Impact of Decreasing Respiratory Rate While Tolerating Moderate Hypercapnia on Lung Injury Markers in Patients with Covid-19 Related Acute Respiratory Distress Syndrome

Abstract

Rationale: Acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia is associated with a high mortality rate. Protective ventilation strategies, by decreasing ventilator induced lung injury (VILI), have reduced mortality in patients with ARDS. However, the role of respiratory rate (RR), a central determinant of the energy applied to the lung parenchyma remains uncertain. Objective: To evaluate the role of respiratory rate on systemic pro-inflammatory mediators, as markers of VILI, in patients with Covid-19-associated ARDS (CARDS) Methods: Prospective, randomized crossover trial in patients with CARDS, PaO2:FIO2 ratio less than 200 mmHg, and requiring deep sedation and neuromuscular blockade. All patients were ventilated with a tidal volume of 6 ml/kg IBW, and PEEP and FiO2 according to the ARDSNet table. If PaO2:FIO2 ratio was less than 150 mmHg, patients were positioned in the prone position.Two 12 hours periods with a low RR and a high RR, randomly selected, was conducted. Low RR and high RR periods were set to obtain an 8-10 breaths/min difference between groups while maintaining pH and PaCO2 within recommended limits. I:E ratio was held constant during the study.Hemodynamic and respiratory mechanics were registered, and arterial blood samples drawn for gas exchange and quantification of inflammatory biomarkers at baseline and repeated at 12 and 24 hours. Results: We enrolled 11 patients (10 males, median age 54 [51-66] years, PaO2:FIO2 108 [86-132]), and all of them were in prone position. The low RR (20 [16-23]) vs the high RR (28 [26-32]) was associated with a significantly lower energy applied to the lung (16 [12-19] vs 23 [20-32] J / min, respectively). PaCO2 and pH were kept within the recommended limits (pH 7.30 [7.25-7.35] vs 7.46 [7.43-7.50];PaCO2 48 (45-63) vs 36 (32-38) mmHg for low and high RR, respectively). There were no significant changes in any of the respiratory mechanics parameters.The change in RR did not induce differences in any inflammatory marker (IL-6, IL-8, TNF-R1) or in the markers of epithelial (receptor for advanced glycation end products, s-RAGE;Surfactant protein D, SP-D), endothelial damage (Angiopoietin-2) or the marker of profibrotic activity (transforming growth factor β, TGF-β) (table 1). Conclusion: These preliminary results reveal that a decrease in respiratory rate, tolerating moderate hypercapnia, does not modify the biomarkers of lung damage compared to a strategy of high respiratory rate in patients with CARDS.