Ventilation in Acute Respiratory Distress Syndrome: Less May Be More, in More Than One Way* Eddy Fan, MD, PhD Interdepartmental Division cf Critical Care Medicine University of Toronto; and University Health Network and Mount Sinai Hospital Toronto, ON, Canada Daniel Brodie, MD Division of Pulmonary and Critical Care Medicine Columbia University College of Physicians and Surgeons New York, NY Arthurs. Slutsky, MD Interdepartmental Division of Critical Care Medicine Department of Medicine University of Toronto; and Keenan Research Center for Biomédical Science Li Ka Shing Knowledge Institute St. Michael's Hospital Toronto, ON, Canada
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espite decades of research, there are very few interventions that improve outcomes in patients with acute respiratory distress syndrome (ARDS) other than the way we set the ventilatory strategy. Mechanical ventilation is required to sustain life while the injured lung heals, but it may itself potentiate injury through multiple mechanisms, collectively known as "ventilator-induced lung injury" (VILI) (1). A lung-protective ventilatory strategy aimed at mitigating VILI, through pressure and volume limitation, reduced mortality from 40% to 31% in patients with ARDS (2). However, recent data suggest that this strategy may not be protective against VILI in all patients (3, 4). Extracorporeal carbon dioxide removal (EGGO^R) is a type of extracorporeal support that uses low blood flow rates, variably defined as in the range of 0.2-1.5 L/min, to eliminate Go^. This technique provides minimal improvement in oxygénation because of the relatively low flow rates (5), but may facilitate further lung protection, by
*See also p. e451. Key Words: acute respiratory distress syndrome; artificial ventilation; critical oare; extraoorporeal life support; ventilator-induced lung injury Dr. Brodie oonsulted for Maquet Cardiovascular (research consulting including travel expenses to research meetings; all compensation paid to Columbia University). He served as board member for ALung Technologies (Medioal Advisory Board; all compensation paid to Columbia University) and reoeived grant support from Maquet Cardiovascular (research support in the form of equipment for a study). Dr. Slutsky oonsulted for Maquet Critioal Care, Baxter/Gambro, and Novalung (paid oonsultant). Dr. Fan has disclosed that he does not have any potential oonfliots of interest. Copyright © 2014 by the Society of Critical Care Medioine and Lippinoott Williams & Wilkins DOI: 10.1097/CCM.0000000000000351
Critical Care Medicine
allowing reductions in ventilation intensity. EGGO^R provides an enhanced risk to benefit ratio compared with high-flow extracorporeal support precisely because lower blood flow rates are needed and so it allows for the use of smaller cannulae. In addition, modern EGGO^R devices are more compact and require less anticoagulation, compared with earlier generations, thus providing an enhanced risk to benefit ratio. In this issue of Critical Care Medicine, Grasso et al (6) studied 10 lung-injured pigs and compared a lower respiratory rate (RR)/lower inspiratory flow strategy on plasma and bronchoalveolar lavage (BAL) cytokines—as a surrogate for VILI. They used a crossover design in which ventilatory strategy was randomized to the ARDS Network low tidal volume algorithm with or without a low RR; with the latter strategy, similar Paco^ levels were obtained using EGGO^R. The EGGOjR/lower RR strategy resulted in a significant decrease in some, but not all, measured plasma (interleukin [IL]-6, IL-8, and tumor necrosis factor [TNE]-a) and BAL (IL-6 and TNF-a) cytokine levels, with no differences in hemodynamics, PacOj, pH, or lung aeration on GT scan. The authors concluded that the EGGO^R/lower RR strategy was safe and feasible while attenuating the levels of some inflammatory cytokines. The study by Grasso et al (6) is of interest in two respects. Eirst, from a mechanistic perspective, it highlights the potential importance of RR and inspiratory flow as mechanisms influencing VILI. It is not the first study to demonstrate this effect (7, 8), but most experimental studies addressing VILI in various