Mechanical ventilation is one of the cornerstones of critical care and one of the most frequent life support measures used in severely ill patients (1). The history of intensive care units is deeply linked to the development of mechanical ventilation support. Providing adequate respiratory support through mechanical ventilation has evolved from an understanding of normal respiratory physiology and gas exchange, histological and biomolecular evaluation of lung tissue, and the development of reliable and user-friendly mechanical ventilators. Maximum benefit requires well-defined mechanical ventilator support strategies. While developing such strategies is surely a challenge, important observational studies and randomized controlled trials have provided the results on which these strategies could be based.
Sepsis also presents a formidable clinical challenge (2). Sepsis is a major syndromic cause for intensive care unit admission, and sepsis is associated with high morbidity and mortality (3). Organ failure requiring support is common in sepsis and recovery is slow, with a profound impact on quality of life even months after the onset of sepsis (3). The lungs, as with any other organ, can be affected by sepsis (4); proper sepsis care should therefore consider ventilatory support that minimizes lung injury (2).
The clinical relevance of sepsis-induced lung injury is remarkable. Indeed, sepsis (including pneumonia) was the most frequent cause of acute respiratory distress syndrome (ARDS) in most randomized controlled trials and observational studies (5, 6). Over 50% of patients with severe sepsis or septic shock will develop ARDS (4). In an epidemiological study of mechanically ventilated patients published in 2002, sepsis accounted for 8.8% of all causes of acute respiratory failure (1). Sepsis-associated lung injury is a fearsome complication associated with high mortality (7). When ARDS supervenes, mortality is especially high (6).
In this narrative review, we will reappraise the role of mechanical ventilation in septic patients, including a brief review of the interplay between sepsis and ventilation-induced lung injury (VILI) and the available evidence for lung protective ventilation in sepsis patients. The main search terms used were: “sepsis,” “mechanical ventilation,” and “acute lung injury,” using AND as a Boolean operator. References were selected according to the author's judgement of relevance for the topic.
INTERPLAY BETWEEN SEPSIS AND VENTILATOR-INDUCED LUNG INJURY
The link between injurious mechanical ventilation and mortality has long been known (8). The association between ventilatory strategies that can overstretch the lung and induce systemic inflammation and subsequent organ dysfunction (biotrauma) was proposed a little over 15 years ago (9). Local lung production of inflammatory mediators can affect other organs due to organ crosstalk. Organ crosstalk refers to any interaction between anatomically distant organs that is mediated by endocrine, humoral, or neurological factors. Organ crosstalk is deeply related to organ dysfunction in critical illness (10). Therefore, two interconnected pathways cause lung injury in mechanically ventilated patients: direct mechanical injury and indirect effects due to systemic inflammation. Figure 1 summarizes the interaction between sepsis, multiple organ failure, and the lungs.
Ventilator-induced lung injury
Positive pressure mechanical ventilation delivers a tidal volume to the lung by increasing airway pressure to increase transmural pressure across the lung. Both lung stress and lung strain are related to VILI. Strain can be defined as the change of volume over resting volume, which can be written as (equation 1):
where Vt is tidal volume and FRC is functional residual capacity.
Stress is the measure of pressure over area; lung stress refers to the change of airway pressure applied to the lungs. Stress is the product of strain and lung elastance, as shown in Eq. (2). Elastance is defined by the change of pressure over change in volume (equation 3):
Therefore, the higher the lung elastance, the higher the lung stress will be for a given tidal volume. Higher stress values are associated with damage to the extracellular matrix of the lung tissue (9).
Lung strain can be divided into static and dynamic (11). Static stress arises from the addition of positive end expiratory pressure (PEEP) to the circuit and therefore represents the increase in FRC. Dynamic strain, on the other hand, represents the ratio between tidal volume and functional residual capacity. Therefore, dynamic strain represents the stretching that occurs in the lung tissue with every breath. While both forms of strain have been implicated in the genesis of VILI, apparently higher static strain values are less deleterious than higher dynamic strains (12). Regional lung strain appears to be an important inducer of inflammation and further lung injury (13).
