Effect of Mechanical Ventilation on Inflammatory ...

CARING FOR THE CRITICALLY ILL PATIENT

Effect of Mechanical Ventilation on Inflammatory Mediators in Patients With Acute Respiratory Distress Syndrome A Randomized Controlled Trial V. Marco Ranieri, MD Peter M. Suter, MD Cosimo Tortorella, MD, PhD Renato De Tullio, MD Jean Michel Dayer, MD Antonio Brienza, MD Francesco Bruno, MD

Context Studies have shown that an inflammatory response may be elicited by mechanical ventilation used for recruitment or derecruitment of collapsed lung units or to overdistend alveolar regions, and that a lung-protective strategy may reduce this response. Objective To test the hypothesis that mechanical ventilation induces a pulmonary and systemic cytokine response that can be minimized by limiting recruitment or derecruitment and overdistention. Design and Setting Randomized controlled trial in the intensive care units of 2 European hospitals from November 1995 to February 1998, with a 28-day follow-up.

Arthur S. Slutsky, MD

Patients Forty-four patients (mean [SD] age, 50 [18] years) with acute respiratory distress syndrome were enrolled, 7 of whom were withdrawn due to adverse events.

A

Interventions After admission, volume-pressure curves were measured and bronchoalveolar lavage and blood samples were obtained. Patients were randomized to either the control group (n = 19): tidal volume to obtain normal values of arterial carbon dioxide tension (35-40 mm Hg) and positive end-expiratory pressure (PEEP) producing the greatest improvement in arterial oxygen saturation without worsening hemodynamics; or the lungprotective strategy group (n = 18): tidal volume and PEEP based on the volume-pressure curve. Measurements were repeated 24 to 30 and 36 to 40 hours after randomization.

CUTE RESPIRATORY DISTRESS

syndrome (ARDS) is a clinical syndrome characterized by severe hypoxemia, stiff lungs, and decreased respiratory system compliance. Early ARDS is characterized by acute and diffuse endothelial and epithelial injury termed diffuse alveolar damage,1 which leads to increased vascular permeability with protein-rich exudative edema. Although originally thought to be relatively homogeneous, a number of recent studies have highlighted the marked heterogeneity of the pathological process with consolidation in the dependent regions of the lung and relatively normal aeration of the nondependent regions.2,3 Despite apparent improvement in management and outcome of ARDS, the mortality rate of ARDS remains high, ranging from 35% to 65%. 4,5 Mechanical ventilation delays mortality in many patients with acute respiratory failure and is used to maintain adequate systemic oxygenation and to rest the respiratory muscles. However, over the last 2 decades, it has become evident that mechanical ventilation 54

Main Outcome Measures Pulmonary and systemic concentrations of inflammatory mediators approximately 36 hours after randomization. Results Physiological characteristics and cytokine concentrations were similar in both groups at randomization. There were significant differences (mean [SD]) between the control and lung-protective strategy groups in tidal volume (11.1 [1.3] vs 7.6 [1.1] mL/kg), end-inspiratory plateau pressures (31.0 [4.5] vs 24.6 [2.4] cm H2O), and PEEP (6.5 [1.7] vs 14.8 [2.7] cm H2O) (P,.001). Patients in the control group had an increase in bronchoalveolar lavage concentrations of interleukin (IL) 1b, IL-6, and IL-1 receptor agonist and in both bronchoalveolar lavage and plasma concentrations of tumor necrosis factor (TNF) a, IL-6, and TNF-a receptors over 36 hours (P,.05 for all). Patients in the lung-protective strategy group had a reduction in bronchoalveolar lavage concentrations of polymorphonuclear cells, TNF-a, IL-1b, soluble TNF-a receptor 55, and IL-8, and in plasma and bronchoalveolar lavage concentrations of IL-6, soluble TNF-a receptor 75, and IL-1 receptor antagonist (P,.05). The concentration of the inflammatory mediators 36 hours after randomization was significantly lower in the lung-protective strategy group than in the control group (P,.05). Conclusions Mechanical ventilation can induce a cytokine response that may be attenuated by a strategy to minimize overdistention and recruitment/derecruitment of the lung. Whether these physiological improvements are associated with improvements in clinical end points should be determined in future studies. www.jama.com

JAMA. 1999;282:54-61 Author Affiliations are listed at the end of this article. Corresponding Author and Reprints: V. Marco Ranieri, MD, University of Toronto, Mount Sinai Hospital, Room 656A, 600 University Ave, Toronto, Ontario, Canada M5G 1X5 (e-mail: [email protected]).

