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Various animal models exist to study the complex pathomechanisms of the acute respiratory distress syndrome (ARDS). These models include pulmo-arterial infusion of oleic acid, infusion of endotoxins or bacteria, cecal ligation and puncture, various pneumonia models, lung ischemia/reperfusion models and, of course, surfactant depletion models, among others. Surfactant depletion produces a rapid, reproducible deterioration of pulmonary gas exchange and hemodynamics and can be induced in anesthetized pigs using repeated lung lavages with 0.9% saline (35 mL/kg body weight, 37 °C). The surfactant depletion model supports investigations with standard respiratory and hemodynamic monitoring with clinically applied devices. But the model suffers from a relatively high recruitability and ventilation with high airway pressures can immediately reduce the severity of the injury by reopening atelectatic lung areas. Thus, this model is not suitable for investigations of ventilator regimes that use high airway pressures. A combination of surfactant depletion and injurious ventilation with high tidal volume/low positive end-expiratory pressure (high Tv/low PEEP) to cause ventilator induced lung injury (VILI) will reduce the recruitability of the resulting lung injury. The advantages of a timely induction and the possibility to perform experimental research in a setting comparable to an intensive care unit are preserved.

Background: Uncertainty persists regarding the optimal ventilatory strategy in trauma patients developing acute respiratory distress syndrome (ARDS). This work aims to assess the effects of two mechanical ventilation strategies with high positive end-expiratory pressure (PEEP) in experimental ARDS following blunt chest trauma., Methods: Twenty-six juvenile pigs were anesthetized, tracheotomized and mechanically ventilated. A contusion was applied to the right chest using a bolt-shot device. Ninety minutes after contusion, animals were randomized to two different ventilation modes, applied for 24 h: Twelve pigs received conventional pressure-controlled ventilation with moderately low tidal volumes (VT, 8 ml/kg) and empirically chosen high external PEEP (16 cmH2O) and are referred to as the HP-CMV-group. The other group (n = 14) underwent high-frequency inverse-ratio pressure-controlled ventilation (HFPPV) involving respiratory rate of 65 breaths · min(-1), inspiratory-to-expiratory-ratio 2:1, development of intrinsic PEEP and recruitment maneuvers, compatible with the rationale of the Open Lung Concept. Hemodynamics, gas exchange and respiratory mechanics were monitored during 24 h. Computed tomography and histology were analyzed in subgroups., Results: Comparing changes which occurred from randomization (90 min after chest trauma) over the 24-h treatment period, groups differed statistically significantly (all P values for group effect <0.001, General Linear Model analysis) for the following parameters (values are mean ± SD for randomization vs. 24-h): PaO2 (100% O2) (HFPPV 186 ± 82 vs. 450 ± 59 mmHg; HP-CMV 249 ± 73 vs. 243 ± 81 mmHg), venous admixture (HFPPV 34 ± 9.8 vs. 11.2 ± 3.7%; HP-CMV 33.9 ± 10.5 vs. 21.8 ± 7.2%), PaCO2 (HFPPV 46.9 ± 6.8 vs. 33.1 ± 2.4 mmHg; HP-CMV 46.3 ± 11.9 vs. 59.7 ± 18.3 mmHg) and normally aerated lung mass (HFPPV 42.8 ± 11.8 vs. 74.6 ± 10.0 %; HP-CMV 40.7 ± 8.6 vs. 53.4 ± 11.6%). Improvements occurring after recruitment in the HFPPV-group persisted throughout the study. Peak airway pressure and VT did not differ significantly. HFPPV animals had lower atelectasis and inflammation scores in gravity-dependent lung areas., Conclusions: In this model of ARDS following unilateral blunt chest trauma, HFPPV ventilation improved respiratory function and fulfilled relevant ventilation endpoints for trauma patients, i.e. restoration of oxygenation and lung aeration while avoiding hypercapnia and respiratory acidosis.

Introduction: Automatic ventilation for patients with respiratory failure aims at reducing mortality and can minimize the workload of clinical staff, offer standardized continuous care, and ultimately save the overall cost of therapy. We therefore developed a prototype for closed-loop ventilation using acute respiratory distress syndrome network (ARDSNet) protocol, called autoARDSNet., Methods: A protocol-driven ventilation using goal-oriented structural programming was implemented and used for 4 hours in seven pigs with lavage-induced acute respiratory distress syndrome (ARDS). Oxygenation, plateau pressure and pH goals were controlled during the automatic ventilation therapy using autoARDSNet. Monitoring included standard respiratory, arterial blood gas analysis and electrical impedance tomography (EIT) images. After 2-hour automatic ventilation, a disconnection of the animal from the ventilator was carried out for 10 seconds, simulating a frequent clinical scenario for routine clinical care or intra-hospital transport., Results: This pilot study of seven pigs showed stable and robust response for oxygenation, plateau pressure and pH value using the automated system. A 10-second disconnection at the patient-ventilator interface caused impaired oxygenation and severe acidosis. However, the automated protocol-driven ventilation was able to solve these problems. Additionally, regional ventilation was monitored by EIT for the evaluation of ventilation in real-time at bedside with one prominent case of pneumothorax., Conclusions: We implemented an automatic ventilation therapy using ARDSNet protocol with seven pigs. All positive outcomes were obtained by the closed-loop ventilation therapy, which can offer a continuous standard protocol-driven algorithm to ARDS subjects.

