Lung protection during non-invasive synchronized assist versus volume control in rabbits.

INTRODUCTION: Experimental work provides insight into potential lung protective strategies. The objective of this study was to evaluate markers of ventilator-induced lung injury after two different ventilation approaches: (1) a "conventional" lung-protective strategy (volume control (VC) with low tidal volume, positive end-expiratory pressure (PEEP) and paralysis), (2) a physiological approach with spontaneous breathing, permitting synchrony, variability and a liberated airway. For this, we used non-invasive Neurally Adjusted Ventilatory Assist (NIV-NAVA), with the hypothesis that liberation of upper airways and the ventilator's integration with lung protective reflexes would be equally lung protective. METHODS: In this controlled and randomized in vivo laboratory study, 25 adult White New Zealand rabbits were studied, including five non-ventilated control animals. The twenty animals with aspiration-induced lung injury were randomized to ventilation with either VC (6 mL/kg, PEEP 5 cm H2O, and paralysis) or NIV-NAVA for six hours (PEEP = zero because of leaks). Markers of lung function, lung injury, vital signs and ventilator parameters were assessed. RESULTS: At the end of six hours of ventilation (n = 20), there were no significant differences between VC and NIV-NAVA for vital signs, PaO2/FiO2 ratio, lung wet-to-dry ratio and broncho-alveolar Interleukin 8 (Il-8). Plasma IL-8 was higher in VC (P <0.05). Lung injury score was lower for NIV-NAVA (P = 0.03). Dynamic lung compliance recovered after six hours in NIV-NAVA but not in VC (P <0.05). During VC, peak pressures increased from 9.2 ± 2.4 cm H2O (hour 1) to 12.3 ± 12.3 cm H2O (hour 6) (P <0.05). During NIV-NAVA, the tracheal end-expiratory pressure was similar to the end-expiratory pressure during VC. Two animals regurgitated during NIV-NAVA, without clinical consequences, and survived the protocol. CONCLUSIONS: In experimental acute lung injury, NIV-NAVA is as lung-protective as VC 6 ml/kg with PEEP.

Injurious mechanical ventilation causes kidney apoptosis and dysfunction during sepsis but not after intra-tracheal acid instillation: an experimental study.

BACKGROUND: Intratracheal aspiration and sepsis are leading causes of acute lung injury that frequently necessitate mechanical ventilation (MV), which may aggravate lung injury thereby potentially increasing the risk of acute kidney injury (AKI). We compared the effects of ventilation strategies and underlying conditions on the development of AKI. METHODS: Spraque Dawley rats were challenged by intratracheal acid instillation or 24 h of abdominal sepsis, followed by MV with a low tidal volume (LVT) and 5 cm H2O positive end-expiratory pressure (PEEP) or a high tidal volume (HVT) and no PEEP, which is known to cause more lung injury after acid instillation than in sepsis. Rats were ventilated for 4 hrs and kidney function and plasma mediator levels were measured. Kidney injury was assessed by microscopy; apoptosis was quantified by TUNEL staining. RESULTS: During sepsis, but not after acid instillation, MV with HVT caused more renal apoptosis than MV with LVT. Increased plasma active plasminogen activator inhibitor-1 correlated to kidney apoptosis in the cortex and medulla. Increased apoptosis after HVT ventilation during sepsis was associated with a 40% decrease in creatinine clearance. CONCLUSIONS: AKI is more likely to develop after MV induced lung injury during an indirect (as in sepsis) than after a direct (as after intra-tracheal instillation) insult to the lungs, since it induces kidney apoptosis during sepsis but not after acid instillation, opposite to the lung injury it caused. Our findings thus suggest using protective ventilatory strategies in human sepsis, even in the absence of overt lung injury, to protect the kidney.

Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis.

Although bone marrow-derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. Total RNA from lungs, hearts, kidneys, livers, and spleens harvested 28 hours after cecal ligation and puncture was hybridized to mouse expression bead arrays. Common transcriptional responses were analyzed using a network knowledge-based approach. A total of 4751 genes were significantly changed between placebo- and MSC-treated mice (adjusted P ≤ 0.05). Transcriptional responses identified three common effects of MSC administration in all five organs examined: i) attenuation of sepsis-induced mitochondrial-related functional derangement, ii down-regulation of endotoxin/Toll-like receptor innate immune proinflammatory transcriptional responses, and iii) coordinated expression of transcriptional programs implicated in the preservation of endothelial/vascular integrity. Transcriptomic analysis indicates that the protective effect of MSC therapy in sepsis is not limited to a single mediator or pathway but involves a range of complementary activities affecting biological networks playing critical roles in the control of host cell metabolism and inflammatory response.