The clear biological mechanisms behind lung inflammation due to increase in stress and strain are not known. In order to trigger a local response, changes in cellular structure due to the application of stress must be transduced to a biochemical response (9). Several putative mechanisms could be involved, including stretch-sensitive channels and conformational changes in cytoskeleton. Once transduced, the signal will usually result in an increase in local production of adhesion molecules (such as ICAM-1), tissue growth factor β, and nitric oxide synthase (9). Martínez-Claro et al. (14) suggested that increased peroxynitrite formation could also play a role in lung inflammation. Local inflammatory response will further damage the lung tissue.
Sepsis-associated lung injury
Sepsis, regardless of its source, is capable of inducing lung inflammation through several mechanisms independent of mechanical ventilation, including production of inflammatory cytokines, alveolar cell apoptosis (mediated by Fas/Fas-L), collagen and fibronectin deposit, and production of peroxynitrite (15, 16). The lung inflammation profile may depend on the causative agent. For example, lung injury due to Pseudomonas aeruginosa may be associated with higher IL-1 and IL-13 and lower nitric oxide synthesis when compared with Staphylococcus aureus infection (17).
The mediator expression of sepsis-associated lung injury may fluctuate during the progression of the disease. For example, in an ovine model of pulmonary sepsis, pulmonary lipid peroxidation peaked as early as 4 h after injury while cytokine production (IL-6) peaked 8 h after. Neutrophil activation in the lung, on the other hand, increased throughout the progression of lung injury (18).
Sepsis and susceptibility to ventilator injury
Bench studies suggest that noxious ventilatory strategies may have profound systemic effects and reduce survival (19, 20). The presence of systemic inflammation has been shown to increase the susceptibility of the lung to ventilator injury (13, 19). Nin et al. (19), in a rat model of bacterial sepsis, showed that septic rats submitted to high tidal volume ventilation had more pulmonary and systemic dysfunction than rats exposed to the same tidal volume. Interestingly, dexamethasone appeared to mitigate both inflammatory and systemic dysfunctions. In another elegant, experimental study in sheep, Wellman et al. (13) showed that the addition of lipopolysaccharide to a ventilation strategy that included high lung strain (tidal volumes close to 18 mL/kg) dramatically increased lung inflammation when compared with ventilation with high strain alone. Importantly, the addition of PEEP and reduction of tidal volume was associated with reduced lung inflammation (13). Finally, Su et al. (20) have shown that septic sheep ventilated with higher tidal volumes (12 mL/kg) had lower survival times and higher wet/dry ratios of lung tissue when compared with animals ventilated with lower tidal volumes.
CLINICAL EVIDENCE FOR LUNG PROTECTIVE VENTILATION
As of September 2015, there are 1,700 manuscripts indexed in PubMed containing “Lung protective ventilation” as a keyword. Of those, over 160 are clinical trials in humans. Surprisingly, there is scant data focusing exclusively on sepsis-associated acute lung injury. The current Surviving Sepsis Campaign Guideline advocates in favor of low tidal volume ventilation (i.e., 6 mL/kg) and PEEP use, but acknowledges that most evidence came from lato sensu ARDS studies (2). Nevertheless, as mentioned, all experimental and clinical evidence points toward a higher susceptibility of the septic lung to VILI and it is very likely that a lung protective strategy would be beneficial in septic patients (21). At this point, it would be unethical to randomize septic patients to any intervention that did not consider the core components of lung protective ventilation.
Principles of lung protective ventilation are based on the aforementioned causes of VILI. By reducing tidal volume, dynamic lung strain is reduced. Tailored use of PEEP also contributes to reduction of strain, since it increases residual lung capacity. PEEP also reduces cyclic collapsing of the airways (atelectrauma), which further increases pulmonary injury. By limiting plateau pressure, a threshold for lung stress is attained. Hypercapnia should be tolerated if needed to maintain low stretch strategy (4). Change in body position (prone position) may also improve oxygenation and outcome. This modern lung protective ventilation strategy in septic patients is based on the results of several randomized controlled trials (RCT) on ARDS.
