Changes in Driving Pressure vs Oxygenation as Predictor of Mortality in Moderate to Severe Acute Respiratory Distress Syndrome Patients Receiving Prone Position Ventilation

HIGHLIGHTS

This study showed that even a significant improvement in PaO₂/FiO₂ after PPV in moderate-severe ARDS patients, is not translated to a reduction in mortality. The DP remaining high at ≥16 cmH₂O after sessions of PPV is a reliable predictor of mortality. The significant reduction of DP after PPV in moderate-severe ARDS patients discriminates the survivors from non-survivors, whereas the significant improvement in oxygenation cannot.

INTRODUCTION

Prone position ventilation (PPV) has led to an improvement in oxygenation in seven randomized controlled trials (RCTs).^1–7 However, the improvement in oxygenation was not translated to mortality benefit in six out of the seven RCTs.^2–7 This indicates that factors other than mere improvement in oxygenation determine outcomes in moderate – severe acute respiratory distress syndrome (ARDS) patients who received PPV, like global lung strain and stress. Changes in driving pressure (DP) predicted survival in ARDS patients in the trial by Amato et al.⁸ However, this study consisted of an important proportion of only mild ARDS patients.⁸

In a recent computational study on ARDS patients, investigators tried to establish a “link” between DP and survival outcomes. The dynamic lung strain or overdistension of newly recruited normal alveolar units and consequent cyclical alveolar strain during ventilation is a major factor causing ventilator-induced lung injury (VILI). The investigators concluded that this cyclical dynamic alveolar strain was linked to a higher DP and mortality.⁹ The DP reduction from 21 cmH₂O to 12 cmH₂O lead to reduction in the repeated strain during opening and closing of alveolar units from 16 to <4% of the total lung.⁹ Investigators had used a high-fidelity computational simulator of cardio-pulmonary pathophysiology, and concluded that cyclic alveolar strain along with tidal recruitment provides a reliable mechanistic understanding for proposed correlation between higher DP and mortality.⁹ We hypothesized that the cyclical alveolar dynamic strain will be most relevant in patients of moderate-severe ARDS, as compared to mild-moderate ARDS.

The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) <100 with positive end expiratory pressure (PEEP) >5 cmH₂O is categorized as moderate–severe ARDS.¹⁰ Despite using lower tidal volume (V_T) and lower plateau pressure (P_plat), moderate-severe ARDS can cause mortality of 60%.^11,12

As PPV is known to recruit collapsed alveolar units and improve the mechanical characteristics of already opened alveolar units that locate a favorable position on the pressure-volume loop indicating more homogeneous ventilation and perfusion distribution.¹³ This phenomenon can hypothetically lead to improvement in respiratory system compliance (C_RS). Driving pressure is also measured as a ratio between V_T and C_RS and hence DP is inversely proportional to C_RS.

In a patient requiring PPV, the DP can be measured at various time points such as before PPV, during the period of PPV, and after the session of PPV when the patient is again turned supine. There is a scarcity of literature regarding the utility of changes in DP post-PPV in moderate- severe ARDS patients as a predictor of outcomes and which of the DP at different time points (pre, during, and post-PPV) is the best predictor of mortality.

With this background, we aimed to determine the changes and the role of DP as compared to improvement in oxygenation (PaO₂/FiO₂) at different time points as predictors of mortality outcomes in moderate-severe ARDS patients with PPV.¹⁴

METHODS

A prospective observational study was conducted at level III ICU of a tertiary care medical college from September 2020 to April 2023. After Institutional Ethics Committee (IEC: 765/2019) approval, the study was registered in India’s Clinical Trial Registry (CTRI/2020/04/024940).

Sample Size

Since it was a 3-year time period study on moderate-severe ARDS patients receiving PPV, post-hoc power of the study was calculated based on sample size. With mean DP post-PPV of 13.91 ± 1.74 cmH₂O among survivors (n ₁ = 22) vs 19.70 ± 3.15 cmH₂O among the non-survivors (n₂ = 30), the post-hoc power as 95% as per the calculation below:

Where φ = Function converting a critical Z value to power

Z1–α/2 = 1.96 for 95% CI, α = 0.05

σ₁ and σ₂ = variance of mean n₁ and mean n₂

n₁ = number of survivors

n₂ = number of non-survivors

RESULTS

A total of 52 patients with moderate-severe ARDS receiving PPV were included in the study within the study period. The 28-day ICU mortality was 57%. The median and IQR in hours of PPV were 18 (16–32). Demographic details and study variables are depicted in Table 1.

