Model Of ARDS Research Articles

The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro

To investigate the modulation of lung local immune responses of hesperidin (HES) on the acute lung inflammation induced by LPS in vivo. Mice were challenged with intratracheal lipopolysaccharide (100 μg) 30 min before with treatment hesperidin (200 mg/kg oral administration) or vehicle. After 4 and 24 h, bronchoalveolar lavage fluid was obtained to measure proinflammatory (TNF-α, IL-1β, IL-6), anti-inflammatory (IL-10, IL-4, IL-12) cytokines, chemokines (KC, MCP-1 and MIP-2), total cell counts, nitric oxide production, and proteins. Lung histology was performed in inflated-fixed lungs. Hesperidin downregulate the LPS-induced expression of TNF-α, IL-1β, IL-6, KC, MIP-2, MCP-1, and IL-12. It also enhanced the production of IL-4, IL-10. Total leukocyte counts; nitric oxide production, iNOS expression, and proteins were significantly decreased by hesperidin. In vitro, HES suppressed the expression of IL-8 on A549 cells and THP-1 cells, the expression of TNF-α, IL-1β, and IL-6 on THP-1 cells, the expression of ICAM-1 and VCAM-1 on A549 cells which effect cell adhesion function. The suppression of those molecules is controlled by NF-κB and AP-1, which are activated by IκB and MAPK pathways. HES inhibits those pathways, thereby suppressing the expression of IL-8, TNFα, IL-1β, IL-6, IL-12, ICAM-1 and VCAM-1. This study indicates that HES had a markedly immunomodulatory effect in a clinically relevant model of ARDS. Nevertheless, further investigations are required to determine the potential clinical usefulness of HES in the adjunctive therapy of ARDS.

Effect of positive end-expiratory pressure and tidal volume on lung injury induced by alveolar instability.

IntroductionOne potential mechanism of ventilator-induced lung injury (VILI) is due to shear stresses associated with alveolar instability (recruitment/derecruitment). It has been postulated that the optimal combination of tidal volume (Vt) and positive end-expiratory pressure (PEEP) stabilizes alveoli, thus diminishing recruitment/derecruitment and reducing VILI. In this study we directly visualized the effect of Vt and PEEP on alveolar mechanics and correlated alveolar stability with lung injury.MethodsIn vivo microscopy was utilized in a surfactant deactivation porcine ARDS model to observe the effects of Vt and PEEP on alveolar mechanics. In phase I (n = 3), nine combinations of Vt and PEEP were evaluated to determine which combination resulted in the most and least alveolar instability. In phase II (n = 6), data from phase I were utilized to separate animals into two groups based on the combination of Vt and PEEP that caused the most alveolar stability (high Vt [15 cc/kg] plus low PEEP [5 cmH2O]) and least alveolar stability (low Vt [6 cc/kg] and plus PEEP [20 cmH2O]). The animals were ventilated for three hours following lung injury, with in vivo alveolar stability measured and VILI assessed by lung function, blood gases, morphometrically, and by changes in inflammatory mediators.ResultsHigh Vt/low PEEP resulted in the most alveolar instability and lung injury, as indicated by lung function and morphometric analysis of lung tissue. Low Vt/high PEEP stabilized alveoli, improved oxygenation, and reduced lung injury. There were no significant differences between groups in plasma or bronchoalveolar lavage cytokines or proteases.ConclusionA ventilatory strategy employing high Vt and low PEEP causes alveolar instability, and to our knowledge this is the first study to confirm this finding by direct visualization. These studies demonstrate that low Vt and high PEEP work synergistically to stabilize alveoli, although increased PEEP is more effective at stabilizing alveoli than reduced Vt. In this animal model of ARDS, alveolar instability results in lung injury (VILI) with minimal changes in plasma and bronchoalveolar lavage cytokines and proteases. This suggests that the mechanism of lung injury in the high Vt/low PEEP group was mechanical, not inflammatory in nature.