Advanced liver disease is associated with hypoxemia and respiratory failure by various mechanisms. Patients with cirrhosis are especially prone to episodes of decompensation requiring intensive care unit admission and management. Such patients may already be in acute liver failure or have decompensated due to a concurrent illness such as spontaneous bacterial peritonitis, sepsis, encephalopathy, varices, or hepatorenal syndrome. Acute respiratory distress syndrome is one of the main reasons for intensive care unit admission and mortality. Overall, critically ill cirrhotic patients frequently progress to multiorgan failure requiring mechanical ventilation. Caring for such patients is therefore understandably complex and extremely challenging. Patients with end-stage liver disease are especially at risk for developing acute respiratory failure and hypoxemia secondary to hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. They should therefore be screened for these conditions because failure to recognize and adequately treat these serious complications of cirrhosis may have devastating consequences. This article is based on a review of the current literature on how to approach and manage acute respiratory failure in advanced liver disease, which is important to intensivists, anesthesiologists, and physicians as a whole., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Rationale: Compositional changes in surfactant and/or decreased surfactant content of the lungs are common features in patients with acute respiratory failure. Instillation of exogenous surfactant into the lungs of neonates with respiratory distress syndrome or pediatric patients with acute respiratory distress syndrome (ARDS) has resulted in improved survival., Objectives: We conducted this trial to determine whether the instillation of exogenous surfactant would improve the Day 28 outcome of adult patients with acute lung injury (ALI) or ARDS., Methods: A total of 418 patients with ALI and ARDS were included in an international, multicenter, stratified, randomized, controlled, open, parallel-group study. We randomly assigned 418 patients to receive usual care either with or without instillation of exogenous natural porcine surfactant HL 10 as large boluses., Measurements and Main Results: The primary endpoint was death rate before or on Day 28. Secondary endpoints were adverse event and death rate on day 180. The 28-day death rate in the usual care group was 24.5% compared with 28.8% in the HL 10 group. The estimated odds ratio for death at Day 28 in the usual care group versus the HL 10 group was 0.75 (95% CI, 0.48-1.18; P = 0.22). The most common adverse events related to HL 10 administration were temporary hypoxemia defined as oxygen saturation less than 88% (51.9% in HL 10 group vs. 25.2% in usual care) and hypotension defined as mean arterial blood pressure less than 60 mm Hg (34.1% in HL 10 group vs. 17.1% in usual care)., Conclusions: In this study, instillation of a large bolus of exogenous natural porcine surfactant HL 10 into patients with acute lung injury and ARDS did not improve outcome and showed a trend toward increased mortality and adverse effects. Clinical trial registered with www.clinicaltrials.gov (NCT 00742482).

Background: It has been suggested that propofol with ethylenediaminetetraacetic acid (EDTA) can modulate the systemic inflammatory response. Prolonged higher levels of pulmonary inflammation are associated with poor outcome of patients with acute lung injury. In the present study, we hypothesized that pulmonary inflammation could be modulated by propofol with EDTA compared with propofol with sulfite., Methods: Respiratory distress was induced in rats (n=25) by intratracheal nebulization of lipopolysaccharide (LPS). After 24 h, animals were randomized to either propofol with EDTA (Propofol(EDTA)), propofol with sulfite (Propofol(sulfite)) or ketamine/midazolam (Ket/Mid); control animals received saline (n=30). Animals were ventilated for 4 h and blood gases were measured hourly. Bronchoalveolar lavage (BAL) was performed for cytokine analysis of: tumor necrosis factor (TNF), interleukin (IL)-6 and macrophage inflammatory protein (MIP)-2., Results: LPS led to increased pulmonary inflammation in all groups compared with the control groups. Gas exchange deteriorated over time only in the LPS Propofol(sulfite) group and was significantly lower than the Ket/Mid group. Only IL-6 was significantly higher in the LPS Propofol(sulfite) group compared with both the Ket/Mid group and the Propofol(EDTA) group., Conclusion: Pulmonary IL-6 can be modulated by additives in systemic anesthesia., Implication Statement: This study demonstrates that pulmonary inflammation caused by direct lung injury can be modulated by intravenous anesthesia used in critically ill patients.

Rationale: In acute inflammatory lung disease in newborn infants, exogenous surfactant only transiently improves lung function. We hypothesized that the transient nature of this protection is in part explained by elevated acid sphingomyelinase (a-SMase) activity that may inactivate surfactant and promote proinflammatory responses., Objectives: We investigated the intermediate-term effects (>12 h) of a-SMase inhibition in a neonatal piglet model of repeated airway lavage by the intratracheal use of the a-SMase inhibitor imipramine, together with exogenous surfactant as a carrier substance., Methods: After surfactant washout and induction of pulmonary inflammation, lung function was monitored over 24 hours of mechanical ventilation and followed by ex vivo analyses. In addition, we studied the effect of lipopolysaccharide inhalation in a-SMase-deficient mice at 48 hours., Measurements and Main Results: Surfactant washout increased both pulmonary a-SMase activity and ceramide content; this was attenuated by surfactant and prevented in the surfactant plus imipramine group. Compared with surfactant alone, Pa(O(2)), dynamic compliance, and extravascular lung water were improved in the final 12 hours in the surfactant plus imipramine group. At 24 hours, lavage fluid leukocyte counts and IL-8 concentrations decreased, and physical surfactant film properties improved. In the mouse model at 48 hours, a-SMase-deficient mice showed reduced pulmonary ceramide levels and attenuated leukocyte influx into the alveolar space., Conclusions: We conclude that stabilization of exogenous surfactant by adding imipramine to create a "fortified surfactant preparation" improves lung function in a clinically relevant piglet model, and that this effect can be attributed to the inhibition of a-SMase as evidenced in the mouse model.

This article describes the pathophysiologic basis and clinical role for lung recruitment maneuvers. It reviews the literature and presents the authors' clinical experience of over 15 years in the collaboration between Erasmus MC and the University of Rochester. The authors are hopeful that these lung-protective strategies are presented in a useful format that may be useful to the practicing intensivist, thus bringing laboratory and clinical research to bedside practice.

This review addresses the physiological background and the current status of evidence regarding ventilator-induced lung injury and lung protective strategies. Lung protective ventilatory strategies have been shown to reduce mortality from adult respiratory distress syndrome (ARDS). We review the latest knowledge on the progression of lung injury by mechanical ventilation and correlate the findings of experimental work with results from clinical studies. We describe the experimental and clinical evidence of the effect of lung protective ventilatory strategies and open lung strategies on the progression of lung injury and current controversies surrounding these subjects. We describe a rational strategy, the open lung strategy, to accomplish an open lung, which may further prevent injury caused by mechanical ventilation. Finally, the clinician is offered directions on lung protective ventilation in the early phase of ARDS which can be applied on the intensive care unit.