Low tidal volume
Six essential RCT studies evaluated the role of low tidal volume in ARDS (22–27); one of them specifically addressed patients with persistent ARDS. Most also assessed the role of different methods to set the PEEP and different limits of plateau pressure (Pplateau), thereby evaluating the role of a ventilatory strategy and not only tidal volume. A summary of those studies is provided in Table 1. Sepsis and pneumonia were the most common reasons for ARDS, accounting for more than half of all etiologies. The results of a fixed effect model pooling of the RCTs described by Table 1 are shown in Figure 2. Results were largely determined by the ARDSNet trial (17), which is the largest study available (and therefore had the higher weight in the fixed effect model) and confirmed the protective role of low tidal volume ventilation in ARDS (pooled relative risk 0.83; 95% confidence interval (CI) 0.72–0.95). Consequently, aiming for a tidal volume close to 6 mL/kg and limiting Pplateau to below 30 cmH2O (even at the expense of hypercapnia) is the current suggested approach for ARDS.
One of the side effects of low tidal volume ventilation is hypercapnia (4, 22). Current consensus states that hypercapnia should be tolerated while pH is higher than 7.20. Importantly, hypercapnia may be associated with reduced pulmonary inflammation in sepsis (28), but its immunosuppressive effects may reduce bacterial clearance and have deleterious effects in prolonged lung injury (29). The exact role of hypercapnia in ARDS has yet to be established. It should be highlighted that there are no grounds on which to induce hypercapnia in sepsis-associated lung injury outside the context of a clinical trial.
Timing and dynamic management of ventilatory strategy also plays an important role in the treatment of ARDS. In a prospective study, Needham has shown that an increase of 1 mL/kg over the initial tidal volume was associated with higher mortality in ARDS patients (adjusted hazard ratio 1.23; 95% CI 1.06–1.44; P = 0.008) (19). Additionally, the higher the initial tidal volume, the higher the mortality.
The current consensus is that some degree of PEEP should be applied in ARDS patients (2). Nevertheless, the precise way to define PEEP in ARDS is yet to be established. One of the most common approaches is to set predefined PEEP values according to the inspired oxygen fraction needed to attain adequate oxygenation (the so-called PEEP table). Another approach involves setting PEEP at the maximum possible value until Pplateau reaches 30 cmH2O (30), along with careful titration using pulmonary mechanics and or imaging techniques (22, 31). The use of higher PEEP values may be associated with lower mortality in ARDS (32); therefore, one practical approach would be setting the PEEP according to the high values of PEEP table shown in the ALVEOLI trial (33). One exception may be in the presence of right ventricle failure, which is common in ARDS patients and is an important marker of poor prognosis. In this situation, increase in PEEP values may worsen hemodynamic status by an increase in right ventricle afterload (34). It is advisable to assess right ventricle function (by use of echocardiography, for example) in ARDS patients.
The prone position has a number of interesting physiological benefits that are relevant to ARDS management. It exerts a number of interesting physiological functions in the respiratory system, resulting in the occasional unloading of the right ventricle (35). Interestingly, the oxygenation benefit of the prone position is linked to redistribution of blood flow and improved ventilation/perfusion match, and not to an increase in lung aeration (36). The prone position is also capable of reducing VILI (by improving stress/strain distribution) and modulating biotrauma in ARDS (37).
It is not surprising that use of the prone position in patients with severe ARDS offers a survival advantage in selected populations. In a large RCT, Guérin et al. (38) randomized 466 ARDS patients with PaO2/FiO2 ratios below 150 (and FiO2 of at least 60%) to the prone position for at least 16 h or standard care and found a hazard rate for 28-day mortality of 0.39 (95% CI 0.25–0.63). While this study provides a strong evidence for the use of prone position, it should be highlighted that mortality was lower than expected, thereby limiting study power. In a recent meta-analysis, the relative risk for mortality was 0.90 (95% CI 0.82–0.98; P = 0.02), with an even higher benefit when the prone position was applied for more than 12 h (relative risk of 0.75; 95% CI 0.65–0.87; P < 0.001) (39).
