Primary analysis of mortality and independent predictive information
Table 3 displays the multivariable logistic regression model related to driving pressure. After adjusting for all identified significant confounders, driving pressure was independently associated with mortality [adjusted OR, 1.04 (1.01–1.07)].
Separate logistic regression models were constructed for plateau pressure, compliance, and PEEP (Supplemental Digital Content 1, Supplemental Table 1, http://links.lww.com/SHK/A627). For the model related to plateau pressure, the predictors of outcome were the same as for driving pressure. Plateau pressure was also independently associated with mortality with the same effect size and similar interval estimate as driving pressure [adjusted OR, 1.04 (1.02–1.07)].
Plateau pressure, compliance, and PEEP were added separately as covariates to the driving pressure model (Supplemental Digital Content 2, Supplemental Table 2, http://links.lww.com/SHK/A628) (6). In this model, plateau pressure conferred independent predictive information [adjusted OR, 1.04 (1.02–1.07)], while driving pressure was no longer significantly associated with mortality.
There were 152 patients who progressed to ARDS after admission (8.9%). Baseline characteristics and ventilator variables, according to ARDS status, are presented in Supplemental Digital Content 3, Supplemental Table 3, http://links.lww.com/SHK/A629. Compared with patients without ARDS, those who progressed to ARDS had significantly higher driving pressure [18.1 (5.2) vs. 14.9 (4.6), P < 0.001], plateau pressure [24.9 (5.5) vs. 20.3 (4.7), P < 0.001], and mechanical power [17.5 (6.1) vs. 15.7 (6.0), P = 0.001]. Supplemental Digital Content 4, Supplemental Table 4, http://links.lww.com/SHK/A630, displays the multivariable logistic regression models for ARDS. After adjusting for all identified significant confounders, driving pressure was independently associated with ARDS development [adjusted OR, 1.08 (1.04–1.12)]. Separate multivariable models also revealed that plateau pressure [adjusted OR, 1.12 (1.08–1.17)], and mechanical power [adjusted OR, 1.03 (1.00–1.06)] were independently associated with ARDS development.
Figure 2 displays the unadjusted rate of ARDS across the tertiles of driving pressure, plateau pressure, compliance, and mechanical power. ARDS incidence increased across tertiles, with a steep increase between tertiles two and three.
The main components of lung-protective ventilation address tidal volume, inspiratory plateau pressure, and PEEP. Manipulation of each, along with rate and flow, can attenuate VALI (2). However, limitations exist for each element of this lung-protective bundle. Scaling tidal volume to PBW can be an imprecise estimate of the functional lung volume available for gas exchange (11). Inspiratory plateau pressure does not consider the contribution of the chest wall to respiratory system compliance, and therefore can be an inaccurate surrogate of true transalveolar stretch, especially in the setting of increased pleural pressure (2). While PEEP recruits and stabilizes alveolar units, it can also overdistend and contribute to VALI (12). Therefore, novel and more individualized approaches to lung-protection are needed and could improve outcome. Given the recent data suggesting that driving pressure is a principal determinant of mortality risk in patients with ARDS, but a lack of data in patients without ARDS, the primary hypothesis of the current analysis focused on driving pressure in a non-ARDS cohort. The results of this study expand upon the potential use of driving pressure to guide ventilator settings and prevent clinical lung injury. The primary findings were: driving pressure is associated with hospital mortality and ARDS development; the information provided by driving pressure and plateau pressure is largely redundant; across tertiles of pulmonary mechanics, both hospital mortality and ARDS incidence increase; and mechanical power is associated with the development of ARDS.
The majority of data regarding driving pressure comes from patients with established ARDS or from the operating room (5, 6, 13). In secondary analyses of randomized trials of ARDS patients, driving pressure was independently associated with mortality, and a meta-analysis of patients mechanically ventilated for general anesthesia, driving pressure was associated with the development of postoperative pulmonary complications (5, 6, 13). Our results suggest that in mechanically ventilated ICU patients without ARDS, targeting driving pressure could potentially improve outcome.