The lung in the balance: arginine, methylated arginines, and nitric oxide

the lung is a major source of nitric oxide (NO), be it from nitric oxide synthase (NOS) III in the endothelium of the vast pulmonary circulation, NOS II in the epithelium of the large surface area of the airways, or NOS I in the nonadrenergic noncholinergic nerves ([6][1]). NO produced in the lung

Assessment of Lung Inflammation in a Mouse Model of Smoke Inhalation and Burn Injury

Introduction To test concepts developed in our ovine model of ARDS, methods for quantitative assessment of acute inflammation in the lung were applied to our murine model of smoke inhalation and burn (S+B) injury. Methods Mice received S+B injury per protocol, n = 5 to 8 per group. Mice were anesthetized, intubated and exposed to cooled cotton smoke (4X 30 sec for Balb/C, 2X 30 sec for C57). After s.q. injection of 1 ml 0.9% saline, they received a 40% total body surface area (TBSA) burn. Buprenorphene (2 mg/kg) was given i.p. for analgesia. 0.9% saline was given i.p. at 4 ml/kg per %TBSA burn. Evans Blue dye (EB) was injected i.v. 15 min before sacrifice. Lung wet/dry weight ratio was measured. After vascular perfusion, lungs were sampled for myeloperoxidase (MPO), using an EIA kit, and content of EB dye. Results There was a significant (* = p < 0.05) increase in EB dye content, wet/dry weight ratio and MPO 24 h after injury in Balb/C mice. Similar increases were seen in C57 mice 48 h after S+B injury, but not at 24 h. Conclusions C57 mice tolerated less smoke inhalation than Balb/C mice, and required 48 hr to show significant increases in these variables. The mouse model can be used effectively to assess acute inflammation in the lung. Supported by Shriners of North America and National Institutes of Health

Fecal peritonitis in pigs as a model of extrapulmonary ALI/ARDS

Although extrapulmonary ALI/ARDS is a common clinical entity, most animal models used to study this disease are induced by direct lung injuries. Our intention was therefore to investigate whether a condition resembling ALI/ARDS develops during the course of a fecal peritonitis in pigs; in that case experimental peritonitis would also prove as a clinically relevant ARDS model.

Analysis of discrete and continuous distributions of ventilatory time constants from dynamic computed tomography

In this study, an algorithm was developed to measure the distribution of pulmonary time constants (TCs) from dynamic computed tomography (CT) data sets during a sudden airway pressure step up. Simulations with synthetic data were performed to test the methodology as well as the influence of experimental noise. Furthermore the algorithm was applied to in vivo data. In five pigs sudden changes in airway pressure were imposed during dynamic CT acquisition in healthy lungs and in a saline lavage ARDS model. The fractional gas content in the imaged slice (FGC) was calculated by density measurements for each CT image. Temporal variations of the FGC were analysed assuming a model with a continuous distribution of exponentially decaying time constants. The simulations proved the feasibility of the method. The influence of experimental noise could be well evaluated. Analysis of the in vivo data showed that in healthy lungs ventilation processes can be more likely characterized by discrete TCs whereas in ARDS lungs continuous distributions of TCs are observed. The temporal behaviour of lung inflation and deflation can be characterized objectively using the described new methodology. This study indicates that continuous distributions of TCs reflect lung ventilation mechanics more accurately compared to discrete TCs.

Reduction in the aggressiveness of ventilation by inhalation of perfluorohexane after therapy of oleic acid-induced respiratory failure

The application of perfluorohexane (PFH) vapor led to an improvement of oxygenation and mechanical lung function in a model of oleic acid-induced ARDS in sheep. The aim of this study was to investigate the effects of PFH on gas exchange over an extended time period and to reduce the invasiveness of ventilation. ARDS was induced in sheep ( n=12) by injecting 0.1 ml/kg body weight oleic acid intravenously. Six sheep were treated for 30 min with 18 vol.% PFH (PFH-Tx) and followed up over a time period of 240 min while untreated sheep ( n=6) served as controls. Subsequently the F(I)O(2) was reduced to generate a p(a)O(2) between 100-140 mmHg. Gas exchange, respiratory and hemodynamic data were collected at regular intervals. Data were analysed using covariance analysis. PFH treatment led to an improvement in oxygenation ( p<0.01) and in mechanical lung function ( p<0.01). Furthermore, mean pulmonary artery pressure ( p<0.01) and shunt ( p<0.01) were lower in PFH-Tx. F(I)O(2) could be reduced in all PFH-treated animals ( p<0.01). Treatment of oleic acid-induced lung injury with PFH vapor improved oxygenation and mechanical lung function over a extended time period allowing a reduction in the invasiveness of ventilation.