JAMA, July 7, 1999—Vol 281, No. 1

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Caring for the Critically Ill Patient Section Editor: Deborah J. Cook, MD, Consulting Editor, JAMA. Advisory Board: David Bihari, MD; Christian BrunBuisson, MD; Timothy Evans, MD; John Heffner, MD; Norman Paradis, MD.

©1999 American Medical Association. All rights reserved.

INFLAMMATORY MEDIATORS AND RESPIRATORY DISTRESS SYNDROME

itself can augment or cause acute lung injury. This has been demonstrated in animal studies6-9 and has been highlighted in a recent randomized trial, which found that the mortality rate from ARDS could be reduced by 40% when a lung-protective strategy was used compared with a conventional strategy of mechanical ventilation.10 The lung-protective strategy in this trial involved limiting peak airway pressures or tidal volumes and using positive end-expiratory pressure (PEEP) levels that were individualized to each patient based on respiratory system mechanics, as assessed by the volume-pressure curve.10,11 One reason for the efficacy of this approach may have been the decreased stress on the lung since Mead et al12 have predicted that in a nonuniformly inflated lung, shear forces due to expansion of collapsed alveolar regions surrounded by expanded regions could exceed 100 cm H2O even though the transpulmonary pressure may only be 30 cm H2O. ARDS is an inflammatory disease and clinical studies have suggested increased mortality in patients who continue to manifest elevated cytokine levels during their clinical course.13-16 Recent experimental studies in various animal models have provided 3 lines of evidence suggesting that mechanical ventilation can initiate or exacerbate an inflammatory response: (1) pathologic evidence of neutrophil infiltration,17,18 (2) increased cytokine levels in lung lavage,8 and (3) increased cytokine levels in the systemic circulation.9,19 In addition, ventilatory strategies that were designed to minimize ventilator-induced lung injury (low end-inspiratory lung volumes or high end-expiratory lung volumes) in these animal studies were associated with strikingly lower cytokine levels.8 To examine the influence of mechanical ventilation on lung and systemic cytokine levels in patients with ARDS, we compared a ventilatory strategy designed to minimize ventilator-induced lung injury (high PEEP, low end-inspiratory stretch) with a conventional ventilatory strategy.

METHODS Patient Selection

Following approval of institutional review boards and after obtaining informed consent from the patient or next of kin, patients were recruited from the intensive care units of the university hospitals of Bari, Italy, and Geneva, Switzerland. Inclusion criteria were (1) age of 18 years or older and (2) diagnosis of ARDS based on American-European Consensus Conference criteria.20 Exclusion criteria were (1) anticipated to require mechanical ventilation less than 48 hours (determined by the attending physician), (2) more than 8 hours of mechanical ventilation prior to admission to the study, (3) cardiogenic pulmonary edema (clinically suspected, or pulmonary artery occlusion pressure .18 mm Hg), (4) history of ventricular fibrillation or tachyarrhythmia, unstable angina, or myocardial infarction within preceding month, (5) preexisting chronic obstructive pulmonary disease, (6) major chest wall abnormalities (kyphoscoliosis, open or flail chest), chest tube with persistent air leak, or abdominal distention, (7) pregnancy, (8) known intracranial abnormality, and (9) enrollment in another interventional study. Study Protocol

Patients were sedated (0.01 mg/kg of fentanyl citrate and 5-20 mg of diazepam), paralyzed (4-8 mg of pancuronium bromide), and ventilated for 1 to 2 hours with a fixed ventilatory management protocol consisting of volumetargeted control mechanical ventilation: PEEP of 10 cm H2O, fraction of inspired oxygen (FIO2) of 100%, tidal volume of 5 to 8 mL/kg (ideal body weight), and inspiratory to expiratory ratio of 1:2. The PEEP was then removed and a volume-pressure curve was measured as described below. The volume-pressure curve of the respiratory system of patients with early ARDS often has a characteristic sigmoidal shape with a lower inflection point (Pflex) thought to approximate the pressure required to reopen collapsed lung regions and an upper inflection point