This review addresses the current state of lung protective strategies and their physiological rationale. Lung protective ventilation can reduce mortality in adult respiratory distress syndrome (ARDS) patients. We review the latest knowledge on the progression of lung injury by mechanical ventilation. Results from clinical studies on mechanical ventilation are compared with results obtained in experimental studies. Furthermore, we discuss possible future improvements to mechanical ventilation; especially the open lung maneuver. The rationale behind the open lung maneuver and steps to accomplish an open lung are described, as well as data from animal and human studies. Finally, guidelines for future strategies and/or investigations are presented.

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.

Objective: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response, which is correlated with outcome. We hypothesized that ventilation according to the open lung concept (OLC) attenuates cytokine release., Methods: A prospective, single center randomized controlled clinical study containing 62 patients scheduled for elective coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass. Before surgery, patients were randomly assigned to three groups: (1) conventional mechanical ventilation (CV), (2) OLC started after arrival on the ICU (late open lung, LOL), and (3) OLC started directly after intubation (early open lung, EOL). In both OLC groups, recruitment maneuvers were applied until PaO(2)/FiO(2)>50. The CV group received no recruitment maneuvers. Interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured preoperatively, immediately after cessation of CPB, and 3h, 5h, 24h, 2, and 3 days after cessation of CPB., Results: CPB caused a significant increase of IL-6, IL-8, and IL-10 in all groups. Thereafter, IL-8 decreased significantly more rapidly in both OLC groups compared to CV. IL-10 decreased significantly more rapidly after CPB only in the EOL group, compared with CV. Three hours after cessation of the CPB, IL-10 was already comparable with preoperative levels in the EOL group, but not in the LOL or CV group. IL-6, TNF-alpha, and IFN-gamma did not differ significantly between groups., Conclusions: OLC ventilation leads to an attenuated inflammatory response, presumably by reducing additional lung injury after cardiac surgery. Studies on cytokines after cardiac surgery should take these findings into account.

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.

Mechanical ventilation is known to induce bacterial translocation from the lung into the systemic circulation. This study determined the effect of immunoglobulin M (IgM)-enriched polyclonal immunoglobulins on bacteremia due to ventilation-induced translocation in an acute respiratory distress syndrome (ARDS) rat model with Klebsiella-induced pneumonia. After whole lung lavage, Sprague-Dawley rats intravenously received either a high dose or a low dose of an immunoglobulin preparation, or an albumin solution as control, followed by an intratracheal injection of a Klebsiella pneumoniae solution. Blood colony-forming units (CFUs) in the treatment groups were significantly lower during the 3-hour ventilation period compared to the control group. The authors conclude that IgM-enriched polyclonal immunoglobulins lead to a reduction of bacteria in blood of surfactant-deficient, ventilated rats infected with Klebsiella pneumoniae.

Purpose of Review: Currently, three phase III surfactant replacement trials for acute lung injury (ALI)/acute respiratory distress syndromes (ARDS) patients are underway. Although the efficacy of surfactant replacement therapy will first have to be proved in these phase III trials, recent reports indicate some enticing possibilities for the future of surfactant therapy., Recent Findings: Patients requiring mechanical ventilation show alterations in their endogenous surfactant composition. Depending on the type of lung injury or the elapsed time, modifications to surfactant preparations could enhance the efficacy of these preparations. Surfactants that closely resemble natural surfactant, especially those containing surfactant proteins (SP-B/C) and nonphospholipids (cholesterol), are able to restore normal surfactant physiology. Furthermore, lipids that are able to withstand degradation by lipases could further enhance surfactant therapy., Summary: If surfactant therapy fulfills the promises expected from the ongoing phase III trials, future surfactant preparations may even enhance therapy efficacy and restore the altered endogenous surfactant pool as soon as possible.

In acute respiratory distress syndrome patients, protective ventilation strategies reduce mortality and proinflammatory mediator levels. It has been suggested that some of the side effects of mechanical ventilation are caused by the excessive release of mediators capable of causing pulmonary inflammation and tissue destruction (biotrauma). Selective inhibition of this process might be used to minimize the side effects of artificial mechanical ventilation. This study was designed to identify the cell types and specific signaling mechanisms that are activated by ventilation with increased pressure/volume (overventilation). In isolated perfused mouse lungs, overventilation caused nuclear translocation of nuclear factor-kappaB (NF-kappaB) and enhanced expression of interleukin-6 mRNA in alveolar macrophages and alveolar epithelial type II cells. The phosphoinositide 3-OH kinase inhibitor Ly294002 prevented nuclear translocation of NF-kappaB and the subsequent release of interleukin-6 and macrophage inflammatory protein-2alpha in overventilated but not in endotoxic lungs. Similar results were obtained in rats in vivo, where Ly294002 prevented NF-kappaB activation by overventilation but not by endotoxin. These findings show that alveolar macrophages and alveolar epithelial type II cells contribute to the ventilation-induced release of proinflammatory mediators and that selective inhibition of this process is possible without inhibiting the activation of NF-kappaB by endotoxin.

Every year, millions of patients worldwide receive ventilator support during surgery. Mechanical ventilation has become an important therapy in the treatment of patients with impaired pulmonary function and particularly in patients suffering from adult respiratory distress syndrome (ARDS). ARDS is caused by multiple factors and is characterized by respiratory dysfunction including hypoxemia and decreased lung compliance. It is known that the decrease in lung distensibility is due to a disturbed surfactant system with an elevated surface tension. This increase in surface tension leads to an increase in forces acting at the air-liquid interface, resulting finally in end-expiratory collapse, atelectasis, an increase in right-to-left shunt and a decrease in paO2.

In vivo experiments showed no increased production of tumour necrosis factor (TNF) in response to injurious ventilation strategies in otherwise untreated animals. Because interleukin-6 (IL-6) and macrophage inflammatory protein-2 (MIP-2) are more sensitive markers of ventilation-induced cytokine release, serum and bronchoalveolar lavage (BAL) samples were examined for these mediators. Eighty-five adult rats were randomized to three different ventilation strategies. Rats were ventilated with low pressures and low tidal volumes [13/3; peak inspiratory pressure (PIP)/positive end-expiratory pressure (PEEP) in cmH2O], the second group of rats was ventilated with high pressures and low PEEP resulting in high tidal volumes (32/6), and the third group was ventilated with the same high pressures but without PEEP (32/0). Animals were ventilated either for 90 or 240 min, subsequently serum and BAL were collected for analyses on IL-6 and MIP-2 content. Non-ventilated animals served as healthy controls. Ventilation with 32/0 for 90 or 240 min, led to increased serum IL-6 levels. Serum MIP-2 levels were increased by ventilation with 32/6 (90 min) and 32/0 (240 min). Ventilation under any condition, even at 13/3, resulted in elevated MIP-2 levels in the BAL fluid. Even at normal pressures pulmonary MIP-2 levels were increased, suggesting that ventilation may promote pro-inflammatory responses in healthy subjects.