Lung protective ventilation in sepsis without lung injury
There is no clear consensus on the use of lung protective strategies outside the context of acute lung injury. Recent meta-analysis suggested that low tidal volume ventilation could be associated with clinical benefit, but most studies focused on surgical patients (40, 41). The use of low tidal volumes in non-ARDS patients may reduce progression to lung injury (42). This is in accordance with the concept that septic patients are highly susceptible to VILI. Therefore, it is strongly advisable to start a lung protective ventilatory strategy shortly after initiating mechanical ventilation in septic individuals (21).
Tidal volume versus driving pressure control
Amato et al. (43), using a sophisticated mediation analysis with grouped data from large randomized controlled trials on ARDS, suggested that driving pressure (i.e., the distending pressure applied to the lung, defined as plateau pressure minus PEEP) and not tidal volume was the most important factor associated with mortality. In their analysis, driving pressure values above 15 mm Hg were associated with increased mortality irrespective of tidal volume. Nevertheless, it is unclear if a ventilatory strategy based on driving pressure is superior to the current tidal volume targeted approach. This issue should be evaluated in future studies.
Recruitment maneuvers and open lung approach
A recruitment maneuver may be defined as a systematic increase in airway pressure aimed at opening closed alveolar units. Since the closing pressure is lower than the opening pressure, units will remain open at lower airway pressures once opened. This will result in an increase in residual lung capacity and, therefore, may theoretically decrease dynamic lung strain. Nevertheless, there is no consensus regarding how and when a recruitment maneuver should be performed. A recent systematic review suggested that recruitment maneuvers were associated with mortality improvement but it was underpowered (44). Recruitment maneuvers are, therefore, an interesting second tier therapy for hypoxemia in ARDS.
Several pilot studies assessed the role of a ventilatory strategy based on recruitment maneuvers and decremental PEEP titration (known as the “open lung approach”) in ARDS (45, 46). The open lung approach has been associated with improved oxygenation and respiratory mechanics (45). In a recent study with 200 patients, Kacmarek et al. (46) reported that the open lung approach was associated with reduced driving pressure in ARDS patients, but the study was not powered to detect hard outcomes (such as mortality). The role of the open lung approach is currently the subject of a large multicenter trial in Brazil (47).
Ultra protective lung ventilation with extracorporeal CO2 removal
While the widespread use of extracorporeal membrane oxygenation in ARDS cannot currently be recommended (48), it has been hypothesized that extracorporeal CO2 removal coupled with an ultra protective tidal volume (i.e., very low tidal volume—3 mL/kg) could be associated with improved outcome. In one small RCT, doing so increased ventilator-free days, but the sample size was too small to draw any conclusions regarding robust outcomes (49). Therefore, despite a physiological background, extracorporeal CO2 removal with ultralow tidal volume should still be considered experimental.
Sepsis is a common cause of lung injury and increases lung susceptibility to VILI. While the particularities of the management of sepsis induced lung injury are largely unknown, it is prudent to apply a protective strategy for all septic patients requiring mechanical ventilation, regardless of the presence of ARDS.
1. Esteban A, Anzueto A, Frutos F, Alía I, Brochard L, Stewart TE, Benito S, Epstein SK, Apezteguía C, Nightingale P, et al. Characteristics and outcomes in adult patients receiving mechanical ventilation. JAMA
2002; 287 3:345–355.
2. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med
2013; 39 2:165–228.
3. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med
2013; 369 9:840–851.
4. Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis
-induced acute lung injury/acute respiratory distress syndrome: an evidence-based review. Crit Care Med
2004; 32 (11 suppl):S548–S553.
5. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med
2005; 353 16:1685–1693.
6. Villar J, Blanco J, Añón JM, Santos-Bouza A, Blanch L, Ambrós A, Gandía F, Carriedo D, Mosteiro F, Basaldúa S, et al. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med
2011; 37 12:1932–1941.
7. Kojicic M, Li G, Hanson AC, Lee KM, Thakur L, Vedre J, Ahmed A, Baddour LM, Ryu JH, Gajic O. Risk factors for the development of acute lung injury in patients with infectious pneumonia. Crit Care
2012; 16 2:R46.
8. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med
2013; 369 22:2126–2136.
9. Dos Santos CC, Slutsky AS. Invited review: mechanisms of ventilator-induced lung injury: a perspective. J Appl Physiol
2000; 89 4:1645–1655.
10. Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med
2007; 35 10:2408–2416.
11. Waikar SS, Liu KD, Chertow GM. Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol
2008; 3 3:844–861.
12. Protti A, Andreis DT, Monti M, Santini A, Sparacino CC, Langer T, Votta E, Gatti S, Lombardi L, Leopardi O, et al. Lung stress and strain during mechanical ventilation: any difference between statics and dynamics? Crit Care Med
2013; 41 4:1046–1055.
13. Wellman TJ, Winkler T, Costa EL, Musch G, Harris RS, Zheng H, Venegas JG, Vidal Melo MF. Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep. Crit Care Med
2014; 42 7:e491–e500.
14. Martínez-Caro L, Nin N, Sánchez-Rodríguez C, Ferruelo A, El Assar M, de Paula M, Fernández-Segoviano P, Esteban A, Lorente JA. Inhibition of nitro-oxidative stress attenuates pulmonary and systemic injury induced by high–tidal volume mechanical ventilation. Shock
2015; 44 1S:36–43.
15. Rojas M, Woods CR, Mora AL, Xu J, Brigham KL. Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses. Am J Physiol Lung Cell Mol Physiol
2005; 288 2:L333–L341.
16. Kitamura Y, Hashimoto S, Mizuta N, Kobayashi A, Kooguchi K, Fujiwara I, Nakajima H. Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice. Am J Respir Crit Care Med
2001; 163 3:762–769.
17. Sousse LE, Jonkam CC, Traber DL, Hawkins HK, Rehberg SW, Traber LD, Herndon DN, Enkhbaatar P. Pseudomonas aeruginosa is associated with increased lung cytokines and asymmetric dimethylarginine compared with methicillin-resistant Staphylococcus aureus. Shock
2011; 36 5:466–470.
18. Lange M, Szabo C, Traber DL, Horvath E, Hamahata A, Nakano Y, Traber LD, Cox RA, Schmalstieg FC, Herndon DN, et al. Time profile of oxidative stress and neutrophil activation in ovine acute lung injury and sepsis. Shock
2012; 37 5:468–472.
19. Nin N, Lorente JA, Fernández-Segoviano P, De Paula M, Ferruelo A, Esteban A. High-tidal volume ventilation aggravates sepsis-induced multiorgan dysfunction in a dexamethasone-inhibitable manner. Shock
2009; 31 4:429–434.
20. Su F, Nguyen ND, Creteur J, Cai Y, Nagy N, Anh-Dung H, Amaral A, Bruzzi de Carvalho F, Chochrad D, Vincent JL. Use of low tidal volume in septic shock may decrease severity of subsequent acute lung injury. Shock
2004; 22 2:145–150.
21. Calzia E, Radermacher P. Vili in patients with sepsis: just fate or can we avoid it? Shock
2004; 22 6:586–587.
22. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med
1998; 338 6:347–354.
23. Stewart TE, Meade MO, Cook DJ, Granton JT, Hodder RV, Lapinsky SE, Mazer CD, McLean RF, Rogovein TS, Schouten BD, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med
1998; 338 6:355–361.
24. Brochard L, Roudot-Thoraval F, Roupie E, Delclaux C, Chastre J, Fernandez-Mondéjar E, Clémenti E, Mancebo J, Factor P, Matamis D, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med
1998; 158 6:1831–1838.
25. Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P Jr, Wiener CM, Teeter JG, Dodd-o JM, Almog Y, Piantadosi S. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med
1999; 27 8:1492–1498.
26. The Acute Respiratory Distress Syndrome NetworkVentilation 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 Engl J Med
2000; M342 18:1301–1308.
27. Villar J, Kacmarek RM, Pérez-Méndez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med
2006; 34 5:1311–1318.
28. Ni Chonghaile M, Higgins BD, Costello JF, Laffey JG. Hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism. Crit Care Med
2008; 36 12:3135–3144.
29. Curley G, Contreras MMB, Nichol AD, Higgins BD, Laffey JG. Hypercapnia and acidosis in sepsis: a double-edged sword? Anesthesiology
2010; 112 2:462–472.
30. Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA
2008; 299 6:646–655.
