The prognostic value of early measures of the ventilatory ratio in the ARDS ROSE trial

Abstract

Background: The ventilatory ratio (VR, [minute ventilation × PaCO₂]/[predicted body weight × 100 × 37.5]) is associated with mortality in ARDS. The aims of this study were to test whether baseline disease severity or neuromuscular blockade (NMB) modified the relationship between VR and mortality.

Methods: This was a post hoc analysis of the PETAL-ROSE trial, which randomized moderate-to-severe ARDS patients to NMB or control. Survival among patients with different VR trajectories or VR cutoff above and below the median was assessed by Kaplan-Meier analysis. The relationships between single-day or 48-h VR trajectories with 28- or 90-day mortality were tested by logistic regression. Randomization allocation to NMB and markers of disease severity were tested as confounders by multivariable regression and interaction term analyses.

Results: Patients with worsening VR trajectories had significantly lower survival compared to those with improving VR (n = 602, p < 0.05). Patients with VR > 2 (median) at day 1 had a significantly lower 90-day survival compared to patients with VR ≤ 2 (HR 1.36, 95% CI 1.10-1.69). VR at day 1 was significantly associated with 28-day mortality (OR = 1.40, 95% CI 1.15-1.72). There was no interaction between NMB and VR for 28-day mortality. APACHE-III had a significant interaction with VR at baseline for the outcome of 28-day mortality, such that the relationship between VR and mortality was stronger among patients with lower APACHE-III. There was a significant association between rising VR trajectory and mortality that was independent of NMB, baseline PaO₂/FiO₂ ratio and generalized markers of disease severity (Adjusted OR 1.81, 95% CI 1.28-2.84 for 28-day and OR 2.07 95% CI 1.41-3.10 for 90-day mortality). APACHE-III and NMB were not effect modifiers in the relationship between VR trajectory and mortality.

Conclusions: Elevated baseline and day 1 VR were associated with higher 28-day mortality. The relationship between baseline VR and mortality was stronger among patients with lower APACHE-III. APACHE-III was not an effect modifier for the relationship between VR trajectory and mortality, so that the VR trajectory may be optimally suited for prognostication and predictive enrichment. VR was not different between patients randomized to NMB or control, indicating that VR can be utilized without correcting for NMB.

Keywords: APACHE-III; ARDS; Neuromuscular blockade; ROSE trial; VR; Ventilatory ratio.

Fig. 1

Daily distribution of ventilatory ratio (VR) categorized by randomization control (0) or NMB (1). N for subgroups after censoring (control and NMB groups, respectively), 874 at baseline (434 and 440), 808 at day 1 (386 and 422), 693 at day 2 (325 and 368), 561 at day 3 (249 and 312), 487 at day 4 (220 and 267) and 307 at day 7 (144 and 163), p values per Wilcoxon rank sum test

Fig. 2

Daily distribution of ventilatory ratio (VR) categorized by 28-day survivor (0) or non-survivor (1). N for subgroups (survivor and non-survivor groups, respectively), 874 at baseline (5658 and 309), 811 at day 1 (532 and 276), 693 at day 2 (459 and 234), 561 at day 3 (374 and 187), 487 at day 4 (325 and 162) and 307 at day 7 (203 and 104). p values, **p < 0.01, *p < 0.05, per Wilcoxon rank sum test

Fig. 3

Kaplan–Meier survival curves for patients with VR equal to or below 2 versus those with VR above 2. The outcome measured was 28-day survival. Left, 28-day survival for baseline VR values (n = 874, p < 0.1 (NS), log-rank test), Right, 28-day survival for day 1 VR. Values (n = 808, p < 0.01, log-rank test)

Fig. 4

Patients with improving (downtrending) VR trajectories within the first 2 days have higher probability of 90-day survival compared to patients with worsening (up trending) VR trajectories. Kaplan–Meier survival curve with VR trajectory tertiles as categories. Improving, slope of − 2.99 to − 0.18, unchanged, slope of − 0.18 to 0.13, worsening, slope of 0.13–1.91. (n = 602, p < 0.05 for improving versus worsening groups at 90 days by Cox proportional analysis, and p < 0.05 comparing all three groups at 90 days, log-rank test)