In this pragmatic, observational open study of capnodynamic monitoring in mechanically ventilated patients with moderate to severe C-ARDS, an improved PaO2/FiO2 ratio in response to increased PEEP was associated with increased end-expiratory lung volume and pulmonary perfusion. The change in end-expiratory lung volume was positively correlated with the lung volume recruited and the recruitment-to-inflation ratio. In patients without an improvement in PaO2/FiO2 ratio, PEEP increased end-expiratory lung volume with a decrease lung perfusion consistent with increased dead space. This study demonstrates the feasibility of capnodynamic monitoring to assess physiological responses to PEEP at the bedside to facilitate an individualised setting of PEEP.
Patients were studied about a week after their COVID-19 diagnosis with the majority developing moderate ARDS. A majority of patients in this study improved the PaO2/FiO2 >20 mm Hg in response to increased PEEP. Compared to recent observational reports of PEEP interventions in C-ARDS, the Crs was similarly low [7, 22] or lower [6, 23, 24] with Pdr correspondingly higher. Patients in this study were class 2 obese with half having a body mass index above 35. This suggests that the prevalence and degree of obesity leading to an increased load on the chest wall should be considered together with the reduced lung compliance associated with C-ARDS. A lung protective ventilation strategy limiting airway pressures was employed including permissive hypercapnia. The associated moderate respiratory acidosis might have aggravated pulmonary vasoconstriction. The changes in EELVCO2 and EPBF in response to increased PEEP should be interpreted with those characteristics of the study cohort in mind.
The EELVCO2 at PEEPlow (mean PEEP 8 cm H2O) was overall similar to the range of end-expiratory lung volumes, 1000–1400 mL, at PEEP 5–8 cm H2O reported in C-ARDS [6, 7, 22, 24] and non-COVID ARDS [25] using chest computed tomography. The EPBF, that does not include shunt flow, was numerically consistent with a normal cardiac output reflecting the inclusion criterion of haemodynamic stability prior to study procedures. The increased PaO2/FiO2 in response to PEEPhigh was associated with increases in both EELVCO2 and EPBF and this positive correlation supports an improved ventilation/perfusion matching. The greater EELVCO2 is consistent with recruitment of previously non-aerated pulmonary tissue that is in line with the concomitant improvement in Crs and decrease in Pdr. Importantly, a reduced shunt fraction would result in an increased EPBF and this plausibly explains the observed response in gas exchange to PEEPhigh. A PEEPhigh induced decrease in cardiac output from the typical hyperdynamic haemodynamic state of C-ARDS [26, 27] would reduce the shunt fraction as would recruitment of previously perfused but not ventilated lung areas. The increase in EPBF could furthermore indicate a maintained or potentially increased cardiac output as PEEPhigh reduced pulmonary vascular resistance along with decreased atelectases. A previous study of C-ARDS patients who underwent pulmonary artery catheterisation reported an inverse relation between PaO2/FiO2 and shunt at both low (5 cm H2O) and high (15 cm H2O) PEEP levels without a significant reduction in cardiac output [28]. The improved ventilation/perfusion matching is also supported by the reduced dead space observed in responders. In contrast, patients without a significant improvement of PaO2/FiO2 in response to PEEPhigh demonstrated an increased EELVCO2 but decreased EPBF. This is consistent with overstretching the lungs, increased pulmonary vascular resistance and right ventricular strain that would reduce pulmonary perfusion. While these changes point to increased dead space, the numerical increase in Vd/Vt and the negative correlation between EELVCO2 and EPBF failed, however, to attain statistical significance.
The significant correlation between the change in EELVCO2 and the independently measured ∆Volrec in response to PEEP lends support to the validity of capnodynamic monitoring of lung volumes in C-ARDS. The correlation coefficient was similar to that reported between absolute EELVCO2 and functional residual capacity in a porcine experimental model [29] and superior to that previously reported in anaesthetised patients [14]. Since tidal volumes in this study were kept unchanged from PEEPlow to PEEPhigh, the increased EELVCO2 represents a true recruitment effect. In 6 patients the EELVCO2 failed to increase during PEEPhigh using a threshold of at least + 10% to consider random measurements error. This represents a lack of alveolar recruitment where additional PEEP contributes to increased lung stress without any benefit in gas exchange. The capacity of capnodynamic monitoring at the bedside to facilitate an individualised setting of PEEP warrants further clinical investigation to evaluate if it can contribute to minimising ventilator induced lung injury in C-ARDS and non-COVID ARDS [30].
Haemodynamic changes may affect EELVCO2 since CO2 kinetics are dependent on pulmonary blood flow. Experimental observations, however, demonstrate EELVCO2 and EPBF as independent factors in the capnodynamic equation [29] in a wide range of cardiac output states. Within this study three sets of observations were made for patients who progressed to veno-venous extracorporeal membrane oxygenation support (Additional File 1: Fig. 1). The EELVCO2 remained stable during variable pump flow and native pulmonary perfusion states that corroborates the potential to separately monitor EELVCO2 and EPBF by the capnodynamic algorithm.
The change in EELVCO2 was also significantly correlated to alveolar recruitment as indicated by the R/I ratio. The median R/I ratio of 1 was higher compared to other studies reporting a median around 0.7 [10, 31] and higher than the threshold of 0.5 previously used to differentiate poorly from highly recruitable patients in C-ARDS [23, 32] and non-COVID ARDS [19]. Recruitability in acute respiratory failure may be highly variable between patients and over time. In this study, a similar proportion (17/27; 63%) of patients would have been considered highly recruitable by an R/I ratio > 0.5 compared to what has been reported in patients intubated early after ICU admission [23] but higher than that in patients intubated late [32]. Most patients in this study demonstrated low compliance and high recruitability consistent with the high elastance (“H”) phenotype based on recruitability idiosyncratic to C-ARDS [33]. More recent studies have questioned this distinction and instead reported similar patterns in C-ARDS and non-COVID ARDS [34]. Irrespectively, capnodynamic monitoring allowed changes in functional lung volume to be continuously monitored during manoeuvres aimed at alveolar recruitment in C-ARDS.
This study has some important limitations. External validity might be limited by the relatively small sample size, non-consecutive enrolment dependent on availability of the clinical research team and a high proportion of responders to recruitment by increased PEEP. No standard comparators were included for EELVCO2 or EPBF since this pragmatic study was primarily designed to evaluate the feasibility of capnodynamic monitoring and validation studies have already been published [14, 29]. Levels of PEEP above the PEEPhigh might be considered for alveolar recruitment but were not investigated for effects on EELVCO2 and EPBF. The R/I ratio was not measured from the 15 to 5 cm H2O pressure drop as originally described [19] with less of a pressure difference achieved between PEEPhigh and PEEPlow. A formal assessment of airway opening pressure was not performed. Visual inspection, however, confirmed progressive, steep increases in both volume and pressure curves from the start of a breath.