Objective: To investigate the effect of mechanical ventilation with no PEEP (ZEEP) and 4 cmH(2)O PEEP on heat shock protein 70 (HSP70) and pulmonary inflammatory cytokine expression in a model of lipopolysaccharide (LPS) induced lung inflammation., Design and Setting: Prospective, randomized, experimental animal study., Subjects and Interventions: We challenged 42 male Sprague-Dawley rats intratracheally with LPS. After 24 h the rats were randomly assigned to one of the ventilation strategies. Rats received either 4 h of mechanical ventilation with ZEEP or mechanical ventilation with 4 cmH(2)O PEEP. A nonventilated control group received LPS only. Lung pathology after LPS challenge was evaluated by histology to assess baseline lung injury. HSP70 and cytokine mRNA levels were measured in total lung homogenates., Results: PaO(2) levels and lung histology revealed no deterioration after PEEP ventilation and severe deterioration after ZEEP ventilation. There was a significant higher expression of HSP70 and IL-1beta mRNA in the lungs of the ZEEP group than in the PEEP group and nonventilated controls. In the ZEEP group high HSP70 levels were correlated inversely with low IL-1beta mRNA and low IL-6 mRNA., Conclusions: We propose that HSP70 expression protects the lung against ventilator-induced lung injury by decreasing cytokine transcription in the lung.

Lung protective ventilation such as the ARDSnet low tidal volumes strategy can reduce mortality in ARDS patients. The knowledge that an essential therapy such as mechanical ventilation on the intensive care influences patient outcome has given rise to the re-evaluation of current ventilation practices. This review addresses the current state of lung protective strategies and their physiological rationale. Latest knowledge on the instigation and progression of lung injury by mechanical ventilation is explored, particularly the interaction between ventilation and the inflammatory response occurring in an ARDS lung. Furthermore, the role of tidal volume, PEEP, recruitment manoeuvres and surfactant on lung injury is discussed. Finally, we discuss results from clinical studies on mechanical ventilation and elucidate these results with data acquired in experimental studies. Guidelines for future strategies and/or investigations are presented.

Several elements of the "open lung concept", like ventilation with small tidal volumes, were incorporated into various ventilatory strategies. Our study demonstrates how the whole concept can be applied in an animal model using a standardized protocol with the following possible results. Eighteen pigs weighing between 30 and 45 kg were anaesthetized, tracheotomized and ventilated. Acute lung injury was induced by surfactant washout. Blood gases were monitored via a continuous arterial sensor system (Trendcare system). After washout, the ventilatory pattern of the American "ARDS Network study" was applied (PEEP = 9 cmH2O, volume controlled mode with a tidal volume of 6 ml/kg body weight and a respiratory rate of 25 breaths per minute). Afterwards, the opening pressure and the pressure at which the lung collapses were titrated. Both levels were used as the basis for adjusting the recruitment pressure and PEEP, which was necessary to keep the lung open. The respiratory rate was chosen in such a way that at a low intrapulmonary pressure difference between inspiration and expiration as well as normocapnia was reached. After induction of an acute lung injury by surfactant washout, the oxygenation index (OI) dropped from 556 +/- 54 to 176 +/- 89 mmHg. In the "ARDS Network" mode, OI increased to 285 +/- 49 mmHg. After alveolar recruitment with a peak pressure of 53 +/- 7 cmH2O and application of a median PEEP of 17 +/- 3 cmH2O, oxygenation returned close to baseline. A pCO2 of 33 +/- 4 mmHg resulted after using a respiratory rate of 39 breaths per minute. The median tidal volume was 8 ml/kg body weight. Despite a short arterial systolic blood pressure drop of 23 +/- 11 mmHg during recruitment, no significant difference was detectable afterwards compared to the baseline. Using low tidal volumes alone, complete reopening was not achieved in an experimentally induced acute lung injury. After recruitment manoeuvres, it was possible to reopen the lung and keep it open by application of a sufficient PEEP.

Respiratory failure is a common finding in the ICU and in the management of complex cases in the operating room. Over the last ten years, it has become clear that modes of mechanical ventilation and lung recruitment may play a role both in cytokine modulation and patient outcome. Early lung recruitment and alveolar stabilization may play a very important role in the management of patients with respiratory failure and adult respiratory distress syndrome (ARDS). The open lung concept may be the key to decreasing mortality and morbidity in these patients. This technique not only improves oxygenation, but also affects surfactant function and cytokine modulation. The open lung concept is physiologically based on the Law of Laplace. Adhering to the principles of the open lung concept, pressure-controlled ventilation may improve patient outcome by reducing the extent of irreversible structural damage to the lungs caused by mechanical ventilation.

Objective: It has been demonstrated that pulmonary surfactant plays a role in the pathophysiology of ventilation-induced lung injury (VILI). Therefore, we investigated whether exogenous surfactant might restore lung function and lung mechanics in an established model of VILI., Design: Prospective, randomized, animal study., Setting: Experimental laboratory of a university., Subjects: Twenty-four adult male Sprague-Dawley rats., Interventions: First, a group of six animals were killed immediately after induction of anesthesia and used as healthy controls. Then, in 18 rats, VILI was induced by increasing peak inspiratory pressure (PIP) to 45 cmH2O without positive end-expiratory pressure (PEEP) for 20 min. Thereafter, animals were randomly divided into three groups of six animals each: one group was killed immediately after VILI and served as VILI-control. In the other two groups, ventilator settings were changed to a PIP of 30 cmH2O and a PEEP of 10 cmH2O, and a respiratory rate of 40 bpm. One group received a bolus of surfactant and the other group received no treatment., Measurements and Results: Blood gas tension and arterial blood pressures were recorded every 30 min for 2 h. After the study period, a pressure-volume curve was recorded. Then, a broncho-alveolar lavage (BAL) was performed to determine protein content, minimal surface tension, and surfactant composition in the BAL fluid. Oxygenation, lung mechanics, surfactant function and composition were significantly improved in the surfactant-treated group compared to the ventilated and non-ventilated control groups., Conclusion: We conclude that exogenous surfactant can be used to treat VILI.