Table 2 shows comparison of parameters between survivors and non-survivor and shows that DP and PaO₂/FiO₂ pre, during, and post-PPV were significant between the survivors and non-survivors along with SOFA score and LIS. Table 3 compares DP and PaO₂/FiO₂ pre- and post-PPV among survivors and non-survivors separately. It depicts that though there was a significant improvement in the PaO₂/FiO₂ among non-survivors pre- and post-PPV, there was no significant improvement in the DP (Table 3). Among the survivors, however, there was a significant improvement in both the parameters DP and PaO₂/FiO₂ post-PPV as compared to pre-PPV (Table 3).

Univariate and multivariate logistic regression was performed to determine if it was the change in PaO₂/FiO₂ or the change in DP that was the most reliable predictor of mortality. The DP and PaO₂/FiO₂ values pre, during, and post-PPV as predictors of mortality showed that it was the DP post-PPV that was the best predictor of mortality [OR 3.24, 95% CI (1.033–10.158), p-value < 0.001] (Table 4).

The ROC curve plotted for DP after PPV as a predictor of mortality (Fig. 1) showed that post-PPV DP >16 cmH₂O was a reliable predictor of mortality, AUC 0.939, 95% CI (0.868–0.999) with sensitivity and specificity as 90 and 82%, respectively. Among the patients who had high DP ≥ 16 cmH₂O after the last prone session, 87% expired, whereas for those who had DP <16 cmH₂O, only 13% expired ([p < 0.001], Chi-square test’ Phi and Cramer V strength of association is 0.644) indicating a very strong association between post-PPV DP >16 cmH₂O and mortality.

Comparison of Kaplan–Meier survival function (Fig. 2) between patients with DP <16 cmH₂O and DP ≥16 cmH₂O post-PPV session was significantly different with Log–rank (Mantel–Cox) p < 0. 001. The mean survival times with DP post-PPV <16 cmH₂O was 29.96 days with 95% CI (23.34–36.57), whereas it was significantly lesser at 12.11 with 95% CI (7.18–17.05) in those with DP ≥ 16 cmH₂O post-PPV session. Cox proportional model comparing the mortality outcomes between patients with DP post-PPV <16 cmH₂O vs DP post-PPV ≥16 cmH₂O showed HR of 6.583 (p < 0.001, 95% CI [2.271–19.082]).

Figure 3 depicts the values of post-PV of DPs among the survivors and non-survivors. A majority of patients who had expired had post-PPV DP >16 cmH₂O. DP, driving pressure; PPV, prone position ventilation

DISCUSSION

One of the criteria for cessation of PPV in PROSEVA trial was based on the improvement in oxygenation (PaO₂/FiO₂) ratio.¹⁵ However, the PaO₂/FiO₂ has been shown to be an imprecise predictor of mortality in ARDS.¹⁶ The AUC of oxygenation to predict mortality in ARDS is just 0.577. Recently, it has been shown that it is not the PaO₂/FiO₂ but rather the incorporation of PEEP in this ratio, which is a much better predictor of mortality, and more so in moderate-severe ARDS.¹⁷

Amato et al. proved that DP is an independent predictor of survival among the ventilator and oxygenation parameters in ARDS patients.⁸ Subsequently, it has been said that DP <15 cmH₂O should prompt clinicians to continue the same ventilator strategy. However, a DP ≥15 cmH₂O should prompt modifications in ventilator strategies as it indicated worsening C_RS.¹⁸

Despite this evidence, we tend to target PaO₂/FiO₂ to decide whether or not moderate-severe ARDS patients need initiation and cessation of PPV, rather than DP.¹⁵ To date, no safe limit of DP has been suggested during PPV strategies, regarding when the further requirement of PPV will be necessitated or considered unnecessary.¹⁹ We found that it is not PaO₂/FiO₂ improvement after PPV sessions, but rather the significant reduction in DP which is the independent predictor of survival in moderate-severe ARDS. Among the values of PaO₂/FiO₂ and DP pre, during, and post-PPV, it is DP ≥ 16 cmH₂O after the last session of PPV which is the independent predictor of mortality in moderate-severe ARDS receiving PPV.

The findings of our study are congruent with the recommendations by Bugedo et al. and Fanelli et al., where the authors recommend a DP < 15 cmH₂O as a possible target while optimizing ventilator strategies in moderate-severe ARDS patients.^18–20

The findings of our study that DP ≥ 16 cmH₂O despite PPV predicts poor outcomes may be due to the fact that a higher DP not only reflects poor C_RS, but also promotes pathophysiological alterations like right ventricular failure and cor pulmonale, ventilator-induced pulmonary hypertension, rise in pulmonary vascular permeability, pulmonary epithelial cell apoptosis, ferroptosis, rise in inflammatory mediators like interleukin-6 (IL-6), and tumor necrosis factor – alpha (TNF-α).^21,22 The cascade of all these pathophysiological process is hastened by high DP, and may be the reason why high DP may be a predictor of mortality.²³