31. Blankman P, Hasan D, Erik G, Gommers D. Detection of “best” positive end-expiratory pressure derived from electrical impedance tomography parameters during a decremental positive end-expiratory pressure trial. Crit Care
2014; 18 3:R95.
32. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA
2010; 303 9:865–873.
33. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT. National Heart, Lung, and Blood Institute ARDS Clinical Trials NetworkHigher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med
2004; 351 4:327–336.
34. Repessé X, Charron C, Vieillard-Baron A. Acute cor pulmonale in ARDS: rationale for protecting the right ventricle. Chest
2015; 147 1S:259–265.
35. Pelosi P, Caironi P, Taccone P, Brazzi L. Pathophysiology of prone positioning in the healthy lung and in ALI/ARDS. Minerva Anestesiol
2001; 67 4:238–247.
36. Nyrén S, Radell P, Lindahl SG, Mure M, Petersson J, Larsson SA, Jacobsson H, Sánchez-Crespo A. Lung ventilation and perfusion in prone and supine postures with reference to anesthetized and mechanically ventilated healthy volunteers. Anesthesiology
2010; 112 3:682–687.
37. Guérin C, Mancebo J. Prone positioning and neuromuscular blocking agents are part of standard care in severe ARDS patients: yes. Intensive Care Med
2015; 41 12:2195–2197.
38. Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med
2013; 368 23:2159–2168.
39. Park SY, Kim HJ, Yoo KH, Park YB, Kim SW, Lee SJ, Kim EK, Kim JH, Kim YH, Moon JY, et al. The efficacy and safety of prone positioning in adults patients with acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. J Thorac Dis
2015; 7 3:356–367.
40. Fuller BM, Mohr NM, Drewry AM, Carpenter CR. Lower tidal volume at initiation of mechanical ventilation may reduce progression to acute respiratory distress syndrome: a systematic review. Crit Care
2013; 17 1S:R11.
41. Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Espósito DC, Pasqualucci Mde O, Damasceno MC, Schultz MJ. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA
2012; 308 16:1651–1659.
42. Yilmaz M, Keegan MT, Iscimen R, Afessa B, Buck CF, Hubmayr RD, Gajic O. Toward the prevention of acute lung injury: protocol-guided limitation of large tidal volume ventilation and inappropriate transfusion. Crit Care Med
2007; 35 7:1660–1666.
43. Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, Stewart TE, Briel M, Talmor D, Mercat A, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med
2015; 372 8:747–755.
44. Suzumura EA, Figueiró M, Normilio-Silva K, Laranjeira L, Oliveira C, Buehler AM, Bugano D, Passos Amato MB, Ribeiro Carvalho CR, Berwanger O, et al. Effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Intensive Care Med
2014; 40 9:1227–1240.
45. Cinnella G, Grasso S, Raimondo P, D’Antini D, Mirabella L, Rauseo M, Dambrosio M. Physiological effects of the open lung approach in patients with early, mild, diffuse acute respiratory distress syndrome: an electrical impedance tomography study. Anesthesiology
2015; 123 5:1113–1121.
46. Kacmarek RM, Villar J, Sulemanji D, Montiel R, Ferrando C, Blanco J, Koh Y, Soler JA, Martínez D, Hernández M, et al. Open lung approach for the acute respiratory distress syndrome. Crit Care Med
2015; 44 1S:32–42.
47. Investigators TA. Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): study protocol for a randomized controlled trial. Trials
2012; 13 1S:153.
48. Zampieri FG, Mendes PV, Ranzani OT, Taniguchi LU, Pontes Azevedo LC, Vieira Costa EL, Park M. Extracorporeal membrane oxygenation for severe respiratory failure in adult patients: a systematic review and meta-analysis of current evidence. J Crit Care
2013; 28 6:998–1005.
49. Bein T, Weber-Carstens S, Goldmann A, Müller T, Staudinger T, Brederlau J, Muellenbach R, Dembinski R, Graf BM, Wewalka M, et al. Lower tidal volume strategy (≈3 ml/kg) combined with extracorporeal CO2 removal versus “conventional” protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Med
2013; 39 5:847–856.