Objective: To evaluate a noninvasive system for obtaining information about alveolar recruitment and derecruitment in a model of acute lung injury., Design: Prospective experimental study., Setting: Animal research laboratory., Subjects: Nine anesthetized pigs., Interventions: Electrical impedance tomography measurements were performed. Electrical impedance tomography is an imaging technique that can register the ventilation-induced impedance changes in different parts of the lung. In nine anesthetized pigs, repeated lung lavages were performed until a PaO2 of <80 mm Hg was reached. Thereafter, the lungs were recruited according to two different recruitment protocols: the open lung approach and the open lung concept. Five time points for measurements were chosen: healthy (reference), lavage (atelectasis), recruitment, derecruitment, and maintain recruited (final)., Measurements and Main Results: After lavage, there was a significant increase in the impedance ratio, defined as the ventilation-induced impedance changes of the anterior part of the lung divided by that of the posterior part (from 1.75 +/- 0.63 to 4.51 +/- 2.22; p < .05). The impedance ratio decreased significantly after performing the recruitment protocol (from 4.51 +/- 2.22 to 1.18 +/- 0.51). During both recruitment procedures, a steep increase in baseline impedance change was seen. Furthermore, during derecruitment, a decrease in the slope in baseline impedance change was seen in the posterior part of the lung, whereas the anterior part showed no change., Conclusion: Electrical impedance tomography is a technique that can show impedance changes resembling recruitment and derecruitment of alveoli in the anterior and posterior parts of the lung. Therefore, electrical impedance tomography may help in determining the optimal mechanical ventilation in a patient with acute lung injury.

The use of a ventilation strategy with high positive end-expiratory pressure (PEEP) that is intended to recruit collapsed alveoli and to prevent recurrent collapse can reduce alveolar protein influx in experimental acute lung injury (ALI). This could affect the pulmonary response to treatment with surfactant, since plasma proteins inhibit surfactant function. We studied the effect of exogenous surfactant on lung mechanics after 4 h of mechanical ventilation with high or low PEEP. Twenty-two adult male Sprague-Dawley rats were anaesthetized, tracheotomized and submitted to pressure-controlled mechanical ventilation with 100% oxygen. One group served as healthy controls (n = 6). In the remaining animals acute lung injury was induced by repeated lung lavages to obtain a PaO2 < 13 kPa during ventilation with a peak inspiratory pressure (PIP) of 26 cm H2O and a PEEP of 6 cm H2O. These animals were allocated randomly to ventilation with high PEEP (n = 8; 100 breaths min-1, I:E = 1:1 PIP 35 cm H2O, PEEP 18 cm H2O) or to conventional mechanical ventilation (PIP 28 cm H2O, PEEP 8 cm H2O; n = 8; ventilated control group). After 4 h of ventilation, all animals were given surfactant (120 mg kg-1) via the trachea and ventilation was continued for 15 min. At the end of the study, pressure-volume curves were constructed to measure total lung capacity at 35 cm H2O (TLC35) and maximal compliance (Cmax), and bronchoalveolar lavage was then used to measure alveolar protein influx. After lavage, PaO2, remained around 13 kPa in the ventilated control group and was > 66 kPa in the high-PEEP group. After surfactant treatment, PaO2 increased to > 53 kPa in both groups. In the ventilated control group alveolar protein influx was greater and TLC35 and Cmax were lower than in the high-PEEP group. We conclude that the pulmonary response to exogenous surfactant after mechanical ventilation in experimental ALI is improved when a ventilation strategy with high PEEP is used.

Objectives: To determine the effect on compartmentalization of the tumor necrosis factor (TNF)-alpha response in the lung and systemically after ventilation with high peak inspiratory pressure with and without positive end-expiratory pressure (PEEP)., Design and Setting: Prospective, randomized, animal study in an experimental laboratory of a university., Subjects and Interventions: 85 male Sprague-Dawley rats. Lipopolysaccharide was given intratracheally or intraperitoneally to stimulate TNF-alpha production; control animals received a similar amount of saline. Animals were subsequently ventilated for 20 min in a pressure control mode with peak inspiratory pressure/PEEP ratio of either 45/0 or 45/10 (frequency 30 bpm, I/E ratio 1:2, FIO2 = 1)., Measurements and Results: Blood gas tension and arterial pressures were recorded at 1, 10, and 20 min after start of mechanical ventilation. After killing of the animals pressure-volume curves were recorded, and bronchoalveolar lavage (BAL) was performed for assessment of protein content and the small/large surfactant aggregate ratio. TNF-alpha was determined in serum and BAL. TNF-alpha levels were significantly increased after lipopolysaccharide stimulation; furthermore ventilation without PEEP resulted in a significant shift of TNF-alpha to the nonstimulated compartment as opposed to ventilation with a PEEP level of 10 cmH2O., Conclusions: Ventilation strategies which are known to induce ventilation-induced lung injury (VILI) disturb the compartmentalization of the early cytokines response in the lung and systemically. Furthermore, the loss of compartmentalization is a two-way disturbance, with cytokines shifting from the vascular side to the alveolar side and vice versa. A ventilation strategy (PEEP level of 10 cmH2O) which prevents VILI significantly diminished this shift in cytokines.