Salutary effect of resveratrol on sepsis-induced myocardial depression.

OBJECTIVES: We hypothesized that resveratrol administration would reverse sepsis-dependent downregulation of peroxisome proliferator activated receptor-γ coactivator 1α, preserve mitochondrial integrity, and rescue animals from sepsis-induced myocardial failure. SETTING: Teaching hospital research laboratory. INTERVENTIONS: Cecal ligation and puncture in mice was performed to induce sepsis. Mice that underwent cecal ligation and puncture were randomly assigned to receive resveratrol (30 mg/kg or 60 mg/kg) or vehicle 1 mL sodium chloride 0.9% subcutaneously in the scruff of the neck directly after surgery and at 16, 24, and 40 hrs, respectively. MEASUREMENTS AND RESULTS: Forty-eight hrs after cecal ligation and puncture, cardiac performance was established using echocardiography. Mitochondrial integrity was evaluated with electron microscopy, and changes in gene expression were evaluated with microarray analysis. Survival at 48 hrs was just under 50% and comparable between groups. Myocardial contractile function significantly improved after resveratrol treatment. Resveratrol-treated mice developed focal areas of edema, whereas vehicle-treated mice developed significant, diffuse myocardial edema. Electron microscopy revealed widespread swollen mitochondria with ruptured outer membranes, autophagosomes, and vacuolation of the internal compartment, which were significantly attenuated in resveratrol-treated animals. Resveratrol treatment significantly increased cardiac expression of peroxisome proliferator-activated receptor-γ coactivator 1a. Microarray analysis revealed that resveratrol treatment resulted in upregulation of the peroxisome proliferator-activated receptor-γ coactivator gene set containing genes known to be regulated by this transcriptional coactivator. Our data strongly suggest that administration of resveratrol modulates bioenergy metabolism, substrate utilization, oxidative stress, and detoxification pathways associated with both mitochondrial and cardiac pathological conditions, but does not alter mortality from sepsis. CONCLUSIONS: The salutary effects of resveratrol on cecal ligation and puncture-induced myocardial dysfunction are associated with increased peroxisome proliferator-activated receptor-γ coactivator 1a abundance and function. Preservation of myocardial energy production capacity, prevention of secondary injury, mitigation of inflammation, and reversal of sepsis-induced myocardial remodeling are likely to underlie its beneficial effects. This however, does not result in improved survival.

Neuroimmune regulation of ventilator-induced lung injury.

RATIONALE: Ventilator-induced lung injury (VILI) contributes to the mortality in patients with acute lung injury by increasing inflammation. Recent evidence suggests that stimulation of the cholinergic antiinflammatory pathway may be an attractive way to attenuate inflammatory injury. OBJECTIVES: To determine the role of vagus nerve signaling in VILI and establish whether stimulation of the vagus reflex can mitigate VILI. METHODS: We performed bilateral vagotomy in a mouse model of high-tidal volume-induced lung injury. We performed pharmacological and electrical vagus nerve stimulation in a rat model of VILI following ischemia/reperfusion injury. To determine the contribution of the alpha 7 acetylcholine nicotinic receptor to pulmonary cell injury, we exposed human bronchial epithelial cells to cyclic stretch in the presence of specific agonist or antagonist of the alpha 7 receptor. MEASUREMENTS AND MAIN RESULTS: Vagotomy exacerbates lung injury from VILI in mice as demonstrated by increased wet-to-dry ratio, infiltration of neutrophils, and increased IL-6. Vagal stimulation attenuates lung injury in rats after ischemia/reperfusion injury ventilated with high-volume strategies. Treatment of both mice and rats with the vagus mimetic drug semapimod resulted in decreased lung injury. Vagotomy also increased pulmonary apoptosis, whereas vagus stimulation (electrical and pharmacological) attenuated VILI-induced apoptosis. In vitro studies suggest that vagus-dependent effects on inflammation and apoptosis are mediated via the α7 nicotinc acetylcholine receptor-dependent effects on cyclic stretch-dependent signaling pathways c-jun N-terminal kinase and tumor necrosis factor receptor superfamily, member 6. CONCLUSIONS: Stimulation of the cholinergic antiinflammatory reflex may represent a promising alternative for the treatment of VILI.

Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.

RATIONALE: Sepsis refers to the clinical syndrome of severe systemic inflammation precipitated by infection. Despite appropriate antimicrobial therapy, sepsis-related morbidity and mortality remain intractable problems in critically ill patients. Moreover, there is no specific treatment strategy for the syndrome of sepsis-induced multiple organ dysfunction. OBJECTIVES: We hypothesized that mesenchymal stem cells (MSCs), which have been shown to have immunomodulatory properties, would reduce sepsis-induced inflammation and improve survival in a polymicrobial model of sepsis. METHODS: Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture (CLP), followed 6 hours later by an intravenous injection of MSCs or saline. Twenty-eight hours after CLP, plasma, bronchoalveolar lavage fluid and tissues were collected for analyses. Longer-term studies were performed with antibiotic coadministration to assess the effect of MSCs on survival. MEASUREMENTS AND MAIN RESULTS: MSC treatment significantly reduced mortality in septic mice receiving appropriate antimicrobial therapy. MSCs alone reduced systemic and pulmonary cytokine levels in mice with CLP-induced sepsis, preventing acute lung injury and organ dysfunction, despite the low levels of cell persistence. Microarray data highlighted an overall down-regulation of inflammation and inflammation-related genes (such as IL-10, IL-6) and a shift toward up-regulation of genes involved in promoting phagocytosis and bacterial killing. Finally, bacterial clearance was significantly greater in MSC-treated mice, in part due to enhanced phagocytotic activity of the host immune cells. CONCLUSIONS: These data demonstrate that MSCs have beneficial effects on experimental sepsis, possibly by paracrine mechanisms, and suggest that immunomodulatory cell therapy may be an effective adjunctive treatment to reduce sepsis-related morbidity and mortality.

Activating transcription factor 3 confers protection against ventilator-induced lung injury.

RATIONALE: Ventilator-induced lung injury (VILI) significantly contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. Understanding the molecular basis for response to cyclic stretch (CS) and its derangement during high-volume ventilation is of high priority. OBJECTIVES: To identify specific molecular regulators involved in the development of VILI. METHODS: We undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of CS-responsive genes using microarray analysis. Analysis of stretched versus nonstretched cells identified significant enrichment for genes containing putative binding sites for the transcription factor activating transcription factor 3 (ATF3). To determine the role of ATF3 in vivo, we compared the response of ATF3 gene-deficient mice to wild-type mice in an in vivo model of VILI. MEASUREMENTS AND MAIN RESULTS: ATF3 protein expression and nuclear translocation is increased in the lung after mechanical ventilation in wild-type mice. ATF3-deficient mice have greater sensitivity to mechanical ventilation alone or in conjunction with inhaled endotoxin, as demonstrated by increased cell infiltration and proinflammatory cytokines in the lung and bronchoalveolar lavage, and increased pulmonary edema and indices of tissue injury. The expression of stretch-responsive genes containing putative ATF3 cis-regulatory regions was significantly altered in ATF3-deficient mice. CONCLUSIONS: ATF3 deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. We propose ATF3 acts to counterbalance CS and high volume-induced inflammation, dampening its ability to cause injury and consequently protecting animals from injurious CS.

High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study.

BACKGROUND: To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses. METHODS: Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured. RESULTS: Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed. CONCLUSIONS: During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.

Diaphragmatic dysfunction in mechanical ventilation.

PURPOSE OF REVIEW: It has become clear from experimental data that prolonged mechanical ventilation can induce diaphragm dysfunction, also known as ventilator-induced diaphragm dysfunction. In this article we will discuss most recent understanding on ventilator-induced diaphragm dysfunction and data on diaphragm dysfunction in patients. RECENT FINDINGS: Over the last year several studies confirmed the existence of diaphragm dysfunction in patients. Known atrophy pathways are activated in patients undergoing prolonged conventional ventilation resulting in muscle proteolysis and a decrease in myofiber content. The loss of diaphragm force is time-dependent, but current data do not distinguish between the role played by other factors involved in diaphragm dysfunction. SUMMARY: Diaphragm dysfunction occurs in patients, especially when ventilated with controlled modes of ventilation that minimize diaphragm activity. Time on the ventilator seems to be one of the biggest risk factors resulting in difficulties in weaning patients and prolonging time on the ventilator. Future trials should investigate whether improved patient-ventilator synchrony can reduce ventilator-induced diaphragm dysfunction and decrease weaning failure.

Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients.

BACKGROUND: Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation. METHODS: Plasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation. RESULTS: Plasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed. CONCLUSION: Plasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.

Activation of PPARgamma reverses a defect of surfactant synthesis in mice lacking two types of fatty acid binding protein.

Lung surfactant is a lipid-protein-film covering the inner alveolar surface. We have previously shown that double knock-out (d-ko) mice lacking both the epidermal-type (E-) and the heart-type (H-) fatty acid binding protein (FABP) exhibit a defect of surfactant synthesis in alveolar type II cells that can be corrected by feeding pioglitazone, a drug that activates peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we demonstrate first that healthy surfactant at collapse pressure produces protrusions composed of bilayers but not folds, second that the d-ko effect profoundly perturbs lipid/hydrophobic protein composition, pressure-area isotherm, and structural organisation of the surfactant at nanoscale, parameters that are critical for the normal breathing cycle. In support of these data in vivo measurements of lung function reveal that maximum compliance in d-ko vs. wild-type mice is significantly reduced. Further, we show that the biophysical phenotype can be corrected substantially with pioglitazone. Finally, we show that d-ko alveolar cells up-regulate liver-type (L-) FABP, a member of the FABP family that we have previously shown to interact with PPARgamma. Taken together, these data suggest that PPARgamma agonists could be a tool to repair surfactant damage caused by dysfunctional alveolar lipid metabolism, and provide in vivo support for L-FABP aided signaling.

The role of bronchoalveolar hemostasis in the pathogenesis of acute lung injury.

Disturbed alveolar fibrin turnover is intrinsic to acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pneumonia and is important to its pathogenesis. Recent studies also suggest disturbed alveolar fibrin turnover to be a feature of ventilator-induced lung injury (VILI). The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors, and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. Administration of anticoagulant agents (including activated protein C, antithrombin, tissue factor-factor VIIa pathway inhibitors, and heparin) and profibrinolytic agents (including plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ALI/ARDS and pneumonia. In this article, we review the involvement of coagulation and fibrinolysis in the pathogenesis of ALI/ARDS pneumonia and VILI and the potential of anticoagulant and profibrinolytic strategies to reverse pulmonary coagulopathy and pulmonary inflammatory responses.

Ischemia of the lung causes extensive long-term pulmonary injury: an experimental study.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is suggested to be a major risk factor for development of primary acute graft failure (PAGF) following lung transplantation, although other factors have been found to interplay with LIRI. The question whether LIRI exclusively results in PAGF seems difficult to answer, which is partly due to the lack of a long-term experimental LIRI model, in which PAGF changes can be studied. In addition, the long-term effects of LIRI are unclear and a detailed description of the immunological changes over time after LIRI is missing. Therefore our purpose was to establish a long-term experimental model of LIRI, and to study the impact of LIRI on the development of PAGF, using a broad spectrum of LIRI parameters including leukocyte kinetics. METHODS: Male Sprague-Dawley rats (n = 135) were subjected to 120 minutes of left lung warm ischemia or were sham-operated. A third group served as healthy controls. Animals were sacrificed 1, 3, 7, 30 or 90 days after surgery. Blood gas values, lung compliance, surfactant conversion, capillary permeability, and the presence of MMP-2 and MMP-9 in broncho-alveolar-lavage fluid (BALf) were determined. Infiltration of granulocytes, macrophages and lymphocyte subsets (CD45RA+, CD5+CD4+, CD5+CD8+) was measured by flowcytometry in BALf, lung parenchyma, thoracic lymph nodes and spleen. Histological analysis was performed on HE sections. RESULTS: LIRI resulted in hypoxemia, impaired left lung compliance, increased capillary permeability, surfactant conversion, and an increase in MMP-2 and MMP-9. In the BALf, most granulocytes were found on day 1 and CD5+CD4+ and CD5+CD8+-cells were elevated on day 3. Increased numbers of macrophages were found on days 1, 3, 7 and 90. Histology on day 1 showed diffuse alveolar damage, resulting in fibroproliferative changes up to 90 days after LIRI. CONCLUSION: The short-, and long-term changes after LIRI in this model are similar to the changes found in both PAGF and ARDS after clinical lung transplantation. LIRI seems an independent risk factor for the development of PAGF and resulted in progressive deterioration of lung function and architecture, leading to extensive immunopathological and functional abnormalities up to 3 months after reperfusion.