However, the increased benefit afforded by targeting driving pressure in this cohort of patients without ARDS is unclear. There is conflicting data regarding the additive prognostic benefit of driving pressure beyond other pulmonary mechanics, such as plateau pressure and compliance, in patients with established ARDS. Amato et al. (5) concluded that driving pressure was the ventilator variable most significantly associated with mortality and contributed independent information. Guérin et al. (6) also concluded that driving pressure was associated with mortality, but contributed the same information as plateau pressure during lung-protective ventilation. Finally, plateau pressure was found to predict mortality better than driving pressure in a study by Villar et al. (14). In this current cohort of non-ARDS patients, while the results expand upon the role of driving pressure in mechanically ventilated patients without ARDS, its relative contribution beyond inspiratory plateau pressure is open to question. Increases in mortality across tertiles were nearly identical for driving pressure and plateau pressure, and separate multivariable models produced nearly identical results. Furthermore, only plateau pressure conferred independent predictive information to the survival model when driving pressure was a pre-existing covariate. Our data suggest that the information provided by each parameter may be redundant in non-ARDS patients. The extent to which targeting driving pressure as a primary therapeutic endpoint to improve outcome needs investigated further.
ARDS was analyzed as a secondary outcome as it is in the causal pathway between VALI and mortality. An intervention that reduces VALI should theoretically reduce both ARDS incidence and mortality. The results of our ARDS analysis were consistent with the primary analysis of mortality, showing both driving pressure and plateau pressure were independently associated with ARDS incidence.
Furthermore, mechanical power was also associated with ARDS development and is an interesting finding. Mechanical power is the energy load transferred from the ventilator to the lung parenchyma, and is a composite variable determined by the ventilator-related contributors to lung injury (i.e., pressure, volume, rate, flow) (1). In an experimental model, a mechanical power of approximately 12 joules per minute was found to be a threshold above which VALI occurred (15). This threshold value was also demonstrated to be associated with mortality in a clinical study of ARDS patients receiving lung-protective ventilation (6). In our present study, those patients progressing to ARDS had a mean mechanical power of 17.5 joules per minute on day 1 of mechanical ventilation. There was also an increase in the incidence of ARDS when comparing mechanical power in tertiles 1 (below threshold value of 12 joules per minute), with that in tertiles 2 and 3 (above power threshold). Our data suggest that mechanical power could be a novel target to prevent ARDS, but needs confirmed with larger clinical trials.
There are several important limitations to consider. This is an observational study and only describes associations. The pulmonary mechanics investigated in this study are highly correlated (mathematically, physiologically, and statistically), so any results that demonstrate a lack of additive benefit of one parameter over another should not be surprising. Prior investigations in this area have all used different statistical methodology to untangle the independent and/or additive contribution that these pulmonary mechanics may have on outcome (5, 6, 14, 16). Without a prospective, randomized trial it is impossible to say if limiting driving pressure to reduce VALI matters more than targeting other variables at the bedside. Furthermore, most patients were on a PEEP of 5 cm H2O, which is congruent with prior epidemiological studies of mechanically ventilated patients without ARDS (16, 17). However, it may limit the ability to detect differences in the predictive ability of driving pressure versus plateau pressure, since driving pressure equals plateau pressure minus PEEP. Our results may temper the enthusiasm for the use of driving pressure to improve outcome, but this question cannot be answered under the auspice of an observational study. Prior investigations on driving pressure excluded patients with respiratory rates that exceeded set ventilator rates. It is difficult to interpret driving pressure in the setting of active respirations; it is unknown how spontaneous respirations affected the true correlation between driving pressure and transalveolar stretch in this study. However, our results are consistent with prior investigations in ARDS patients and those in the operating room, with similar effect sizes (5, 6, 13). This study only reflects driving pressure of the respiratory system, and not driving pressure of the lung. We have no knowledge of the chest wall's contribution to our observed driving pressure, which can be substantial (18). The observed differences between pulmonary mechanics in this study were significant but clinically small. This is similar to previous work in which a mean difference of 1 cm H2O existed between ARDS survivors and non-survivors, and a median difference of 1.5 cm H2O existed between mechanically ventilated patients who did and did not progress to ARDS (6, 16). This fact brings into question the clinical implications with respect to adjusting ventilator settings at the bedside, and these findings are to be interpreted with caution. Finally, we did not capture the exact cause of death in these patients. While we have no reason to suspect that our cohort's deaths would be different than the most common causes of death in critically ill patients, namely multi-organ dysfunction and limitations of support, it is possible that there was imbalance in non-VALI-related causes of death between survivors and non-survivors.
To conclude, in mechanically ventilated patients without ARDS, driving pressure and plateau pressure are risk factors for mortality and ARDS, and provide similar information. Mechanical power is also a risk factor for ARDS.
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ARDS; driving pressure; mechanical ventilation; pulmonary mechanics
Supplemental Digital Content
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