Hg) and significant increases in minute volume (V(E))(9.0+/-2.3 L/min to 12.0+/-4.0 L/min) and arterial blood pH (7.405+/-0.054 to 7.435+/-0.064), with stable oxygenation and hemodynamics. In patients who were hypercapnic (PaCO2 >50 mm Hg) during CPPV, the V(E) increase was higher than in normocapnic patients. In the latter patients, PaCO2 and pH did not change significantly going from CPPV to PSV. A total of 38 patients (79%) were allocated to Group S and the remaining 10 patients were included in Group F. In Group S, positive endexpiratory pressure of 9.4+/-2.9 cm H2O (range, 3-14 cm H2O) and a PSV level of 14.9+/-3.8 cm H2O (range, 9-22 cm H2O) were applied. In Group F, positive end-expiratory pressure of 8.9+/-3.1 cm H2O (range, 5-15 cm H2O) and a PSV level of 21.6+/-4.6 cm H2O (range, 16-31 cm H2O) were adopted. Compared with Group S, Group F had a longer duration of intubation (20.2+/-19.2 days vs. 9.2+/-13.5 days), a lower static compliance of the respiratory system (30.4+/-16.5 mL/cm H2O vs. 41.7+/-15.0 mL/cm H2O), and a higher V(D)/V(T) (0.70+/-0.09 vs. 0.52+/-0.10), but similar oxygenation and positive end-expiratory pressure. V(E) was higher in Group F during both CPPV and PSV. CONCLUSIONS: In a relatively high proportion of the investigated patients, PSV was successful. The institution of PSV led to no major changes in oxygenation or in hemodynamics. PSV was associated with increases in V(E) and respiratory frequency. In patients who had been hypercapnic during CPPV, PaCO2 decreased despite a compensated pH. Compared with PSV success patients, patients who failed PSV appeared to be sicker, as shown by the higher duration of respiratory support, increased ventilatory needs, and decreased respiratory system compliance, despite similar arterial oxygenation and positive end-expiratory pressure.     

Pumpless extracorporeal lung assist for protective mechanical ventilation in experimental lung injury

OBJECTIVE: To test the hypothesis that ventilation with 3 mL/kg tidal volume combined with extracorporeal CO2 removal by arteriovenous interventional lung assist reduces ventilator-associated organ injury in experimental acute lung injury when compared with ventilation with 6 mL/kg tidal volume without interventional lung assist. DESIGN: Prospective, randomized, controlled trial. SETTING: A university research laboratory. SUBJECTS: A total of 14 pigs weighing 46 +/- 4 kg (mean +/- sd). INTERVENTIONS: Acute lung injury was induced by repeated lung lavages until Pao2 was <100 mm Hg, with Fio2 of 1.0 and positive end-expiratory pressure of 5 cm H2O, for 1 hr without additional lavages. Animals were randomized to an interventional group with a tidal volume of 3 mL/kg with interventional lung assist (n = 7) or to a control group with a tidal volume of 6 mL/kg without interventional lung assist (n = 7) for 24 hrs. Organ function in vivo was determined by laboratory analyses, including calculations of pulmonary ventilation/perfusion distribution. Histologic assessment of organ injury was performed post mortem after 24 hrs. MEASUREMENTS AND MAIN RESULTS: In both groups, gas exchange improved in the course of the study (p < .05). However, in contrast to control animals, animals with lower tidal volumes and interventional lung assist had severe ventilation/perfusion mismatch, as indicated by increased perfusion to lung areas with a low ventilation/perfusion ratio (p < .05). Other variables of organ function in vivo and results of histologic examination post mortem did not reveal any statistical difference between groups. CONCLUSIONS: Combined ventilation with lower tidal volumes and extracorporeal CO2 removal as compared with traditional low tidal volumes without extracorporeal CO2 removal is not associated with differences in organ injury. Obviously, ventilation with tidal volumes of <6 mL/kg may cause pulmonary de-recruitment when positive end-expiratory pressure is not adequately increased.     

Effect of high-frequency ventilation on histamine-induced lung injury in dogs

We compared the effects of high-frequency oscillation (HFO) and conventional mechanical ventilation (CMV) on dynamic lung compliance (Cdyn), venous admixture (Qsp/Qt), cardiac output, and total lung resistance (RL) in seven mongrel dogs with histamine-induced lung injury. Baseline measurements during CMV were followed by iv infusion of histamine at 100 micrograms/min. Cdyn, Qsp/Qt, cardiac output, and RL were measured in triplicate during CMV and then during HFO. Subsequently, at least one complete set of measurements was recorded again on CMV. During HFO, animals were ventilated at 15 Hz with a tidal volume of 70 to 80 ml. CMV was delivered at 15 to 18 breath/min with a tidal volume of 15 ml/kg. Histamine infusion produced a marked fall in Cdyn, a variable rise in RL, an inconsistent but usually progressive rise in Qsp/Qt, and hypotension. A period of ventilation with HFO made no difference in the Cdyn, Qsp/Qt, or cardiac output changes produced by histamine infusion.     