Inhibition of poly(adenosine diphosphate-ribose) polymerase attenuates ventilator-induced lung injury.

BACKGROUND: Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. METHODS: Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. RESULTS: The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. CONCLUSION: The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

High positive end-expiratory pressure levels promote bacterial translocation in experimental pneumonia.

OBJECTIVE: A previous study in piglets with experimental pneumonia showed that reducing atelectasis by means of open lung ventilation attenuated bacterial translocation compared to conventional ventilation settings. This study examined the effect of open lung ventilation with higher than necessary positive end-expiratory pressures (PEEP) on bacterial translocation. DESIGN AND SETTING: Prospective animal study in a university-affiliated research laboratory. SUBJECTS: Thirty piglets. INTERVENTIONS: Animals were surfactant-depleted by whole-lung lavage and infected with group B streptococci. Thereafter the animals were ventilated for 5 h according to either a conventional ventilation strategy, open lung strategy, or open lung/high-PEEP strategy. Blood samples for blood gas analysis and blood bacterial counts were taken every hour. After 5 h of ventilation surviving animals were killed, and lung colony forming units and lung mechanics parameters were determined. RESULTS: All animals in both open lung groups survived but only 30% of those in the conventional ventilation group. Open lung ventilation resulted in significantly less bacterial translocation than either conventional or high-PEEP ventilation. Lung function in the conventional ventilated group was significantly less than in the two open lung groups. CONCLUSIONS: The lowest level of bacterial translocation was observed during optimal ventilation (open lung) which was achieved by using individually tailored settings. Deviation to either side can be harmful, as shown by the increased bacterial translocation during conventional and high-PEEP ventilation.

Physiology of mechanical ventilation.

Mechanical ventilation, although essential in taking care of acute lung injury and widely used during surgical procedures worldwide, remains a highly debated field. Clinical trials in the last decade have shown convincingly that mechanical ventilation can result in additional mortality in patients with acute lung injury. This understanding has resulted in a resurged interest in mechanical ventilation, and especially in techniques and strategies to further improve mechanical ventilation. This article discusses physiological principles to improve the understanding of mechanical ventilation.

Year in review 2005: Critical Care--respirology: mechanical ventilation, infection, monitoring, and education.

We summarize all original research in the field of respiratory intensive care medicine published in 2005 in Critical Care. Twenty-seven articles were grouped into the following categories and subcategories to facilitate rapid overview: mechanical ventilation (physiology, spontaneous breathing during mechanical ventilation, high frequency oscillatory ventilation, side effects of mechanical ventilation, sedation, and prone positioning); infection (pneumonia and sepsis); monitoring (ventilatory monitoring, pulmonary artery catheter and pulse oxymeter); and education (training and health outcome).

The effect of open lung ventilation on right ventricular and left ventricular function in lung-lavaged pigs.

INTRODUCTION: Ventilation according to the open lung concept (OLC) consists of recruitment maneuvers, followed by low tidal volume and high positive end-expiratory pressure, aiming at minimizing atelectasis. The minimization of atelectasis reduces the right ventricular (RV) afterload, but the increased intrathoracic pressures used by OLC ventilation could increase the RV afterload. We hypothesize that when atelectasis is minimized by OLC ventilation, cardiac function is not affected despite the higher mean airway pressure. METHODS: After repeated lung lavage, each pig (n = 10) was conventionally ventilated and was ventilated according to OLC in a randomized cross-over setting. Conventional mechanical ventilation (CMV) consisted of volume-controlled ventilation with 5 cmH2O positive end-expiratory pressure and a tidal volume of 8-10 ml/kg. No recruitment maneuvers were performed. During OLC ventilation, recruitment maneuvers were applied until PaO2/FiO2 > 60 kPa. The peak inspiratory pressure was set to obtain a tidal volume of 6-8 ml/kg. The cardiac output (CO), the RV preload, the contractility and the afterload were measured with a volumetric pulmonary artery catheter. A high-resolution computed tomography scan measured the whole lung density and left ventricular (LV) volumes. RESULTS: The RV end-systolic pressure-volume relationship, representing RV afterload, during steady-state OLC ventilation (2.7 +/- 1.2 mmHg/ml) was not significantly different compared with CMV (3.6 +/- 2.5 mmHg/ml). Pulmonary vascular resistance (OLC, 137 +/- 49 dynes/s/cm5 versus CMV, 130 +/- 34 dynes/s/cm5) was comparable between groups. OLC led to a significantly lower amount of atelectasis (13 +/- 2% of the lung area) compared with CMV (52 +/- 3% of the lung area). Atelectasis was not correlated with pulmonary vascular resistance or end-systolic pressure-volume relationship. The LV contractility and afterload during OLC was not significantly different compared with CMV. Compared with baseline, the LV end-diastolic volume (66 +/- 4 ml) decreased significantly during OLC (56 +/- 5 ml) ventilation and not during CMV (61 +/- 3 ml). Also, CO was significantly lower during OLC ventilation (OLC, 4.1 +/- 0.3 l/minute versus CMV, 4.9 +/- 0.3 l/minute). CONCLUSION: In this experimental study, OLC resulted in significantly improved lung aeration. Despite the use of elevated airway pressures, no evidence was found for a negative effect of OLC on RV afterload or LV afterload, which might be associated with a loss of hypoxic pulmonary vasoconstriction due to alveolar recruitment. The reductions in the CO and in the mean pulmonary artery pressure were consequences of a reduced preload.