Lung recruitment maneuvers in acute respiratory distress syndrome.

In the experimental setting, repeated derecruitments of the lungs of ARDS models accentuate lung injury during mechanical ventilation, whereas open lung concept strategies can attenuate the injury. In the clinical setting, recruitment manuevers that use a continuous positive airway pressure of 40 cmH2O for 40 secs improve oxygenation in patients with early ARDS who do not have an impairment in the chest wall. High intermittent positive end-expiratory pressure (PEEP), intermitent sighs, or high-pressure controlled ventilation improves short-term oxygenation in ARDS patients. Both conventional and electrical impedance thoracictomography studies at the clinical setting indicate that high PEEP associated with low levels of pressure control ventilation recruit the collapsed portions of the ARDS lungs and that adequate PEEP levels are necessary to keep the ARDS lungs opened allowing a more homogenous ventilation. High PEEP/low tidal volume ventilation was seen to reduce inflammatory mediators in both bronchoalveolar lavage and plasma, compared to low PEEP/high tidal volume ventilation, after 36 hours of mechanical ventilation in ARDS patients. Recruitment maneuvers that used continuous positive airway pressure levels of 35-40 cmH2O for 40 secs, with PEEP set at 2 cmH2O above the lower inflection point of the pressure-volume curve, and tidal volume < 6 mL/kg were associated with a 28-day intensive care unit survival rate of 62%. This contrasted with a survival rate of only 29% with conventional ventilation (defined as the lowest PEEP for acceptable oxygenation without hemodynamic impairment with a tidal volume of 12 mL/kg), without recruitment manuevers (number needed to treat = 3; p < 0.001). In the near future, thoracic computed tomography associated with high-performance monitoring of regional ventilation may be used at the bedside to determine the optimal mechanical ventilation of the ARDS keeping an opened lung with a homogenous ventilation.

Early surfactant administration protects against lung dysfunction in a mouse model of ARDS.

Sepsis can predispose the lung to insults such as mechanical ventilation (MV). It was hypothesized that treating the lung with exogenous surfactant early in the development of sepsis will reduce the lung dysfunction associated with MV 18 h later. Mice underwent sham or cecal ligation and perforation (CLP) surgery. Immediately after surgery, mice were either untreated or given 100 mg/kg of bovine lipid extract surfactant intratracheally. Eighteen hours later, the lungs were removed and analyzed either immediately or following ventilation ex vivo for 2 h by an "injurious" mode of ventilation (20 ml/kg, 0 cm positive end-expiratory pressure). In nonventilated lungs, exogenous surfactant had no impact on compliance or IL-6 concentrations in the lungs. In the ventilated groups, the administered surfactant had a significant protective effect on the lung dysfunction induced by MV, but only in the CLP lungs. We conclude that administration of exogenous surfactant at the time of a systemic insult can protect the lung from the damaging effects of MV 18 h later.

High Frequency Percussive Ventilation with Systemic Heparin Improves Short Term Survival in an LD100 Sheep Model of ARDS

High Frequency Percussive Ventilation with Systemic Heparin Improves Short Term Survival in an LD100 Sheep Model of ARDS

Temporal dynamics of lung aeration determined by dynamic CT in a porcine model of ARDS

We used dynamic CT to identify two different time constants of lung aeration and their individual contribution to the total increase in cross-sectional lung area in healthy and experimentally damaged lungs. In five healthy pigs, inflation and deflation between 0 and 50 cm H2O was imposed during dynamic (250 ms/image) CT acquisition, and repeated after experimental lung injury by saline lavage. The fractional areas of density ranges, which represent aerated lung parenchyma, were determined planimetrically, and their time for expansion during the manoeuvre was fitted using a bi-exponential model. Thus, two compartments, their sizes, i.e. their relative contributions to lung area aerated by the manoeuvre, and their specific time constants (tau) were sought. Healthy lungs were characterized best by a one-compartmental behaviour with one tau only, both during inflation (median tau=0.5 s; range 0.4-0.6 s) and deflation (1.2 s; 1.1-1.3 s). In damaged lungs two compartments were found both during inspiration and expiration, with 86% (78-87%) of the recruitable lung area following a short tau of 0.5 s (0.5-0.6), and 14% (13-22%) following a longer tau of 9.1 s (8-16.8 s) during inflation. During expiration, damaged lungs had a short tau of 0.8 s (0.5-1.0 s) for 94% (84-100%) of deflated lung area, and a longer tau of 26.5 s (7.1-34.3 s) for 6% (0-16%). We conclude that dynamic CT indicates the relative size and temporal behaviour of functional compartments in normal and abnormal lungs. Our findings suggest that after lung damage, cyclic ventilation with inspiratory periods of <10 s duration will not achieve maximum recruitment for a chosen inspiratory pressure. In ARDS, the short expiratory tau predisposes to atelectasis formation if expiratory times are >1 s.