(UIP) thought to correspond to the pressure at which overdistention of some lung units occurs.3 The PEEP was then restored and bronchoalveolar lavage fluid and blood samples were taken 20 to 30 minutes later. A full set of laboratory, hemodynamic, and respiratory variables was obtained. The Acute Physiology and Chronic Health Evaluation II21 and lung injury scores22 (for both scores, higher values indicate greater illness severity) and the number of organ failures as defined by Knaus et al23 were also calculated. At the end of this fixed ventilatory period, patients were randomly assigned to a control group or a lung-protective strategy group. The patients were assigned by a concealed allocation approach using opaque sealed envelopes containing the randomization schedule. Baseline blood gases were then measured 2 to 3 hours after the assigned ventilatory strategy was initiated. Control Group

Mechanical ventilation was performed using control mechanical ventilation with a respiratory rate of 10 to 15/min, an inspiratory to expiratory ratio of 1:2, and a tidal volume targeted to maintain the Pa CO 2 between 35 and 40 mm Hg. For safety reasons, when a plateau airway pressure of 35 cm H2O was reached, the tidal volume was not increased further, irrespective of PaCO2.24 A PEEP trial on 100% FIO2 was performed using incremental (3-5 cm H2O) levels from 3 to 15 cm H2O to determine the PEEP level that produced the greatest improvement in arterial oxygen percent saturation (SaO2) without worsening hemodynamics (.10% drop in mean blood pressure). The FIO2 was then decreased until Sa O 2 was decreased by 1% to 2% or below 90%. Lung-Protective Strategy Group

The following aspects of the ventilatory strategy were used as in the control group: control mechanical ventilation, respiratory rate of 10 to 15/min, inspiratory to expiratory ratio of 1:2, and FIO2 of 100%. The tidal volume and PEEP values were set to minimize stress JAMA, July 7, 1999—Vol 281, No. 1

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on the lung. Tidal volume was set to obtain a value of plateau pressure (Pplat) less than pressure at the UIP regardless of PaCO2. The PEEP was set at 2 to 3 cm H2O higher than the pressure at Pflex. If UIP and Pflex could not be determined on the volume-pressure curve, a tidal volume of 5 to 8 mL/kg (ideal body weight) and a PEEP total level of 15 cm H2O were applied, respectively.10 If arterial pH was less than 7.15, tidal volume was increased until a Pplat of 35 cm H2O was reached or until arterial pH was more than 7.15 mm Hg. The FIO2 was then decreased until the SaO2 fell by 1% to 2% or below 90%. After admission, protocol withdrawal could occur if 1 of the following a priori conditions occurred within the first 24 hours: (1) a 20% increase or decrease in Acute Physiology and Chronic Health Evaluation II21 and lung injury scores,22 (2) an increase or decrease in the initial number of organ failures,23 (3) need for high levels of epinephrine (.0.15 mg/kg per minute) or norepinephrine (.0.1 mg/kg per minute), (4) the patient was ready to be weaned from mechanical ventilation, as determined by the attending intensivist, and (5) high risk of death defined as hemodynamic instability, arrhythmia, or hypoxemia, not responsive to 20 to 30 minutes of standard treatment. Additional ARDS cointerventions (inhaled nitric oxide or prostacycline, administration of almitrine or steroids, prone position) were not allowed in either group during the study. Patients were cared for by attending physicians not involved in the protocol and other management decisions were made at their discretion. All measurements were repeated 24 to 30 hours and 36 to 40 hours after randomization. Sedation was maintained throughout the study. Study Procedures and Outcome Measures

Static Inflation Volume-Pressure Curve of the Respiratory System. The volumepressure curve was constructed by plotting the different inflation volumes against the corresponding values of Pplat as assessed by end-inspiratory occlu56