Contrast media inhibit exogenous surfactant therapy in rats with acute respiratory distress syndrome.

AIM: To test the effects of various contrast media on the pulmonary surfactant system. MATERIAL AND METHODS: In a rat model of acute respiratory distress syndrome (ARDS) induced by lung lavage, the effects of surfactant suspended in saline were compared with surfactant suspended in the contrast media Visipaque, Gastrografin, Omnipaque, Telebrix M, Telebrix and Hexabrix, to establish their influence on oxygenation and lung mechanics. RESULTS: After the induction of ARDS, surfactant instillation improved oxygenation, total lung capacity (TLC(35)), volume at 5 cm H(2)O end-expiration (V(5)) and Gruenwald index. The effects of Visipaque and Gastrografin were comparable with those of surfactant alone from 90 min onwards and at 120 min, respectively. Surfactant suspended in the other contrast media resulted in significantly lower values in the above-mentioned parameters. Surface tension was lowest in surfactant suspended in saline alone. Surfactant suspended in Visipaque and Gastrografin had lower surface tension compared with surfactant suspended in the other contrast media. CONCLUSION: The ionic and non-ionic contrast media used in this study, cause an impairment of the physico-chemical behaviour of exogenous surfactant. Therefore, these contrast media cannot be regarded as safe in case of accidental exposure.

Alveolar fibrinolytic capacity suppressed by injurious mechanical ventilation.

OBJECTIVE: To investigate the effect of mechanical ventilation on alveolar fibrinolytic capacity. DESIGN AND SETTING: Randomized controlled animal study in 66 Sprague-Dawley rats. SUBJECTS AND INTERVENTIONS: Test animals received intratracheal fibrinogen and thrombin instillations; six were killed immediately (fibrin controls), and the others were allocated to three ventilation groups (ventilation period: 225 min) differing in positive inspiratory pressure and positive end-expiratory pressure, respectively: group 1, 16 cmH2O and 5 cmH2O (n=17); group 2, 26 cmH2O and 5 cmH2O (n=16); group 3, 35 cmH2O and of 5 cmH2O (n=17). Ten animals that had not been ventilated served as healthy controls. MEASUREMENTS AND RESULTS: After animals were killed, we measured D-dimers, plasminogen activator inhibitor (PAI) 1, and tumor necrosis factor alpha in the bronchoalveolar lavage fluid and calculated lung weight and pressure/volume (P/V) plots. The median D-dimer concentration (mg/l) decreased with increasing pressure amplitude (192 in group 1, IQR 119; 66 in group 2, IQR 107; 29 in group 3, IQR 30) while median PAI-1 (U/ml) increased (undetectable in group 1; 0.55 in group 2, IQR 4.55; 3.05 in group 3, IQR 4.85). PAI-1 level was correlated with increased lung weight per bodyweight (Spearman's rank correlation 0.708). Tumor necrosis factor alpha concentration was not correlated with PAI-1 level. CONCLUSIONS: Alveolar fibrinolytic capacity is suppressed during mechanical ventilation with high pressure amplitudes due to local production of PAI-1.