Partial liquid ventilation with perfluorocarbons for treatment of ARDS in burns

Pulmonary failure remains the major determinant of mortality and morbidity following burn injury. We hypothesized that intratracheal instillation of perfluorocarbon liquids could be a therapeutic measure in combination with conventional mechanical ventilation to improve pulmonary gas exchange in acute respiratory distress syndrome with thermal injury. Forty-five New Zealand rabbits were used for this prospective and randomized experimental study. The animals were burned by scald to reach full-thickness 40% burn surface area. After inducing respiratory distress by repeated lung lavage with saline, animals were divided randomly into three groups of 15 rabbits each. First group (control group) received conventional treatment (continuous positive-pressure ventilation) using a FiO 2 of 1.0, tidal volume of 12 ml/kg, respiratory frequency of 30 cycles/min and PEEP of 6 cm H 2O. Second group was treated with 9 ml/kg of intratracheal perfluorocarbon. Third group was treated with 15 ml/kg of intratracheal perfluorocarbon. All groups were ventilated for 6 h. In the perfluorocarbon groups, PaO 2 increased significantly ( P<0.05) from 46±4 to 439±10 mmHg compared to the control group in a dose-related manner. In pulmonary parameters we observed significant ( P<0.05) decrease in mean airway pressures from the pre-treatment value of 11.44±0.15 cm H 2O to the post treatment 10.22±0.12 cm H 2O and increase ( P<0.05) in respiratory system compliance from 1.8±0.02 to 2.46±0.07 ml/cm H 2O with the perfluorocarbon. Perfluorocarbon instillation did not result in statistically significant changes in arterial pressure, heart rate and central venous pressure. In conclusion, partial liquid ventilation with perfluorocarbon is a new technique leading to a marked and sustained improvement in oxygenation and pulmonary function in an experimental model of ARDS in burns.

Measurement of Ventilation-Perfusion Ratio Using Multiple Inert Gas Elimination Technique in the Endotoxin-Induced Septic Rabbit

Background: Endotoxin is a complex lipopolysaccharide molecule situated within the outer membrane of Gram-negative bacteria. Sepsis and acute respiratory failure (ARDS) can be induced by endotoxin. In order to introduce and develop the experimental model of ARDS in sepsis, we induced sepsis with the endotoxin and investigated the change of respiratory pathophysiology during sepsis using a multiple inert gas elimination technique (MIGET). Methods: Ten New Zealand white rabbits were anesthetized and ventilated with a Harvard apparatus. In 5 rabbits, 2 mg/kg of lipopolysaccaride from E. coli was infused intravenously for 30 min (Toxin group). At 1, 2, 3, and 4 hours after endotoxin infusion, arterial blood gas, and hemodynamic profiles were checked. To perform the MIGET, six inert gases (SF6, krypton, desflurane, enflurane, diethyl ether, acetone) of widely varying solubility were infused peripherally and the excretion and retention data was determined from measurements of inert gas tensions in pulmonary arterial, systemic arterial blood samples and mixd expiratory gas sampling of pre and post septicemia using gas chromatography. We transformed and analysed the data into a V/Q distribution curve to find out the change of V/Q distribution curve. After the experiments, the animals were dissected and the lungs were extracted for wet/dry weight ratio (WW/DW) and microscopic examination, Results: In the Toxin group, the pulmonary arterial pressures were increased and arterial oxygen tensions were decreased after the endotoxin infusion. The lung WW/DW were increased and inflammatory findings were seen in microscopic examination. In the MIGET, shunt, deadspace and log SDQ were increased in the toxin group, though there were wide V/Q distributions in the control group. Conclusions: We developed a successful endotoxin induced septic animal model, V/Q distribution curve and data using MIGET. The accomplishment of the experiment will not only allow us to better understand pulmonary pathophysiology of endotoxin induced sepsis using MIGET, but it will also contribute to other pulmonary physiology experiments associated with sepsis. (Korean J Anesthesiol 2001; 40: 655~663)