sion at different tidal volumes.3 Each occlusion was maintained until a stable Pplat was observed. Total PEEP (applied PEEP plus auto-PEEP) was measured by performing an end-expiratory occlusion3 (Servo 300, Siemens-Elema, Stockholm, Sweden). Flow (pneumotachograph, Fleisch, Lausanne, Switzerland), pressure (Validyne pressure transducer, Northridge, Calif), and volume (digital integration of flow signal, Anadat software package, Montreal, Quebec) were measured using standard techniques described previously.3 The Pflex and UIP on the volume-pressure curve were quantified using a computer stepby-step regression analysis.3 Pulmonary and Systemic Inflammatory Mediators. Blind bronchoalveolar lavage was performed using a telescoping catheter (Ballard, Draper, Utah) with 2 aliquots of 40 to 50 mL of sterile isotonic saline. Lavage with a third aliquot was performed if there was less than 30 to 40 mL of recovered fluid from the first 100 mL. When a diffuse infiltrate was seen on a chest x-ray, bronchoalveolar lavage was performed in the right lower or middle lobe. When an area of localized pulmonary infiltration was present, bronchoalveolar lavage was blindly performed in the lower lobe of the opposite lung.25 The first aliquot was discarded13-15 and the remaining bronchoalveolar lavage fluid was rapidly filtered through sterile gauze and then spun at 4°C at 400g for 15 minutes. A microscopic cell count was performed on the cell pellet using standard techniques.25 The supernatant was centrifuged at 80 000g for 30 minutes at 4°C to remove the surfactant-rich fraction and then concentrated 10-fold on a 5000 molecular weight cut-off filter (Amicon, Beverly, Mass) under nitrogen. The concentrated supernatant was then frozen at −70°C. Blood samples (20 mL) obtained from a central venous line were placed in a specimen tube containing heparin, centrifuged at 1500g for 10 minutes, and then the plasma was aspirated and stored at −70°C. All cytokine determinations on the bronchoalveolar lavage fluid and plasma were carried out in duplicate in

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Geneva, Switzerland (with the technician blinded to ventilation strategy) using a solid-phase enzyme-linked immunosorbent assay method based on the quantitative immunometric sandwich enzyme immunoassay technique.25 Reagents for the various cytokines were obtained from several sources (tumor necrosis factor [TNF] a, soluble TNF-a receptors [TNFasR55 and TNF-asR75], interleukin [IL] 6, and IL-8 from Medgenix, Fleures, Belgium); IL-1b and IL-1 receptor antagonist [IL-1Ra] from Immunotech, Marseille, France). Ventilator-Free Days and Mortality

In a post hoc fashion, we calculated the number of ventilator-free days (days without mechanical ventilation after extubation) during the 28 days immediately after study entry.26 Results were scored from 0 (worst outcome) to 28. The number of patients who were alive at 28 days was also recorded. Statistics

The values for the cytokine concentrations were not normally distributed so we performed log10 transformations to normalize the data to permit the application of parametric statistics. To evaluate differences over time of cytokine values within each group, repeated measures analysis of variance by Bonferroni method was used. To evaluate differences between the 2 groups, the Fisher exact test for categorical variables, the t test with unequal variance for continuous variables, and the MannWhitney rank sum test for ordinal variables were used. All tests of significance were 2-tailed, and P,.05 was accepted as significant. RESULTS From November 1995 to February 1998, 44 patients were enrolled (34 in Bari and 10 in Geneva). Seven protocol patients withdrew because of an increase in the initial number of organ failures (1 in each group), need for high doses of norepinephrine (1 in each group), high risk of death (1 in the lungprotective strategy group), and initia-



tion of weaning from mechanical ventilation (1 in each group). Baseline characteristics, underlying condition responsible for ARDS, and respiratory mechanics on entry are presented in TABLE 1. Most patients had sepsis and multiple trauma as the underlying condition responsible for ARDS. The Pflex was measurable in all patients, while the UIP was not measurable in 10 patients (4 in the control group and 6 in the lung-protective strategy group). There was no significant difference in Pflex or UIP between groups (Table 1). Values of ventilator settings and of arterial blood gases 2 to 3 hours after randomization are presented in TABLE 2. In the control group, PEEP levels were lower than Pflex in every patient and values of Pplat were higher than UIP in all but 4 patients. By design, PEEP levels were greater than Pflex and Pplat levels were lower than UIP in every patient in the lung-protective strategy group. The PaO2 did not differ between groups, although FIO2 was slightly higher in the control group. A significant increase in PaCO2 (permissive hypercapnia) was observed in the lung-protective strategy group. With the exception of bronchoalveolar lavage concentrations of TNFasR75 (lower in the control group, P,.05; TABLE 3) and plasma values of IL-6 (lower in the control group, P,.01), values of inflammatory mediators prior to randomization did not differ between groups (F IGURE 1 and FIGURE 2, Table 3). There was a trend for polymorphonuclear cell levels in bronchoalveolar lavage to increase over time in the control group (Figure 1). In the control group, bronchoalveolar lavage fluid concentration of IL-1b (P,.001), TNF-a (P,.05), and IL-6 (P,.01) increased over time, as did plasma levels of TNF-a (P,.01) and IL-6 (P,.001) (Figure 1 and Figure 2). The concentrations of other inflammatory mediators did not change significantly. A significant (P,.01) increase over time of both TNF-a receptors in the bronchoalveolar lavage fluid and plasma concentrations and in the bronchoalveo-

