By Betty Tran, MD, MSc
Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago
SYNOPSIS: Using newer methodology in network meta-analysis to compare various protective mechanical ventilation strategies, the authors concluded that a low tidal volume strategy combined with prone ventilation was associated with the greatest risk reduction in mortality for moderate to severe acute respiratory distress syndrome.
SOURCE: Sud S, Friedrich JO, Adhikari NKJ, et al. Comparative effectiveness of protective ventilation strategies for moderate and severe acute respiratory distress syndrome. A network meta-analysis. Am J Respir Crit Care Med 2021;202:1366-1377.
Current clinical guidelines recommend the use of low tidal volume (Vt), high positive end-expiratory pressure (PEEP), and prone ventilation in preventing ventilator-induced lung injury (VILI) in patients with acute respiratory distress syndrome (ARDS). However, few trials compare each of these interventions head-to-head, making it difficult to gauge their comparative effectiveness. Using current network meta-analysis methodology that incorporates not only statistical analyses but also certainty of evidence assessments, Sud et al conducted a network meta-analysis of 34 randomized controlled trials (RCTs) of adult ARDS patients to compare the relative effects of low Vt (< 8 mL/kg of ideal body weight), low Vt combined with high PEEP, venovenous extracorporeal membrane oxygenation (VV ECMO), high frequency oscillation (HFO), and prone ventilation with either low or high Vt on hospital mortality (if this was not available, mortality at the longest available duration of follow-up was used).
Using a frequentist random-effects network meta-analysis method, network risk ratios were calculated for each treatment strategy using low Vt as the standard comparator, given its wide acceptance as standard of care in ARDS.1 A surface under the cumulative ranking curve (SUCRA) statistic (range 0% to 100%) was calculated, with higher values representing a higher likelihood that a therapy was among the best in the network meta-analysis. In addition, the Grading of Recommendations Assessment, Development and Education (GRADE) methodology was used to assess the certainty of evidence (moderate to high vs. low to very low).2 Interventions then were classified by effectiveness (among the most effective, inferior to the most effective/superior to the least effective, and least effective) and certainty of evidence using high Vt as the referent least effective strategy and low Vt as the referent standard of care.
In the 34 RCTs analyzed, 9,085 ARDS patients had mortality data available. Median PaO2/FiO2 was 118 mmHg (interquartile range [IQR], 110-143), and median PEEP level was 12 cm H2O (IQR, 10-13). A combination low Vt and prone strategy reduced mortality compared to low Vt alone (risk ratio [RR], 0.74; 95% confidence interval [CI], 0.60-0.92; high certainty) and when compared to HFO, a high Vt/prone combination, and high Vt strategies. VV ECMO reduced mortality compared to a high Vt or high Vt/prone strategy, but not compared with a low Vt (RR, 0.78; 95% CI, 0.58-1.05; very low certainty) or low Vt/prone strategy (RR, 0.95; 95% CI, 0.66-1.37; very low certainty). When the interventions were categorized as being among the best, intermediate, or worst based on certainty of evidence and SUCRA, a low-Vt/prone strategy was deemed among the most effective (SUCRA, 92%) for reducing ARDS mortality with high confidence. Although VV ECMO had a SUCRA value of 86%, the certainty of evidence was very low/low because of moderate risk of bias, imprecision, and intransitivity due to inclusion of more severely hypoxic patients. Low Vt/high PEEP and low Vt were ranked as being intermediately effective (i.e., not as effective as low Vt/prone, but better than high Vt) with moderate certainty of evidence.
This study had several strengths. The authors had a very specific analysis plan using state-of-the-art methodologies that considered not only statistical results, but also considered other factors (e.g., transitivity, imprecision, bias) that affect certainty of evidence and, thereby, the ability to make appropriate inferences about the best ventilation strategy. They also were meticulous in their classification of interventions, for example, distinguishing between trials with a low Vt vs. low VT/high PEEP strategy. They included a greater number of trials (and, therefore, participants) compared to prior analyses.
These findings do not necessarily contradict prior results from other meta-analyses, although the authors emphasized that their main recommendation (lowest mortality reduction seen in the low Vt/prone group) is distinct from another network meta-analysis, which concluded that both prone positioning and VV ECMO should be used in addition to a lung protective ventilation strategy.3-5 This distinction was attributed to judicious application of GRADE to reveal much higher certainty of evidence supporting low Vt/prone than for VV ECMO rather than the use of SUCRA statistics alone. From a scientific perspective, it highlights and addresses concerns that analyses based solely on statistical methods can lead to errors in inference and, thus, validity.
Based on the conclusions from this study, a low Vt/prone strategy would be reasonable to use first, even in severe ARDS cases, given that proning can be performed in any intensive care unit (ICU) with proper training of staff. In contrast, VV ECMO requires high-risk transfer to one of few expert centers, is highly resource intensive, and comes with risk of serious complications, which are notable concerns in light of the low certainty of evidence. In cases where patients clinically deteriorate despite proning, VV ECMO could be considered for patients with severe ARDS.
- Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med 2002;21:2313-2324.
- Guyatt G, Oxman AD, Aki EA, et al. GRADE guidelines: 1. Introduction — GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383-394.
- Sud S, Friedrich JO, Adhikari NK, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: A systematic review and meta-analysis. CMAJ 2014;186:E381-E390.
- Beitler JR, Shaefi S, Montesi SB, et al. Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: A meta-analysis. Intensive Care Med 2014;40:332-341.
- Aoyama H, Uchida K, Aoyama K, et al. Assessment of therapeutic interventions and lung protective ventilation in patients with moderate to severe acute respiratory distress syndrome. A systematic review and network meta-analysis. JAMA Netw Open 2019;2:e198116.