PEEP in ARDS — How Much Is Enough?
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《新英格兰医药杂志》
In 1967, Ashbaugh et al.1 introduced the use of positive end-expiratory pressure (PEEP) during mechanical ventilation to treat refractory hypoxemia in patients with the acute respiratory distress syndrome (ARDS). Almost 40 years later, the question of how much PEEP is enough remains relevant. Controversy regarding the optimal level of PEEP has persisted despite years of investigation into this question. An increase in our understanding of the pathophysiology of ARDS and ventilator-induced lung injury has led to a renewed interest in the debate.
Studies in animals,2,3,4 designed to illuminate the cause of ventilator-induced lung injury, show that two primary mechanistic factors may contribute to the evolution of ventilator-induced lung injury: overdistention of the alveoli by high transpulmonary pressures and shear-stress forces produced by repetitive alveolar recruitment and derecruitment (collapse) in patients with ARDS who are receiving mechanical ventilation. The first proposed mechanism was addressed by the initial ARDS Clinical Trials Network study.5 This randomized trial demonstrated a significant survival benefit among patients who received a low tidal volume (6 ml per kilogram of body weight) rather than the once widely accepted higher tidal volume of 12 ml per kilogram. This milestone study convincingly illustrated how lung-protective strategies of ventilation could improve the outcome of ARDS.
In this issue of the Journal,6 the ARDS Clinical Trials Network investigators examine the second potential mechanism of ventilator-induced lung injury. In patients with ARDS, the qualitative and quantitative surfactant defect leads to considerable end-expiratory alveolar collapse. During inspiration,7 exaggerated transpulmonary pressures may be generated at the junction of collapsed, nonrecruitable, and recruitable units, leading to the development of shear stress. In animal models, this repetitive cycle of alveolar collapse and re-recruitment has been associated with worsening lung injury.8,9 The extent of this lung injury has been reduced in animals through the use of PEEP levels that prevent derecruitment at end-expiration.10 Computed tomography in patients with ARDS11,12 has shown that PEEP does lead to recruitment of previously collapsed alveoli and that lung regions recruited with PEEP may not completely collapse at end-expiration. These animal models and observational studies led to randomized trials. A previous randomized trial involving 53 patients showed improved survival when a strategy involving a low tidal volume was used in combination with high PEEP levels in order to prevent derecruitment.13 These bench-to-bedside studies have rekindled the debate surrounding optimal PEEP levels for the treatment of ARDS.
The ARDS Clinical Trials Network investigators have conducted a rigorous, prospective, randomized, controlled trial that addresses a vital clinical question posed at the bedside on a daily basis: Does the addition of higher PEEP levels to the strategy of a low tidal volume in an attempt to prevent derecruitment during tidal ventilation further increase survival? Several aspects of this trial provide important insights into the mechanisms and management of ARDS.
One of the most important findings of this study is that the overall rates of death before hospital discharge among patients with ARDS who were receiving mechanical ventilation with a tidal-volume goal of 6 ml per kilogram ranged from 25 to 28 percent. Combining the current results with the results of the initial ARDS Clinical Trials Network study, a total of almost 1000 patients with ARDS have been treated with a protective, low-tidal-volume strategy, resulting in a mortality rate in the intensive care unit of 25 to 31 percent. Although other mechanical-ventilation or pharmacologic approaches may further improve survival among patients with ARDS, the mortality rates in these trials provide a benchmark for clinical practice and future clinical trials.