lung injury models have focused on the impact of tidal volume and airway pressure (9, 10). The hypothesis underlying these studies is that the lower RRs reduce the frequency of stress induced by tidal inflation, and the lower inspiratory flow rates induce a more homogeneous distribution of ventilation. The relative importance of these mechanisms compared to manipulating airway pressures and tidal volumes is certainly worthy of further study. The second reason that the study by Grasso et al (6) is of interest relates to the potential clinical implications. The study by Grasso et al (6) joins a growing body of evidence addressing the use of extracorporeal gas exchange approaches to impact outcomes in patients with ARDS (11-13), by allowing for less injurious ventilatory settings. This study raises the complex question of the appropriate ventilatory target for future studies—whether it is better to lower tidal volumes, with the potential need to increase positive end-expiratory pressure (PEEP) to maintain oxygénation, or to use decreased respiratory and inspiratory flow rates as in the current study. Perhaps the strategy of Grasso et al (6) would be best suited to patients with more severe degrees of hypoxemia, where the use of a very low volume- and pressure-targeted strategy might be more difficult to apply. www.ccmjournal.org
1581
Editorials
Furthermore, because Crasso et al (6) delivered standard of care tidal volumes and plateau pressures under both conditions in the study, we do not know if a combination of ventilatory strategies during ECCO^R would lead to even greater benefit, for instance, if lower tidal volumes (i.e., < 6 mL/kg predicted body weight) were delivered with lower respiratory and inspiratory flow rates. This approach might be limited by the ability of ECCO^R to lower Paco^ due to the use of smaller cannulae and lower blood flow through the extracorporeal circuit. As v\nith any study, there are a number of weaknesses, highlighted by the authors in their discussion. The impact of the ECCOjR/low RR was only assessed for a 3-hour period and the major endpoint suggesting a decrease in VILI was only a surrogate—a decrease in some cytokines. Whether there would have been evidence of less VILI (e.g., structural lung injury) if the study had been carried out over a longer time frame is of course unknown. Whether a reduction in just a handful of inflammatory cytokines mediated by an ECCO^R/lower RR strategy will translate into a difference in patient-important outcomes remains to be proven. For example, in other contexts, clinical trials targeting specific cytokines, or reducing peak concentrations through high-volume hemofiltration, in septic patients have yielded disappointing results (14,15). The use of ECCO^R to facilitate more lung-protective mechanical ventilation in patients with ARDS remains controversial, with no definitive clinical trials. The study by Crasso et al (6) has added another bit of uncertainty to the field with regard to the optimal ventilatory targets for a lung-protective ventilatory strategy during extracorporeal support for ARDS. The Strategies for Optimal Lung Ventilation in ECMO for ARDS (SOLVE ARDS) study (ClinicalTrials.gov NCTO1990456) may shed some light on the contribution of tidal ventilation (i.e., low RRs compared to continuous positive airway pressure) and the role of PEEP. In addition, the degree of COj removal achieved by ECCO^R and hence the magnitude of the decrease in lung stress and strain will be quite variable. At the extreme, sufficient Co^ removal may obviate the need for invasive mechanical ventilation altogether in some patients, perhaps those with milder forms of ARDS where hypoxemia may not be a limiting factor. Would this be ideal? It would mean no ventilation and no VILI or other ventilator-associated complications (e.g., ventilatorassociated pneumonia), but at the cost of the complications of the extracorporeal support. Until this risk to benefit has been adequately addressed, ECCO^R should be restricted to
1582
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well-designed clinical trials aimed at elucidating the potential role for this intervention in patients with ARDS.