Objective: To evaluate whether mechanical ventilation using "the open lung concept" during surfactant depletion can attenuate the deterioration in pulmonary function., Design: Experimental, comparative study., Setting: Research laboratory of a large university., Subjects: Eighteen adult male Sprague-Dawley rats, weighing 280-340 g., Interventions: Twelve rats were anesthetized, mechanically ventilated with 100% oxygen, and randomly divided into two groups (n = 6 each). The open lung group underwent six saline lavages at different ventilator settings that prevented alveolar collapse. The settings (expressed as frequency/peak inspiratory pressure/positive end-expiratory pressure/inspiratory:expiratory ratio) were 30/26/6/1:2 during the first lavage, 100/27/10/1:1 during the next two lavages, and 100/33/15/1:1 during the last three lavages and during the remaining ventilation period. The ventilated control group underwent six saline lavages with settings at 30/26/6/1:2. After the lavages, peak inspiratory pressure and positive end-expiratory pressure were increased in this group by 2 cm H2O each for the remaining study period. An additional group of six animals were killed immediately after induction of anesthesia and served as healthy controls. Blood gases were measured before lavage, immediately after the last lavage, and thereafter hourly. At the end of the 4-hr study period, we constructed pressure-volume curves from which we determined total lung capacity at a distending pressure of 35 cm H2O (TLC35). Subsequently, total lung volume at a distending pressure of 5 cm H2O (V5) was determined, followed by bronchoalveolar lavage., Results: In the ventilated control group, PaO2, V5, and TLC35 were significantly decreased and protein concentration of bronchoalveolar lavage was significantly increased compared with the healthy control group. In the open lung group, PaO2 did not decrease after the lavage procedure, and V5, TLC35, and the protein concentration of bronchoalveolar lavage were comparable with the healthy controls., Conclusion: We conclude that application of the open lung concept during surfactant depletion attenuates deterioration in pulmonary function.

Objective: A new noninvasive method, electrical impedance tomography (EIT), was used to make pressure-impedance (PI) curves in a lung lavage model of acute lung injury in pigs. The lower inflection point (LIP) and the upper deflection point (UDP) were determined from these curves and from the traditional pressure-volume (PV) curves to determine whether the PI curves resemble the traditional PV curves. Furthermore, regional differences in the mentioned determinants were investigated., Design: Prospective, experimental study., Setting: Animal research laboratory., Interventions: In nine anesthetized pigs, repeated lung lavage was performed until a Pao2 <80 torr was reached. Thereafter, an inspiratory PV curve was made using a constant flow of oxygen. During the intervention, EIT measurements were performed., Measurements and Main Results: In this study, the LIP(EIT) was within 2 cm H2O of the LIP(PV). Furthermore, it was possible to visualize regional PI curves by EIT. No significant difference was found between the LIP(PV) (21.3+/-3.0 cm H2O) and the LIP(EIT) of the total lung (21.5+/-3.0 cm H2O) or the anterior parts of the lung (21.5+/-2.9 cm H2O). A significantly higher LIP (29.5+/-4.9 cm H2O) was found in the posterior parts of the lung. A UDP(PV) could be found in three animals only, whereas in all animals a UDP(EIT) could be determined from the anterior part of the lung., Conclusions: Using EIT, determination of LIP and UDP from the regional PI curves is possible. The obtained information from the regional PI curves may help in understanding alveolar recruitment. The use of this new bedside technique for clinical decision making remains to be examined.

Objective: To investigate in a rat model of ventilation-induced lung injury whether metabolic changes in the lung are reflected by an increased purine concentration (adenosine, inosine, hypoxanthine, xanthine, and urate; an index of adenosine-triphosphate breakdown) of the bronchoalveolar lavage fluid and whether purine can, thus, indirectly serve as a marker of ventilation-induced lung injury., Design: Prospective, randomized, controlled trial., Setting: Research laboratory., Subjects: Forty-two male Sprague-Dawley rats., Interventions: Five groups of Sprague-Dawley rats were subjected to 6 mins of mechanical ventilation. One group was ventilated at a peak inspiratory pressure of 7 cm H2O and a positive end-expiratory pressure of 0 cm H2O. A second group was ventilated at a peak inspiratory pressure of 45 cm H2O and a positive end-expiratory pressure of 10 cm H2O. Three groups of Sprague-Dawley rats were ventilated at a peak inspiratory pressure of 45 cm H2O without positive end-expiratory pressure. Before mechanical ventilation, two of these groups received intratracheal administration of saline or exogenous surfactant at a dose of 100 mg/kg and one group received no intratracheal administration. A sixth group served as the nonventilated controls., Measurements and Main Results: Bronchoalveolar lavage fluid was collected in which both purine concentration (microM; mean +/- SD) and protein concentration (mg/mL; mean +/- SD) were determined. Statistical differences were analyzed using the one-way analysis of variance (ANOVA) with a Student-Newman-Keul's post hoc test. Purine and protein concentrations were different between groups (ANOVA p value for purine and protein, <.0001). Both purine and protein concentrations in bronchoalveolar lavage fluid were increased in Group 45/0 (3.2 +/- 1.9 and 4.2 +/- 1.6, respectively) compared with Group 7/0 (0.4 +/- 0.1 [p < .05] and 0.4 +/- 0.2 [p < .001]) and controls (0.2 +/- 0.2 [p < .01] and 0.2 +/- 0.1 [p < .001]) and in Group 45/Na (5.8 +/- 2.5 and 4.2 +/- 0.5) compared with Group 7/0 (purine and protein, p < .001) and the controls (purine and protein, p < .001). Positive end-expiratory pressure prevented an increase in purine and protein concentrations in bronchoalveolar lavage fluid (0.4 +/- 0.3 and 0.4 +/- 0.2, respectively) compared with Group 45/0 (purine, p < .01; protein, p < .001) and Group 45/Na (purine and protein, p < .001). Surfactant instillation preceding lung overinflation reduced purine and protein concentration in bronchoalveolar lavage fluid (2.1 +/- 1.6 and 2.7 +/- 1.0) compared with Group 45/Na (purine, p < .001; protein (p < .01). Surfactant instillation reduced protein concentration compared with Group 45/0 (p < .01)., Conclusions: This study shows that metabolic changes in the lung as a result of ventilation-induced lung injury are reflected by an increased level of purine in the bronchoalveolar lavage fluid and that purine may, thus, serve as an early marker for ventilation-induced lung injury. Moreover, the study shows that both exogenous surfactant and positive end-expiratory pressure reduce protein infiltration and that positive end-expiratory pressure decreases the purine level in bronchoalveolar lavage fluid after lung overinflation.