Room 310, 10/18/2000 2: 00 PM - 3: 30 PM (PD) Effects of Zero Balanced Continuous Venvenous Hemofiltration (CVVH) on Oxygenation in an Animal Model of ARDS

<b>Room 310, 10/18/2000 2: 00 PM - 3: 30 PM (PD) Effects of Zero Balanced Continuous Venvenous Hemofiltration (CVVH) on Oxygenation in an Animal Model of ARDS</b>

AVCO2R PERIOPERATIVE MANAGEMENT

Percutaneous arteriovenous CO2 removal (AVCO2R) is a simple A-V shunt for near-total CO2 removal that allows significant reductions in minute ventilation, decreased ventilator days, and increased survival in our LD40 model of ARDS. We critically reviewed our perioperative anesthetic management in this ovine smoke-burn injury model of ARDS. Sheep (n=16) require general anesthesia for the 3 steps of our protocol allowing AVCO2R outcomes studies. (1) Vascular access: 1–3 days prior to injury, 4.5–11.5 mg/kg IM ketamine and 4–5% halothane by mask for induction. Intubation, then maintenance by 1.5–2.5% halothane in 100% O2 titrated for MAP 70–95 mm Hg. Peak airway pressures were < 25 mmHg and end tidal CO2 30–40 mm Hg. (2) RDS model: Tracheostomy, then smoke insufflation (36 breaths) plus a 40% TBSA III° burn followed by mechanical ventilation. Intraop, Lactated Ringer's (LR) titrated for CVP 4–6 mm Hg. Postop, LR by Parkland formula then CVP titration. (3) AVCO2R/SHAM: When PaO2/FiO2 < 200 (48–52 hours), animals randomized to AVCO2R (n=8) or SHAM (n=8). Induction, 35% N2O and 5% isofluorane in 100% O2; maintenance 1.5–3.2% isofluorane in 100% O2 allowed exposure of the carotid artery and jugular vein. AVCO2R were cannulated (10F arterial; 14F venous) and connected to a membrane gas exchanger. SHAM received identical operative exposure without cannulation. Postop, both underwent algorithmic reduction in vent settings. All received identical heparin (ACT >300 sec) and fluid management. All sheep met criteria for RDS, survived both preps, and were standing in 0.5–5 hrs. Anesthetic time was equivalent for both groups. There were no complications attributable to anesthesia (hypotension requiring pressor support, arrythmias, or arrest). Algorithmic management protocol was followed 90% of the time. 8/8 AVCO2R and 3/8 SHAM survived the study. The absence of critical care and anesthetic related complications allows model development for independent evaluation of AVCO2R in outcomes studies.

Inhibition of CD11-CD18 complex prevents acute lung injury and reduces mortality after peritonitis in rabbits.

Acute lung injury is frequent after severe peritonitis. The aim of this study was to investigate whether inhibition of the adhesion molecule CD11-CD18 on polymorphonuclear leukocytes (PMNs) would have any beneficial effects on pulmonary function and mortality in an animal model reproducing these clinical conditions. Acute peritonitis was induced in 36 rabbits by intraperitoneal injection of zymosan (0.6 g/kg) suspended in mineral oil; 20 were pretreated with a murine-specific IgG2a anti-CD18 monoclonal antibody, 16 (controls) with nonspecific purified murine IgG (1 mg/kg). The animals were followed for 10 d, then killed for histologic examination of the lungs. Blood samples were taken on Days 0, 1, 3, 7, and 10 for red blood cell (RBC), white blood cell (WBC), and platelet counts, pH, PO(2), PCO(2), carbon dioxide content (HCO(3)(-)) measurements, and renal and liver tests. Treatment with the anti-CD18 monoclonal antibody reduced mortality by approximately 40% (p < 0.05). PO(2) was higher in these treated animals than in the control animals throughout the study (p < 0.05 on Day 1, 3, and 10). On Day 1 control animals had significant leukopenia, whereas anti-CD18-treated animals had a moderate increase of the number of circulating WBC compared with baseline values (p < 0.05 between groups). The lungs of the anti-CD18-treated animals showed minor signs of inflammation and PMN infiltration whereas controls had interstitial and intra-alveolar edema and a large number of granulocytes. Quantification of PMNs by morphometry showed that there were constantly less granulocytes in the lungs of the animals treated with the anti-CD18 antibody (p < 0.001). PMN infiltration correlated with the levels of PO(2) (p < 0.001). Lung tissue of anti-CD18-treated rabbits contained less malonyldialdehyde, a by-product of membrane lipid peroxidation by PMN oxygen radicals (950 +/- 120 versus 1,710 +/- 450 pM/mg of protein) and, conversely, more of the antioxidant alpha-tocopherol (136 +/- 22 versus 40 +/- 9 ng/mg of protein), than the control rabbits (p < 0.01). In this particular model of ARDS the monoclonal antibody against the CD11-CD18 complex had a beneficial effect, reducing PMN infiltration and oxygen radical release in the lungs, preventing alveolocapillary membrane damage, improving gas exchange and, finally, significantly reducing mortality.