REFERENCES 1. Slutsky AS, Ranieri VM: Ventilator-induced lung injury. N EngI J Med 2013; 369:2126-2136 2. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N EngI J iWed 2000; 342:1301-1308 3. Hager DN, Krishnan JA, Hayden DL, et al; ARDS Clinical Trials Network: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005; 172:1241-1245 4. Terragni PP, Rosboch G, Tealdi A, et al: Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007; 175:160-166 5. Sorbo LD, Cypel M, Fan E: Extracorporeal life support for adults with severe acute respiratory failure. Lancet Respir Med 20^ 4; 2:154-164 6. Grasso S, Stripoli T, Mazzone P, et al: Low Respiratory Rate Plus Minimally Invasive Extracorporeal Co^ Removal Decreases Systemic and Pulmonary Inflammatory Mediators in Experimental Acute Respiratory Distress Syndrome. Crit Care Med 2014; 42: e451-e460 7. Rich PB, Reickert CA, Sawada S, et al: Effect of rate and inspiratory flow on ventilator-induced lung injury. J Trauma 2000; 49:903-911 8. Hotchkiss JR Jr, Blanch L, Murias G, et al: Effects of decreased respiratory frequency on ventilator-induced lung injury. Am J Respir Crit Care Med 2000; 161:463-468 9. Ranieri VM, Suter PM, Tortorella C, et al: Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial. JAMA 1999; 282:54-61 10. Tremblay L, Valenza F, Ribeiro SP, et al: Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 1997; 99:944-952 11. Terragni PP, Del Sorbo L, Mascia L, et al: Tidal volume lower than 6 ml/kg enhances lung protection: Role of extracorporeai carbon dioxide removal. Anesthesiology 2009; 111:826-835 1 2. Bein T, Weber-Carstens S, Goldmann A, et al: Lower tidal volume strategy (=3 ml/kg) combined with extracorporeal CO^ removal versus 'conventional' protective ventilation (6 ml/kg) in severe ARDS: The prospective randomized Xtravent-study. Intensive Care Med 2013; 39:847-856 13. Pham T, Combes A, Rozé H, et al; REVA Research Network: Extracorporeal membrane oxygénation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: A cohort study and propensity-matched analysis. Am J Respir Orit Oare Med 2013; 187:276-285 14. Abraham E, Wunderink R, Sllverman H, et al: Efficacy and safety of monoclonal antibody to human tumor necrosis factor a in patients with sepsis syndrome: A randomized, controlled, double-blind, multicenter clinical trial. JAMA 1995; 273:934-941 15. Borthwick EMJ, Hill CJ, Rabindranath KS, et al: High-volume haemofiltration for sepsis. Cochrane Database Syst Rev 2013; 1 :CD008075
June 2014 • Volume 42 • Number 6
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
D
espite decades of research, there are very few interventions that improve outcomes in patients with acute respiratory distress syndrome (ARDS) other than the way we set the ventilatory strategy. Mechanical ventilation is required to sustain life while the injured lung heals, but it may itself potentiate injury through multiple mechanisms, collectively known as "ventilator-induced lung injury" (VILI) (1). A lung-protective ventilatory strategy aimed at mitigating VILI, through pressure and volume limitation, reduced mortality from 40% to 31% in patients with ARDS (2). However, recent data suggest that this strategy may not be protective against VILI in all patients (3, 4). Extracorporeal carbon dioxide removal (EGGO^R) is a type of extracorporeal support that uses low blood flow rates, variably defined as in the range of 0.2-1.5 L/min, to eliminate Go^. This technique provides minimal improvement in oxygénation because of the relatively low flow rates (5), but may facilitate further lung protection, by
*See also p. e451. Key Words: acute respiratory distress syndrome; artificial ventilation; critical oare; extraoorporeal life support; ventilator-induced lung injury Dr. Brodie oonsulted for Maquet Cardiovascular (research consulting including travel expenses to research meetings; all compensation paid to Columbia University). He served as board member for ALung Technologies (Medioal Advisory Board; all compensation paid to Columbia University) and reoeived grant support from Maquet Cardiovascular (research support in the form of equipment for a study). Dr. Slutsky oonsulted for Maquet Critioal Care, Baxter/Gambro, and Novalung (paid oonsultant). Dr. Fan has disclosed that he does not have any potential oonfliots of interest. Copyright © 2014 by the Society of Critical Care Medioine and Lippinoott Williams & Wilkins DOI: 10.1097/CCM.0000000000000351