Although the overall results of this study demonstrate no significant difference in mortality between the higher-PEEP and lower-PEEP groups, several aspects do require close scrutiny for a full appreciation and better understanding of the data. After the first 171 patients had been enrolled in the trial, the investigators concluded that "the difference in mean PEEP levels between study groups on study days 1 through 7 was less than the difference in the previous study that tested the effect of higher PEEP levels and smaller tidal volumes."11 In order to maintain an appropriate separation between the two groups and to clearly test the initial hypothesis, the protocol was changed to require a minimal PEEP of 14 cm of water in the higher-PEEP group for the first 48 hours. As clearly stated by the authors, this change was made without knowledge of the clinical-outcome data. Without this change, adequate separation of PEEP between the two groups would not have occurred. Unfortunately, this change raises the question of whether the initial 171 patients enrolled in the trial (31 percent of the total number) should have been included in the analysis. The authors chose to combine the initial 171 patients with the subsequent 378 patients for the purpose of the second interim analysis. With the data from these two groups of patients taken together, the lack of a difference in mortality between the two study groups met the criteria defined a priori for stopping the trial early because of a low probability of a reduced mortality rate in the higher-PEEP group (the futility stopping rule), leading to early termination of the study.
The interpretation of the results is also complicated by significant differences between the two groups at baseline. Patients in the higher-PEEP group were significantly older and had a lower (worse) ratio of the partial pressure of arterial oxygen (PaO2) to the forced inspiratory volume in one second (FiO2) than patients in the lower-PEEP group. When combined with a trend toward a higher score for the Acute Physiology, Age, and Chronic Health Evaluation (APACHE III) in the higher-PEEP group, the differences indicate that these patients were not only older, but perhaps also sicker. After adjustment for age and the PaO2:FiO2 ratio, the mortality rate among the first 171 patients favored the higher-PEEP group, but the difference was very small and not significant. In the subsequent 378 patients, the adjusted absolute mortality rate was 4.5 percent less in the lower-PEEP group than in the higher-PEEP group. This difference was not significant, since the study was powered to show an absolute difference between groups of 10 percent. However, had the interim analysis included only these 378 patients, the study would probably not have met the criteria for early termination. Premature termination of the study may well have resulted.
Given the a priori target of an absolute difference of 10 percent in mortality rates, the authors are correct in their conclusion that higher PEEP did not confer an additional survival benefit beyond that already seen with the use of a tidal volume of 6 ml per kilogram and a low PEEP. However, an absolute difference of 4.5 percent in the adjusted mortality rate, although not statistically significant, may represent a clinically significant difference, making early termination of the trial for meeting the futility stopping rule unfortunate.
In the end, we can conclude that, for the 378 patients in the latter part of the trial, the use of higher PEEP did not result in a statistically significant survival benefit. This trial has contributed important new clinical information regarding the ventilatory management of ARDS. As is often the case with clinical trials, the study also raises new questions. The manner in which "optimal" PEEP is identified and its appropriate duration are being investigated in several ongoing, international PEEP trials. For clinicians, this study is both helpful and challenging. It should establish a mortality rate of 25 to 30 percent as the standard for the management of ARDS to which all future trials and ventilatory strategies should be held. For now, however, a clear answer to the question of optimal PEEP levels remains elusive.
Source Information
From the Brown University School of Medicine and Rhode Island Hospital — both in Providence.
References
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967;2:319-323.
Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998;157:294-323.
Ranieri VM, Suter P, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome. JAMA 1999;282:54-61.
Parker JC, Townsley MI, Rippe B, Taylor AE, Thigpen J. Increased microvascular permeability in dog lungs due to high peak airway pressures. J Appl Physiol 1984;57:1809-1816.
The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308.
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-336.
Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 1970;28:596-608.
Bshouty Z, Ali J, Younes M. Effect of tidal volume and PEEP on rate of edema formation in in situ perfused canine lobes. J Appl Physiol 1988;64:1900-1907.
Argiras EP, Blakeley CR, Dunnill MS, Otremski S, Sykes MK. High PEEP decreases hyaline membrane formation in surfactant deficient lungs. Br J Anaesth 1987;59:1278-1285.
Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994;149:1327-1334.
Gattinoni L, D'Andrea L, Pelosi P, Vitale G, Pesenti A, Fumagalli R. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 1993;269:2122-2127.
Gattinoni L, Pelosi P, Crotti S, Valenze F. Effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome. Am J Respir Crit Care Med 1995;151:1807-1814.
Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347-354.
Related Letters:
High versus Low PEEP in ARDS
Perren A., Rotta A. T., Brower R., Morris A., MacIntyre N., the National Heart, Lung and Blood Institute ARDS Clinical Trials Network , Levy M. M.(Mitchell M. Levy, M.D.)
Studies in animals,2,3,4 designed to illuminate the cause of ventilator-induced lung injury, show that two primary mechanistic factors may contribute to the evolution of ventilator-induced lung injury: overdistention of the alveoli by high transpulmonary pressures and shear-stress forces produced by repetitive alveolar recruitment and derecruitment (collapse) in patients with ARDS who are receiving mechanical ventilation. The first proposed mechanism was addressed by the initial ARDS Clinical Trials Network study.5 This randomized trial demonstrated a significant survival benefit among patients who received a low tidal volume (6 ml per kilogram of body weight) rather than the once widely accepted higher tidal volume of 12 ml per kilogram. This milestone study convincingly illustrated how lung-protective strategies of ventilation could improve the outcome of ARDS.
In this issue of the Journal,6 the ARDS Clinical Trials Network investigators examine the second potential mechanism of ventilator-induced lung injury. In patients with ARDS, the qualitative and quantitative surfactant defect leads to considerable end-expiratory alveolar collapse. During inspiration,7 exaggerated transpulmonary pressures may be generated at the junction of collapsed, nonrecruitable, and recruitable units, leading to the development of shear stress. In animal models, this repetitive cycle of alveolar collapse and re-recruitment has been associated with worsening lung injury.8,9 The extent of this lung injury has been reduced in animals through the use of PEEP levels that prevent derecruitment at end-expiration.10 Computed tomography in patients with ARDS11,12 has shown that PEEP does lead to recruitment of previously collapsed alveoli and that lung regions recruited with PEEP may not completely collapse at end-expiration. These animal models and observational studies led to randomized trials. A previous randomized trial involving 53 patients showed improved survival when a strategy involving a low tidal volume was used in combination with high PEEP levels in order to prevent derecruitment.13 These bench-to-bedside studies have rekindled the debate surrounding optimal PEEP levels for the treatment of ARDS.
The ARDS Clinical Trials Network investigators have conducted a rigorous, prospective, randomized, controlled trial that addresses a vital clinical question posed at the bedside on a daily basis: Does the addition of higher PEEP levels to the strategy of a low tidal volume in an attempt to prevent derecruitment during tidal ventilation further increase survival? Several aspects of this trial provide important insights into the mechanisms and management of ARDS.
One of the most important findings of this study is that the overall rates of death before hospital discharge among patients with ARDS who were receiving mechanical ventilation with a tidal-volume goal of 6 ml per kilogram ranged from 25 to 28 percent. Combining the current results with the results of the initial ARDS Clinical Trials Network study, a total of almost 1000 patients with ARDS have been treated with a protective, low-tidal-volume strategy, resulting in a mortality rate in the intensive care unit of 25 to 31 percent. Although other mechanical-ventilation or pharmacologic approaches may further improve survival among patients with ARDS, the mortality rates in these trials provide a benchmark for clinical practice and future clinical trials.
Although the overall results of this study demonstrate no significant difference in mortality between the higher-PEEP and lower-PEEP groups, several aspects do require close scrutiny for a full appreciation and better understanding of the data. After the first 171 patients had been enrolled in the trial, the investigators concluded that "the difference in mean PEEP levels between study groups on study days 1 through 7 was less than the difference in the previous study that tested the effect of higher PEEP levels and smaller tidal volumes."11 In order to maintain an appropriate separation between the two groups and to clearly test the initial hypothesis, the protocol was changed to require a minimal PEEP of 14 cm of water in the higher-PEEP group for the first 48 hours. As clearly stated by the authors, this change was made without knowledge of the clinical-outcome data. Without this change, adequate separation of PEEP between the two groups would not have occurred. Unfortunately, this change raises the question of whether the initial 171 patients enrolled in the trial (31 percent of the total number) should have been included in the analysis. The authors chose to combine the initial 171 patients with the subsequent 378 patients for the purpose of the second interim analysis. With the data from these two groups of patients taken together, the lack of a difference in mortality between the two study groups met the criteria defined a priori for stopping the trial early because of a low probability of a reduced mortality rate in the higher-PEEP group (the futility stopping rule), leading to early termination of the study.