lar lavage IL-1Ra (P,.01) was observed in the control group (Table 3). A significant reduction over time in bronchoalveolar lavage concentrations of polymorphonuclear cells (P,.001), IL-1b (P,.05), TNF-a (P,.001), IL-8 (P,.001), and IL-6 (P,.005), and in plasma concentrations of IL-6 (P,.002) was observed in the lung-protective strategy group (Figure 1 and Figure 2). Plasma concentrations of TNF-a and IL-8 did not change significantly over

time in the lung-protective strategy group (Figure 2). A significant reduction over time of bronchoalveolar lavage concentrations of TNF-asR55 (P,.001) and bronchoalveolar lavage and plasma concentrations of TNF-asR75 (P,.001) and IL-1Ra (P,.05 and P,.001, respectively) were observed in the lungprotective strategy group (Table 3). With the exception of IL-1Ra in the bronchoalveolar lavage, values of inflammatory mediators 36 to 40 hours

Table 1. Patient Characteristics at Baseline*

Characteristic Men Women Age, y Underlying disease responsible for acute respiratory distress syndrome Pneumonia† Sepsis‡

Control (n = 19)

Lung-Protective Strategy (n = 18)

9 10 49 (18)

11 7 51 (18)

3 8

4 8

Multiple trauma§

5

4

Acute pancreatitis\

2

1

Abdominal aneurysm rupture, shock¶

1

0

Drug overdose PaO2/fraction of inspired oxygen, mm Hg Acute Physiology and Chronic Health Evaluation II score

142 (56) 14 (3)

0

1

Lung injury score Lower inflection point, cm H2O

2.5 (0.6)

2.5 (0.5)

13.6 (3.9)

12.6 (2.8)

Upper inflection point, cm H2O

30.5 (4.5)

31.7 (3.5)

149 (66) 15 (4)

*Higher values indicate greater severity. Values are expressed as mean (SD) or number of cases. Ellipses indicate data not available. †Defined as the presence of an infiltrate on chest radiograph and any 3 of the following: (1) purulent endotracheal aspirate, (2) known pathogens on a Gram stain, or cultures from sputum or blood, (3) core temperature higher than 38.5°C or less than 36°C, or (4) white blood cell count of more than 0.012 3 109/L or less than 0.0035 3 109/L or 20% immature forms. ‡Defined as the presence of 2 or more of the following: (1) core temperature higher than 38.5°C or less than 36°C, (2) white blood cell count of more than 0.012 3 109/L or less than 0.0035 3 109/L or 20% immature forms, (3) 1 blood culture of a common pathogen, (4) a strongly suspected site of infection from which a known pathogen was cultured, or (5) gross pus in a closed space; and 1 or more of the following: (1) systemic arterial hypotension for at least 2 hours (systolic blood pressure ,85 mm Hg or reduction to .40 mm Hg from baseline, or need for inotropes to maintain systolic blood pressure .85 mm Hg), (2) systemic vascular resistance less than 800 dynes/s/cm5 (if pulmonary arterial catheter present), or (3) unexplained metabolic acidosis (base deficit .5 mEq/L). §Defined as the presence of fractures of 2 or more major long bones, an unstable pelvic fracture, or a major long-bone fracture and a major pelvic fracture. \Defined as the presence of severe abdominal pain, nausea, and vomiting with a serum amylase level greater than 3 times the local upper limit of normal. ¶Defined as hypotension lasting 2 hours or more (systolic blood pressure ,85 mm Hg or .40 mm Hg below the baseline value) or need for inotropic drugs to maintain systolic blood pressure of more than 85 mm Hg.