Critical Care Medicine
allowing reductions in ventilation intensity. EGGO^R provides an enhanced risk to benefit ratio compared with high-flow extracorporeal support precisely because lower blood flow rates are needed and so it allows for the use of smaller cannulae. In addition, modern EGGO^R devices are more compact and require less anticoagulation, compared with earlier generations, thus providing an enhanced risk to benefit ratio. In this issue of Critical Care Medicine, Grasso et al (6) studied 10 lung-injured pigs and compared a lower respiratory rate (RR)/lower inspiratory flow strategy on plasma and bronchoalveolar lavage (BAL) cytokines—as a surrogate for VILI. They used a crossover design in which ventilatory strategy was randomized to the ARDS Network low tidal volume algorithm with or without a low RR; with the latter strategy, similar Paco^ levels were obtained using EGGO^R. The EGGOjR/lower RR strategy resulted in a significant decrease in some, but not all, measured plasma (interleukin [IL]-6, IL-8, and tumor necrosis factor [TNE]-a) and BAL (IL-6 and TNF-a) cytokine levels, with no differences in hemodynamics, PacOj, pH, or lung aeration on GT scan. The authors concluded that the EGGO^R/lower RR strategy was safe and feasible while attenuating the levels of some inflammatory cytokines. The study by Grasso et al (6) is of interest in two respects. Eirst, from a mechanistic perspective, it highlights the potential importance of RR and inspiratory flow as mechanisms influencing VILI. It is not the first study to demonstrate this effect (7, 8), but most experimental studies addressing VILI in various lung injury models have focused on the impact of tidal volume and airway pressure (9, 10). The hypothesis underlying these studies is that the lower RRs reduce the frequency of stress induced by tidal inflation, and the lower inspiratory flow rates induce a more homogeneous distribution of ventilation. The relative importance of these mechanisms compared to manipulating airway pressures and tidal volumes is certainly worthy of further study. The second reason that the study by Grasso et al (6) is of interest relates to the potential clinical implications. The study by Grasso et al (6) joins a growing body of evidence addressing the use of extracorporeal gas exchange approaches to impact outcomes in patients with ARDS (11-13), by allowing for less injurious ventilatory settings. This study raises the complex question of the appropriate ventilatory target for future studies—whether it is better to lower tidal volumes, with the potential need to increase positive end-expiratory pressure (PEEP) to maintain oxygénation, or to use decreased respiratory and inspiratory flow rates as in the current study. Perhaps the strategy of Grasso et al (6) would be best suited to patients with more severe degrees of hypoxemia, where the use of a very low volume- and pressure-targeted strategy might be more difficult to apply. www.ccmjournal.org
1581
Editorials
Furthermore, because Crasso et al (6) delivered standard of care tidal volumes and plateau pressures under both conditions in the study, we do not know if a combination of ventilatory strategies during ECCO^R would lead to even greater benefit, for instance, if lower tidal volumes (i.e., < 6 mL/kg predicted body weight) were delivered with lower respiratory and inspiratory flow rates. This approach might be limited by the ability of ECCO^R to lower Paco^ due to the use of smaller cannulae and lower blood flow through the extracorporeal circuit. As v\nith any study, there are a number of weaknesses, highlighted by the authors in their discussion. The impact of the ECCOjR/low RR was only assessed for a 3-hour period and the major endpoint suggesting a decrease in VILI was only a surrogate—a decrease in some cytokines. Whether there would have been evidence of less VILI (e.g., structural lung injury) if the study had been carried out over a longer time frame is of course unknown. Whether a reduction in just a handful of inflammatory cytokines mediated by an ECCO^R/lower RR strategy will translate