Pulmonary Angiopathy in Severe COVID-19: Physiological Conclusions Derived from Ventilatory Ratio?

To the Editor:

We read with interest the article by Patel and colleagues (1) in which they describe imaging, functional, and hematological aspects in 39 patients with acute respiratory distress syndrome due to coronavirus disease (COVID-19). As the authors describe, ventilatory ratio (VR) was calculated in two opportunities, once at admission and once after computed tomographic scan, and it was increased in both. From that, they draw a conclusion about the presence of increased physiological respiratory dead space (Vdphys/Vt) based on a single surrogate parameter, the VR = ($\stackrel{.}{\mathrm{V}}$e × actual Pa_CO2)/(predicted $\stackrel{.}{\mathrm{V}}$e × predicted Pa_CO2), where $\stackrel{.}{\mathrm{V}}$e represents actual minute volume. VR includes assumptions in normalizing data and does not consider CO₂ production ($\stackrel{.}{\text{V}}$co₂) as a variable (2). Furthermore, VR was introduced as a simple bedside method to estimate efficiency of ventilation but not as a means to measure Vdphys/Vt (2). Moreover, VR has not been validated under extracorporeal membrane oxygenation (ECMO) conditions (44% of patients at admission), so because of these reasons, those assumptions lessen support to their conclusion.

Important adjustments are included in the VR formula, where Pa_CO2 is controlled by the physician on the mechanical ventilator, and it excludes $\stackrel{.}{\text{V}}$co₂. So, if a patient suffers changes in his inflammatory behavior, or in his spontaneous ventilatory efforts, the independent variable $\stackrel{.}{\text{V}}$co₂ will increase, but Pa_CO2 is controlled on the ventilator and will remain constant. In this case, $\stackrel{.}{\mathrm{V}}$e and VR increase but do not properly represent Vdphys/Vt. Even more, in patients under ECMO, Pa_CO2 specifically depends on the airflow in the oxygenating machine, and to the best of our knowledge, VR index has not been validated under this condition.

The prognostic significance of Vdphys/Vt has been established in patients with acute respiratory distress syndrome, and the best available index of Vdphys/Vt is the Enghoff equation: (Pa_CO2 – Pe_CO2)/Pa_CO2, in which mean expired partial pressure of CO₂ (Pe_CO2) corresponds to the ratio between $\stackrel{.}{\text{V}}$co₂ and $\stackrel{.}{\mathrm{V}}$e (3). With the increase of Vdphys/Vt, ventilation in nonperfused alveoli impairs CO₂ clearance (4).

Surrogate indices of Vdphys/Vt have commonly been used for patients on mechanical ventilation (MV) at first but not in ECMO. Concerning patients only supported on MV, surrogate indexes include $\stackrel{.}{\mathrm{V}}$e and arterial samples of Pco₂; nevertheless, they always exclude the uncontrolled $\stackrel{.}{\text{V}}$co₂ variable (2). From another point of view, $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂ specifically means ventilatory efficiency to clear CO₂ and depends on Vdphys/Vt. The $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂ ratio corresponds to the $\stackrel{.}{\mathrm{V}}$e used to achieve a certain Pa_CO2 level for a given $\stackrel{.}{\text{V}}$co₂ and is strongly related with Vdphys/Vt.

Under this rationale, in a previous study of our group, in 43 patients on MV without ECMO, we evaluated the performance of common surrogate parameters in relation to Vdphys/Vt, also including VR. Patients were sedated and in stable condition. We tested the correlation between Vdphys/Vt and the following variables: VR, (Pa_CO2 − Et_CO2)/Pa_CO2, Pa_CO2 − Et_CO2, and $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂, where Et_CO2 represents end-tidal CO₂.

Results demonstrated significant correlations between Vdphys/Vt and VR (r = 0.45), (Pa_CO2 − Et_CO2)/Pa_CO2 (r = 0.60), Pa_CO2 − Et_CO2 (r = 0.63), and $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂ (r = 0.88), respectively, highlighting that the best correlated of these indexes was $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂. Even more, $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂ was even better for patients with Pa_O2/Fi_O2 <200 (r = 0.91) and for patients with a Pa_CO2 >45 mm Hg (r = 0.96) (5).

Under controlled MV, Pa_CO2 tightly depends on the mechanical ventilator adjustments; thus, the $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂ ratio excludes the controlled variable Pa_CO2. By the other side, VR ignores the noncontrolled variable $\stackrel{.}{\text{V}}$co₂ but depends on it. From an operational point of view, on MV Vdphys/Vt is obtained by volumetric capnography and an arterial sample of blood gases, while VR is obtained by assumptions of $\stackrel{.}{\mathrm{V}}$e (based on predicted body weight) and Pa_CO2 and only an arterial sample of blood gases. In the measurement of $\stackrel{.}{\mathrm{V}}$e/$\stackrel{.}{\text{V}}$co₂, a volumetric capnography is needed (nowadays present in most mechanical ventilators), with online response and without the lag and intermittency of arterial samples (5). So, in consequence with the high correlation between $\stackrel{.}{\text{V}}$e/$\stackrel{.}{\text{V}}$co₂ and Vdphys/Vt, this ratio could improve the support of their conclusions only on patients with MV.