Relationship between superimposed pressure and pleural pressure gradient in an experimental model of ARDS

Relationship between superimposed pressure and pleural pressure gradient in an experimental model of ARDS

Surfactant Lavage Treatment in a Model of Respiratory Distress Syndrome

In a model of ARDS in adult rabbits, we have compared the capacity of exogenous synthetic surfactant, administered by bolus or by lavage, to reexpand the lungs and to inhibit the inflammatory process. The surfactant used contained DPPC and POPG (3:1) together with palmitic acid (15% by weight) and the peptide KLLLLKLLLLKLLLLKLLLLK (KL4) that mimics SP-B.1 This surfactant preparation, termed KL4-surfactant, has been evaluated in animal studies2 and a clinical trial in 47 patients with idiopathic respiratory distress syndrome.

Levels of Evidence for the Pharmacologic Effectiveness of Prolonged Methylprednisolone Treatment in Unresolving ARDS

ARDS is a life-threatening disease of multifactorial etiology caused by a direct or indirect insult to the pulmonary lobules. We have tested a therapeutic intervention on a previously defined model of ARDS,1 in which the three fundamental elements of a disease process2—pathogenesis, structural alterations, and functional consequences—were described during the course of the disease. In this single “hit” model, degree and duration of the host defense response (HDR) determine the adaptive vs maladaptive evolution of the reparative process and final outcome.

The Physiologic Effects of Inverse Ratio Ventilation

The efficacy of inverse ratio ventilation in ARDS is not clear. Furthermore, the mechanism responsible has not been determined. We designed an animal study to determine if inverse ratio ventilation improves gas exchange and by what mechanism. Prospective randomized, controlled design was used. University of Missouri Pulmonary/Critical Care Animal Laboratory. Nine dogs with oleic acid-induced lung injury as control animals to assess stability of the model, nine in the experimental model. Conventional ventilation with full recruitment extrinsic positive end-expiratory pressure (PEEP) was compared with two other modes of ventilation. One was inverse ratio with extrinsic PEEP and the second was inverse ratio with intrinsic PEEP equal to full recruitment PEEP. Full recruitment levels of PEEP were defined by optimizing compliance, then increasing PEEP by 2.5 cm/H2O. Each type of ventilation was maintained for 45 min after the edema had stabilized. Comparison of lung injury over time requires stability of the model over time. Therefore, we also assessed the stability of the preparation over time by examining compliance, extravascular lung water, and venous admixture in nine control dogs with equivalent lung injury over the same time span. Mean airway pressure was increased by both types of inverse ratio ventilation, while compliance remained stable. Venous admixture was reduced (conv=0.32+/-0.12, inverse ratio with extrinsic PEEP=0.24+/-0.10, inverse ratio with intrinsic PEEP=0.28+/-0.11) with inverse ratio with extrinsic PEEP, but the improvement was less with inverse ratio with intrinsic PEEP, even though the mean airway pressure was higher. We conclude that increasing mean airway pressure by prolongation of the inspiratory time improves gas exchange in our model of ARDS, but when mean airway pressure is increased further, allowing the development of intrinsic PEEP, the beneficial effects on gas exchange are less. Increasing mean airway pressure with intrinsic PEEP is not equivalent to other methods of increasing mean airway pressure.