into a difference in patient-important outcomes remains to be proven. For example, in other contexts, clinical trials targeting specific cytokines, or reducing peak concentrations through high-volume hemofiltration, in septic patients have yielded disappointing results (14,15). The use of ECCO^R to facilitate more lung-protective mechanical ventilation in patients with ARDS remains controversial, with no definitive clinical trials. The study by Crasso et al (6) has added another bit of uncertainty to the field with regard to the optimal ventilatory targets for a lung-protective ventilatory strategy during extracorporeal support for ARDS. The Strategies for Optimal Lung Ventilation in ECMO for ARDS (SOLVE ARDS) study (ClinicalTrials.gov NCTO1990456) may shed some light on the contribution of tidal ventilation (i.e., low RRs compared to continuous positive airway pressure) and the role of PEEP. In addition, the degree of COj removal achieved by ECCO^R and hence the magnitude of the decrease in lung stress and strain will be quite variable. At the extreme, sufficient Co^ removal may obviate the need for invasive mechanical ventilation altogether in some patients, perhaps those with milder forms of ARDS where hypoxemia may not be a limiting factor. Would this be ideal? It would mean no ventilation and no VILI or other ventilator-associated complications (e.g., ventilatorassociated pneumonia), but at the cost of the complications of the extracorporeal support. Until this risk to benefit has been adequately addressed, ECCO^R should be restricted to
1582
\AAAAA/.ccmjournal.org
well-designed clinical trials aimed at elucidating the potential role for this intervention in patients with ARDS.
REFERENCES 1. Slutsky AS, Ranieri VM: Ventilator-induced lung injury. N EngI J Med 2013; 369:2126-2136 2. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N EngI J iWed 2000; 342:1301-1308 3. Hager DN, Krishnan JA, Hayden DL, et al; ARDS Clinical Trials Network: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005; 172:1241-1245 4. Terragni PP, Rosboch G, Tealdi A, et al: Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007; 175:160-166 5. Sorbo LD, Cypel M, Fan E: Extracorporeal life support for adults with severe acute respiratory failure. Lancet Respir Med 20^ 4; 2:154-164 6. Grasso S, Stripoli T, Mazzone P, et al: Low Respiratory Rate Plus Minimally Invasive Extracorporeal Co^ Removal Decreases Systemic and Pulmonary Inflammatory Mediators in Experimental Acute Respiratory Distress Syndrome. Crit Care Med 2014; 42: e451-e460 7. Rich PB, Reickert CA, Sawada S, et al: Effect of rate and inspiratory flow on ventilator-induced lung injury. J Trauma 2000; 49:903-911 8. Hotchkiss JR Jr, Blanch L, Murias G, et al: Effects of decreased respiratory frequency on ventilator-induced lung injury. Am J Respir Crit Care Med 2000; 161:463-468 9. Ranieri VM, Suter PM, Tortorella C, et al: Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial. JAMA 1999; 282:54-61 10. Tremblay L, Valenza F, Ribeiro SP, et al: Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 1997; 99:944-952 11. Terragni PP, Del Sorbo L, Mascia L, et al: Tidal volume lower than 6 ml/kg enhances lung protection: Role of extracorporeai carbon dioxide removal. Anesthesiology 2009; 111:826-835 1 2. Bein T, Weber-Carstens S, Goldmann A, et al: Lower tidal volume strategy (=3 ml/kg) combined with extracorporeal CO^ removal versus 'conventional' protective ventilation (6 ml/kg) in severe ARDS: The prospective randomized Xtravent-study. Intensive Care Med 2013; 39:847-856 13. Pham T, Combes A, Rozé H, et al; REVA Research Network: Extracorporeal membrane oxygénation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: A cohort study and propensity-matched analysis. Am J Respir Orit Oare Med 2013; 187:276-285 14. Abraham E, Wunderink R, Sllverman H, et al: Efficacy and safety of monoclonal antibody to human tumor necrosis factor a in patients with sepsis syndrome: A randomized, controlled, double-blind, multicenter clinical trial. JAMA 1995; 273:934-941 15. Borthwick EMJ, Hill CJ, Rabindranath KS, et al: High-volume haemofiltration for sepsis. Cochrane Database Syst Rev 2013; 1 :CD008075
June 2014 • Volume 42 • Number 6
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