We have compared three treatment strategies, that aim to prevent repetitive alveolar collapse, for their effect on gas exchange, lung mechanics, lung injury, protein transfer into the alveoli and surfactant system, in a model of acute lung injury. In adult rats, the lungs were ventilated mechanically with 100% oxygen and a PEEP of 6 cm H2O, and acute lung injury was induced by repeated lung lavage to obtain a PaO2 value < 13 kPa. Animals were then allocated randomly (n = 12 in each group) to receive exogenous surfactant therapy, ventilation with high PEEP (18 cm H2O), partial liquid ventilation or ventilation with low PEEP (8 cm H2O) (ventilated controls). Blood-gas values were measured hourly. At the end of the 4-h study, in six animals per group, pressure-volume curves were constructed and bronchoalveolar lavage (BAL) was performed, whereas in the remaining animals lung injury was assessed. In the ventilated control group, arterial oxygenation did not improve and protein concentration of BAL and conversion of active to non-active surfactant components increased significantly. In the three treatment groups, PaO2 increased rapidly to > 50 kPa and remained stable over the next 4 h. The protein concentration of BAL fluid increased significantly only in the partial liquid ventilation group. Conversion of active to non-active surfactant components increased significantly in the partial liquid ventilation group and in the group ventilated with high PEEP. In the surfactant group and partial liquid ventilation groups, less lung injury was found compared with the ventilated control group and the group ventilated with high PEEP. We conclude that although all three strategies improved PaO2 to > 50 kPa, the impact on protein transfer into the alveoli, surfactant system and lung injury differed markedly.

Objective: To assess whether bronchoalveolar lavage (BAL) with a diluted surfactant suspension prior to surfactant instillation prevents the only transient improvement in lung function as reported after surfactant instillation in severe acute respiratory distress syndrome (ARDS)., Design: Randomized, prospective, experimental study., Setting: Laboratory and animal facility of a large university., Materials: Adult male Sprague-Dawley rats (280 +/- 30 g)., Interventions: All animals underwent repetitive whole lung saline lavage to induce acute lung injury. Then, animals were randomly divided into seven study groups: the first group received surfactant (150 mg/ kg) within 10 min after the last lavage (early treatment), whereas in the other six groups mechanical ventilation was continued for 3 h before treatment (late treatment). Treatment consisted of: surfactant instillation at a dose of 150 mg/kg; at a dose of 250 mg/kg; BAL with saline; BAL with a diluted surfactant suspension (2.5 mg/ml); BAL with saline, immediately followed by surfactant instillation (150 mg/kg) and BAL with a diluted surfactant suspension (2.5 mg/kg), immediately followed by surfactant instillation (150 mg/kg)., Measurements and Results: Blood gases were measured for 6 h and then BAL was performed to measure the protein concentration and surface tension properties. Mean PaO2 values increased immediately after surfactant instillation to pre-lavage values but remained stable only in the group that received surfactant immediately after the lavage procedure and the group that underwent BAL with a diluted surfactant suspension prior to surfactant instillation., Conclusion: BAL with a diluted surfactant suspension prior to surfactant instillation at a later time point in lung injury resulted in a stable improvement of lung function. This improvement is comparable with the results seen after surfactant instillation immediately after lung lavage.

Acute respiratory distress syndrome (ARDS) is a condition characterized by a high permeability oedema due to loss of the integrity of the alveolo-capillary barrier with impairment of normal surfactant function, resulting in an increased collapse tendency of the alveoli. Mechanical ventilation on such alveoli with repeated alveolar collapse and subsequent reexpansion results in severe lung parenchymal injury and may induce further surfactant impairment. This cam be prevented by maintaining alveolar volume at end-expiration by means of sufficient levels of positive end-expiratory pressure (PEEP). Recent evidence from experimental studies has shown that ventilator modes which allow end-expiratory collapse can induce bacterial translocation from the lung into the bloodstream and trigger the release of inflammatory mediators, which can also be presented by maintaining end-expiratory alveolar volume. These data suggest that the interaction between surfactant changes and mechanical ventilation may play a role in the transition of ARDS into the systematic inflammatory disease process of multiple system organ failure (MSOF).

Objective: To assess the effect of partial liquid ventilation with perfluorocarbons on hemodynamics and gas exchange in large pigs with induced acute lung injury (ALI)., Design: Randomized, prospective, double-control, experimental study. Experimental intensive care unit of a university., Materials: Eighteen large pigs (50 +/- 5 kg body weight) with an average anterior posterior thoracic diameter of 24 cm and induced acute lung injury., Interventions: All animals were surfactant depleted by lung lavage to a PaO2 below 100 mmHg and randomized to receive either perflubron (n = 6) or saline (n = 6) in five intratracheal doses of 5 ml/kg at 20-min intervals, or no instillation (n = 6)., Measurements and Results: In all animals heart rate, arterial pressures, pulmonary pressures, cardiac output and blood gases were recorded at 20-min intervals. There was no deleterious effect on any hemodynamic parameter in the perflubron group, whereas systolic and mean pulmonary arterial pressure values showed a persistent decrease after the first 5 ml/kg of perflubron, from 48.7 +/- 14.1 to 40.8 +/- 11.7 mmHg and from 39.7 +/- 13.2 to 35.2 +/- 12.0 mmHg, respectively. Perflubron resulted in a significant (ANOVA P < 0.01), dose-dependent increase in PaO2 values from 86.3 +/- 22.4 to a maximum of 342.4 +/- 59.4 mmHg at a dose of 25 ml/kg; the other groups showed no significant increase in PaO2., Conclusions: Tracheal instillation of perflubron in induced ALI results in a dose-dependent increase in PaO2 and has no deleterious effect on hemodynamic parameters.