急性肺损伤肺保护性通气乌司他丁干预的临床研究

目的 评价肺保护性通气乌司他丁干预在控制急性肺损伤（ALI）和防治多器官功能障碍综合征（MODS）及降低其病死率中的作用。方法57例ALI患者随机分为肺保护性通气组（n=28）和肺保护性通气乌司他丁干预组（n=29），比较两组患者呼吸力学、动脉血气及血流动力学的变化，观察两组患者肺及肺外器官功能改善率、机械通气并发症发生率、ICU病死率及其死亡的原因等。结果两组患者的年龄和APACHEⅡ评分比较差异无显著性（P〉0.05）；肺保护性通气乌司他丁干预组对ALI患者的呼吸力学、动脉血气及血流动力学的影响均优于肺保护性通气组；肺保护性通气乌司他丁干预组对肺及肺外器官功能改善率明显优于肺保护性通气组，另外，机械通气所致肺损伤的发生率、机械通气相关心肌缺血和心律失常的发生率也均明显下降；肺保护性通气乌司他丁干预组因多器官功能衰竭（MOF）的ICU病死率为20．69％，明显优于肺保护性通气组（46．43％，P〈0．05）。结论肺保护性通气乌司他丁干预能改善ALI患者的呼吸力学、动脉血气及血流动力学，能降低其呼吸机所致肺损伤（VILI）、机械通气相关心肌缺血和心律失常的发生率，在防治MODS及降低ALI患者病死率上有显著的临床效果。     

Simvastatin attenuates ventilator-induced lung injury in mice

Introduction

Different isoforms of nitric oxide synthases (NOS) and determinants of oxidative/nitrosative stress play important roles in the pathophysiology of pulmonary dysfunction induced by acute lung injury (ALI) and sepsis. However, the time changes of these pathogenic factors are largely undetermined.

Methods

Twenty-four chronically instrumented sheep were subjected to inhalation of 48 breaths of cotton smoke and instillation of live Pseudomonas aeruginosa into both lungs and were euthanized at 4, 8, 12, 18, and 24 hours post-injury. Additional sheep received sham injury and were euthanized after 24 hrs (control). All animals were mechanically ventilated and fluid resuscitated. Lung tissue was obtained at the respective time points for the measurement of neuronal, endothelial, and inducible NOS (nNOS, eNOS, iNOS) mRNA and their protein expression, calcium-dependent and -independent NOS activity, 3-nitrotyrosine (3-NT), and poly(ADP-ribose) (PAR) protein expression.

Results

The injury induced severe pulmonary dysfunction as indicated by a progressive decline in oxygenation index and concomitant increase in pulmonary shunt fraction. These changes were associated with an early and transient increase in eNOS and an early and profound increase in iNOS expression, while expression of nNOS remained unchanged. Both 3-NT, a marker of protein nitration, and PAR, an indicator of DNA damage, increased early but only transiently.

Conclusions

Identification of the time course of the described pathogenetic factors provides important additional information on the pulmonary response to ALI and sepsis in the ovine model. This information may be crucial for future studies, especially when considering the timing of novel treatment strategies including selective inhibition of NOS isoforms, modulation of peroxynitrite, and PARP.     

肺保护性通气在重度吸入性损伤中的应用

目的 探讨低潮气量的肺保护性通气对烧伤合并重度吸入性损伤呼吸支持治疗的可行性及效果。方法 对1996年1月～2000年12月入院的吸入性损伤后气管切开需机械通气48h以上者,进行低潮气量（6～8mL/kg）和适度PEEP模式的通气治疗。结果 共34例接受治疗。24例治愈,死亡10例,所有幸存者通气0.5～3h低氧血症即可纠正。结论 低潮气量的肺保护性通气适合重度吸入性损伤的呼吸支持治疗,可明显改善肺通气功能,降低ARDS及肺炎的发病率,长期机械通气后容易脱机。     

Biological markers of lung injury before and after the institution of positive pressure ventilation in patients with acute lung injury

Background  

Several biological markers of lung injury are predictors of morbidity and mortality in patients with acute lung injury (ALI). The low tidal volume lung-protective ventilation strategy is associated with a significant decrease in plasma biomarker levels compared to the high tidal volume ventilation strategy. The primary objective of this study was to test whether the institution of lung-protective positive pressure ventilation in spontaneously ventilating patients with ALI exacerbates pre-existing lung injury by using measurements of biomarkers of lung injury before and after intubation.     

Regional lung aeration and ventilation during pressure support and biphasic positive airway pressure ventilation in experimental lung injury

Introduction  

There is an increasing interest in biphasic positive airway pressure with spontaneous breathing (BIPAP+SB_mean), which is a combination of time-cycled controlled breaths at two levels of continuous positive airway pressure (BIPAP+SB_controlled) and non-assisted spontaneous breathing (BIPAP+SB_spont), in the early phase of acute lung injury (ALI). However, pressure support ventilation (PSV) remains the most commonly used mode of assisted ventilation. To date, the effects of BIPAP+SB_mean and PSV on regional lung aeration and ventilation during ALI are only poorly defined.