The interpretation of the results is also complicated by significant differences between the two groups at baseline. Patients in the higher-PEEP group were significantly older and had a lower (worse) ratio of the partial pressure of arterial oxygen (PaO2) to the forced inspiratory volume in one second (FiO2) than patients in the lower-PEEP group. When combined with a trend toward a higher score for the Acute Physiology, Age, and Chronic Health Evaluation (APACHE III) in the higher-PEEP group, the differences indicate that these patients were not only older, but perhaps also sicker. After adjustment for age and the PaO2:FiO2 ratio, the mortality rate among the first 171 patients favored the higher-PEEP group, but the difference was very small and not significant. In the subsequent 378 patients, the adjusted absolute mortality rate was 4.5 percent less in the lower-PEEP group than in the higher-PEEP group. This difference was not significant, since the study was powered to show an absolute difference between groups of 10 percent. However, had the interim analysis included only these 378 patients, the study would probably not have met the criteria for early termination. Premature termination of the study may well have resulted.
Given the a priori target of an absolute difference of 10 percent in mortality rates, the authors are correct in their conclusion that higher PEEP did not confer an additional survival benefit beyond that already seen with the use of a tidal volume of 6 ml per kilogram and a low PEEP. However, an absolute difference of 4.5 percent in the adjusted mortality rate, although not statistically significant, may represent a clinically significant difference, making early termination of the trial for meeting the futility stopping rule unfortunate.
In the end, we can conclude that, for the 378 patients in the latter part of the trial, the use of higher PEEP did not result in a statistically significant survival benefit. This trial has contributed important new clinical information regarding the ventilatory management of ARDS. As is often the case with clinical trials, the study also raises new questions. The manner in which "optimal" PEEP is identified and its appropriate duration are being investigated in several ongoing, international PEEP trials. For clinicians, this study is both helpful and challenging. It should establish a mortality rate of 25 to 30 percent as the standard for the management of ARDS to which all future trials and ventilatory strategies should be held. For now, however, a clear answer to the question of optimal PEEP levels remains elusive.
Source Information
From the Brown University School of Medicine and Rhode Island Hospital — both in Providence.
References
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967;2:319-323.
Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998;157:294-323.
Ranieri VM, Suter P, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome. JAMA 1999;282:54-61.
Parker JC, Townsley MI, Rippe B, Taylor AE, Thigpen J. Increased microvascular permeability in dog lungs due to high peak airway pressures. J Appl Physiol 1984;57:1809-1816.
The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308.
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-336.
Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 1970;28:596-608.
Bshouty Z, Ali J, Younes M. Effect of tidal volume and PEEP on rate of edema formation in in situ perfused canine lobes. J Appl Physiol 1988;64:1900-1907.
Argiras EP, Blakeley CR, Dunnill MS, Otremski S, Sykes MK. High PEEP decreases hyaline membrane formation in surfactant deficient lungs. Br J Anaesth 1987;59:1278-1285.
Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994;149:1327-1334.
Gattinoni L, D'Andrea L, Pelosi P, Vitale G, Pesenti A, Fumagalli R. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 1993;269:2122-2127.
Gattinoni L, Pelosi P, Crotti S, Valenze F. Effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome. Am J Respir Crit Care Med 1995;151:1807-1814.
Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347-354.
Related Letters:
High versus Low PEEP in ARDS
Perren A., Rotta A. T., Brower R., Morris A., MacIntyre N., the National Heart, Lung and Blood Institute ARDS Clinical Trials Network , Levy M. M.(Mitchell M. Levy, M.D.)