The DP reflects both cyclical strain and stress to which the alveoli are exposed during each ventilator cycle, actually consists of two distinct pressures, the transpulmonary pressure, and the pressure applied to the chest wall as well.²⁴ It is one of the important variables included in calculation of mechanical power (MP) of the ventilator.¹⁸ Thus, the importance of DP has been well validated. However, two aspects were not investigated. First, it was unclear at which time point, before, during, or post-PPV session should the DP value be considered a predictor of outcomes. Secondly, whether clinicians should seek to look at the improvement in oxygenation or reduction in DP for determining the success of PPV, and thereby survival outcomes or further alternative treatment modalities along with PPV, like extracorporeal membrane oxygenation (ECMO). We determined that a DP ≥ 16 cmH₂O post-PPV predicted mortality and not PaO₂/FiO₂ post-PPV. Higher DP is harmful even for shorter durations, the importance of determination of a DP cut-off for initiation of venovenous ECMO among non-responders of PPV has to be investigated.^25,26

Though the initial mean PaO₂/FiO₂ of patients in our study in both survivors and non-survivors before PPV initiation was quite similar (92 vs 88), there was a difference between the initial DP (16 vs 19 cmH₂O). However, even during and post-PPV sessions, the DP did not reduce among the non-survivors. This meant that the lung had more non-recruitable areas which could not be recruited even during proning sessions. Thus, a lack of decrease in DP even during and post-PPV could indicate the futility or non-responders of PPV maneuver. This is significant in light of the fact that PPV also has its own complications like, pressure ulcers, bleeding from oro-nasal sites and accidental extubations.²⁷ Thus, clinicians should be aware of PPV non-responders and avoid complications and futility of PPV in those patients. Rather, much more novel therapeutics like ECMO during PPV may be contemplated in such patients rather than repeated PPV sessions, without any reduction in DP.²⁸ Early PPV after even initiation of ECMO has been shown to improve survival.²⁹ Thus, in the light of the findings of our study, sole PPV non-responders as depicted by no reduction in DP may be administered different strategies to improve survival outcomes.

During ECMO, low V_T <4 mL/Kg ideal body weight as ultra-protective ventilation reduces VILI.³⁰ This shows than reduction dynamic cyclical alveolar overdistension of non-recruitable alveoli, which is mechanistically related to DP reduction, definitely has beneficial outcomes in VILI reduction.

Prone position ventilation is inexpensive and readily available maneuver that has proven to have better outcome in patients with ARDS by improving the ventilation perfusion mismatch, reducing the risk of VILI and improving the lung mechanics.^15,31

The reduction of DP from pre- to post-PPV was found to be approximately –3 cmH₂O in survivors. In non-survivors, the DP from pre- to post-PPV remained same without any reduction. This implies that the response to PPV is due to the resultant of improved C_RS. Our findings are consistent with the findings by Van Meenen et al. where they studied pre- and post-PPV effects of DP, PaO₂/FiO₂, and dead space and found that the changes in only DP were significant to predict outcomes in ARDS.³² This study was done only during the first PPV session unlike ours, and the DP during the PPV session was not analyzed. The AUC for DP to predict mortality was also low (0.63). Prior, few studies that compared pre- and post-PaO₂/FiO₂ values in PPV did not find prognostic significance of PaO₂/FiO₂. They found that the PaO₂/FiO₂ improvement was significant between responders and non-responders which was concurrent with our findings.^12–14 Guerin et al. concluded that though PPV improves oxygenation and ventilation and reduces mortality, there was no association between them.^7,33 This infers that the better prognosis in ARDS patients receiving PPV is due to the ability of PPV to reduce VILI.^34,35

Certain strengths of our study included a very homogeneous population of patients with only moderate-severe ARDS who received PPV, in whom lung compliance and mechanics matter the most. We could conclusively prove that the DP post-PPV (as compared to the PaO₂/FiO₂ ratios at any time point or DP at prior time points) is an independent predictor of mortality in moderate-severe ARDS.

This study limitations are that it was single centered with a smaller sample size. We did not assess right ventricular function, which could have worsened in patients with higher DP, and could have been a factor contributing to the mortality. Being an observational study, not all the patients underwent an equal number of PPV sessions.

CONCLUSION

Driving pressure is a better discriminant of survival among moderate-severe ARDS patients on PPV, as compared to oxygenation. Moderate-severe ARDS patients with post-PPV session DP ≥16 cmH₂O have a HR of 6.5 times for mortality as compared to those with DP <16 cmH₂O. In future, multicenter study with large sample size with DP along with MP is required to confirm the findings of this study.

ORCID

Pratibha Todur https://orcid.org/0000-0003-0967-2252

Anitha Nileshwar https://orcid.org/0000-0002-4556-1851

Souvik Chaudhuri https://orcid.org/0000-0001-8392-2366

Vishal Shanbhag https://orcid.org/0000-0001-5255-6148

Celine Cherisma https://orcid.org/0009-0005-5926-7046

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