Acute respiratory distress syndrome (ARDS) has become a well-recognized condition that can result from a number of different causes that lead to injury of the alveolar-capillary membrane. This results in high-permeability pulmonary oedema that disturbs the pulmonary surfactant system. In ARDS, the treatments available are still inadequate and morbidity, mortality, and costs remain unacceptably high. In the last 15 yrs, the morbidity and mortality rates of premature infants suffering from the respiratory distress syndrome (RDS) due to surfactant deficiency, have been reduced by exogenous surfactant therapy, and this treatment is now routinely used in most neonatal intensive care units. At this moment, only a few case reports and results of limited clinical pilot studies are available, in which patients with ARDS are treated with exogenous surfactant. Although the results from these studies are not consistent, the best results have been seen in patients treated with high concentrations or multiple doses of surfactant. It has been suggested that the increased permeability changes, along with the inflammatory response, lead to accumulation of plasma components in the alveolar space, causing inhibition of the instilled surfactant in a dose-dependent way. Thus, for treatment of ARDS, a high concentration of surfactant is required to overcome the inhibitory effect of plasma components. However, a few questions remain unanswered, including: When should surfactant treatment start? Which dosage? Of which type of surfactant? Which method of administration should be used, in combination with which type of ventilatory support, etc.?

1. We have examined the effects of five different lung surfactant factor (LSF) preparations in the rat lung lavage model. In this model repetitive lung lavage leads to lung injury with some similarities to adult respiratory distress syndrome with poor gas exchange and protein leakage into the alveolar spaces. These pathological sequelae can be reversed by LSF instillation soon after lavage. 2. The tested LSF preparations were: two bovine: Survanta and Alveofact: two synthetic: Exosurf and a protein-free phospholipid based LSF (PL-LSF) and one Recombinant LSF at doses of 25, 50 and 100 mg kg-1 body weight and an untreated control group. 3. Tracheotomized rats (10-12 per dose) were pressure-controlled ventilated (Siemens Servo Ventilator 900C) with 100% oxygen at a respiratory rate of 30 breaths min-1, inspiration expiration ratio of 1:2, peak inspiratory pressure (PIP) of 28 cmH2O at positive end-expiratory pressure (PEEP) of 8 cmH2O. Two hours after LSF administration, PEEP and in parallel PIP was reduced from 8 to 6 (1st reduction), from 6 to 3 (2nd reduction) and from 3 to 0 cmH2O (3rd reduction). 4. Partial arterial oxygen pressure (PaO2, mmHg) at 5 min and 120 min after LSF administration and during the 2nd PEEP reduction (PaO2(PEEP23/3)) were used for statistical comparison. All LSF preparations caused a dose-dependent increase for the PaO2(120'), whereas during the 2nd PEEP reduction only bovine and recombinant LSF exhibited dose-dependency. Exosurf did not increase PaO2 after administration of the highest dose. At the highest dose Exosurf exerted no further improvement but rather a tendency to relapse. The bovine and the Recombinant LSF are superior to both synthetic LSFpreparations.5. In this animal model and under the described specific ventilatory settings, even between bovine LSFpreparations there are detectable differences that are pronounced when compared to synthetic LSFwithout any surfactant proteins. We conclude that the difference between bovine and synthetic LSFpreparations can be overcome by addition of the surfactant protein C.

The purpose of this study was to evaluate whether any benefit of low frequency positive pressure ventilation with extracorporeal carbon dioxide removal (LFPPV-ECCO2R) existed over either volume controlled ventilation (VCV) with measured best-PEEP or pressure regulated volume controlled ventilation (PRVCV) with an inspiration/expiration (I/E) ratio of 4:1, with respect to arterial oxygenation, lung mechanics and haemodynamics, in acute respiratory failure. Fifteen adult pigs were used for the study. Respiratory failure was induced by surfactant depletion by repeated lung lavage. The different therapeutic approaches were applied randomly to each pig for 1 h. Measurements of gas exchange, airway pressures and haemodynamics were performed during ventilatory and haemodynamic steady state. Paco2 was kept constant in all modes. At almost similar total-PEEP, Pao2 values were significantly higher with LFPPV-ECCO2R compared to VCV with best-PEEP. Peak inspiratory pressure (PIP) and intrapulmonary pressure amplitude defined as the difference between PIP and total-PEEP were significantly lower with PRVCV and LFPPV-ECCO2R compared to VCV with best-PEEP. There was no significant difference between the modes concerning cardiocirculatory parameters. PRVCV with I/E ratio of 4:1 and LFPPV-ECCO2R proved to be better modes to achieve better gas exchange and lower PIP at lower intrapulmonary pressure amplitudes. It is concluded that PRVCV is an adequate form of treatment under these experimental conditions imitating acute respiratory failure, without necessitating other invasive measures.

Objectives: To test the efficacy of intratracheal instillation of a perfluorocarbon, combined with conventional mechanical ventilation, as well as to establish the dose response of this application on pulmonary parameters in adult animals with acute respiratory failure., Design: Prospective, randomized, placebo-controlled study., Setting: Anesthesiology laboratory of a university., Subjects: Twelve, adult male New Zealand rabbits., Interventions: After inducing respiratory failure by repeated lung lavage with saline, one group of animals was treated with perfluorocarbon, while another group was treated with saline to serve as controls (n = 6 per group). Treatment consisted of intratracheal instillation of incremental doses of 3 mL/kg of each liquid up to a total volume of 15 mL/kg. Animals were mechanically ventilated for 15 mins after each treatment dose with volume-controlled ventilation, a tidal volume of 12 mL/kg, frequency of 30 breaths/min, FIO2 of 1.0, and a positive end-expiratory pressure of 6 cm H2O., Measurements and Main Results: Arterial blood gases and lung mechanics were determined. In the perfluorocarbon group, PaO2 increased with increases in dosage from 75 +/- 15 to 420 +/- 27 torr (10.0 +/- 2.0 to 55.9 +/- 3.6 kPa); PaCO2 decreased from 49 +/- 6 to 43 +/- 5 torr (6.5 +/- 0.8 to 5.7 +/- 0.6 kPa) after the first dose, and remained stable thereafter. Airway pressures were significantly lower after treatment compared with pretreatment values., Conclusion: The remarkable improvements in pulmonary parameters suggest that this type of ventilatory support offers an effective and simple method of perfluorocarbon application in acute respiratory failure.

In this study a model of acute respiratory failure due to viral pneumonia in rats, closely resembling ARDS, is presented. Severe respiratory failure with lethal outcome in four days was induced by infection concentrated Sendai virus aerosol. This model permits evaluation of different therapeutical approaches for improving gas exchange during ARDS. Furthermore, preliminary results of surfactant substitution therapy in this model are presented.