Table 2. Patients 2 to 3 Hours After Randomization by Group* Characteristic Positive end-expiratory pressure, cm H2O Fraction of inspired oxygen Tidal volume, mL/kg End-inspiratory plateau, mm Hg PaO2, mm Hg

Control

Lung Protective Strategy

P Value

6.5 (1.7) 0.9 (0.1) 11.1 (1.9) 31.0 (4.5)

14.8 (2.7) 0.7 (0.1) 7.6 (1.1) 24.6 (2.4)

,.001 ,.001 ,.001 ,.001

163 (58)

155 (86)

.18

PaCO2, mm Hg Arterial pH, mm Hg

37.4 (1.9) 7.47 (0.06)

46.9 (2.7) 7.35 (0.07)

,.001 ,.001

*Values are expressed as mean (SD).



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after randomization were significantly (P,.05 to P,.001) lower in the lungprotective strategy group. The post hoc analysis showed that the mean (SD) number of ventilatorfree days26 in the lung-protective strategy group was higher (P,.01) than in the control group (12 [11] vs 4 [8] days, respectively). Mortality rates at 28 days from admission were 38% and 58% in the lung-protective strategy and control groups, respectively (P = .19).

COMMENT The major finding of this study is that mechanical ventilation—the therapeutic modality that is invariably used in the treatment of ARDS—can itself lead to an increase in cytokine levels in the lung, as well as in the systemic circulation. These results may partially explain the development of multiple organ failure in many patients with ARDS,27 the high mortality rate of this syndrome (35%-65%),4,5 and perhaps

the decrease in mortality observed in a recent study that used a lungprotective strategy.10 Over the past decade, numerous studies have suggested that mechanical ventilation can cause or exacerbate acute lung injury. This is particularly true in patients with ARDS because of the widespread, heterogeneous distribution of consolidated/atelectatic regions, which produces a small lung volume available for ventilation.2 Using

Table 3. Tumor Necrosis Factor a (TNF-a) and Interleukin Receptor Levels in the Bronchoalveolar Lavage and Plasma Fluids, by Time and Group* Bronchoalveolar Lavage Control (n = 19)

Soluble TNF-asR55, ng/mL Soluble TNF-asR75, ng/mL IL-1 receptor antagonist, ng/mL

Lung-Protective Strategy (n = 18)†

Entry 15.08 (12.7)

Time 1 25.84 (22.9)

Time 2 36.40 (26.9)

P Value ,.001‡

Entry 29.36 (20.6)

Time 1 21.63 (15.9)

Time 2 14.27 (12.4)

P Value ,.001‡

17.56 (16.5)§

32.70 (28.8)

32.03 (29.4)

,.001‡

33.00 (23.8)

22.24 (15.0)

13.31 (11.3)

,.001‡

16 503 (14 935)

24 253 (21 798)

32 425 (48 772)

19 219 (19 037)

14 839 (17 985)

16 361 (15 756)

,.01

,.05

Plasma Control (n = 19)

Soluble TNF-asR55, ng/mL Soluble TNF-asR75, ng/mL IL-1 receptor antagonist, ng/mL

Lung-Protective Strategy (n = 14)

Entry 14.01 (10.9)

Time 1 15.38 (12.2)

Time 2 17.25 (14.4)

P Value ,.05

Entry 11.19 (8.6)

Time 1 13.41 (13.8)

Time 2 12.83 (17.8)

P Value .11

28.32 (16.5)

31.28 (28.8)

35.93 (29.4)

,.01

27.66 (19.1)

25.92 (17.5)

19.77 (13.2)

,.001‡

4218 (3645)

4217 (2940)

4874 (3114)

.08

7972 (9650)

2965 (2906)

2874 (3433)

,.001‡

*Values are expressed as mean (SD). IL indicates interleukin. Time 1 indicates 24 to 30 hours after study entry; time 2, 36 to 40 hours after study entry. Numbers of patients differ from enrolled group size because measurements were not available for all. †Number of subjects is 16 for IL-1 receptor antagonist. ‡Value is for comparison of 36 hours vs entry. §Value is for comparison of entry vs lung-protective strategy group ( P,.05).

Figure 1. Levels of Inflammatory Mediators in Bronchoalveolar Lavage Fluid Control

Control

Lung-Protective Strategy

Lung-Protective Strategy

105

100

IL-1β, pg/mL

PMN, %

P