Mild‐to‐Moderate Chronic Hypercapnia Impairs Adaptation of Acute CO2/H+ Chemosensitivity but Not Steady‐State Ventilation

Abstract

CO2 retention (hypercapnia, CH) presents in a number of etiologies including sedative use, chronic lung disease, and central/peripheral neuromuscular disorders. Acute‐on‐chronic hypercapnia can develop in these disorders during times of acute stress (i.e., infection and postoperative states). Recurrent acute‐on‐chronic CH may lead to respiratory failure and transient, life‐threatening worsening of the hypercapnia. We previously established in awake goats that exposure to mild CH (PaCO2 ~55mmHg) elicits changes across multiple physiologic systems but does not impair the response to acute increases in inspired CO2(InCO2).Herein, we test the hypothesis that progressive exposure from mild‐to‐moderate CH (~55‐to‐65mmHg CO2) results in secondary adaptations across several physiologic systems but increases the risk of pathological responses during acute‐on‐chronic exacerbations. Utilizing our established large animal model of CH, female goats (n=7) were exposed to 7 days (d) of 6% InCO2 followed by 7d of 8% InCO2. Throughout the protocol, we regularly assessed steady‐state cardiorespiratory function (i.e., VI, f, VT, HR, and BP) and acute CO2/H+ chemosensitivity. During 6% InCO2, the temporal pattern of physiologic adaptations was consistent with that previously reported (J. Physiol. 2018). As expected, increasing steady‐state (SS) InCO2 resulted in a sustained 10 mmHg increase in PaCO2 and an increase in arterial [H+] that decreased over the 7d at 6%. During 6% InCO2 there was a transient decrease (6%‐Day 2) in acute chemosensitivity (DVI/DCO2) that returned to control values by Day 5 at 6%. Upon increasing SS InCO2from 6% to 8%, minute ventilation (VI) increased from 23±3.4L/min on Day 7 at 6% InCO2 to 34±2.2L/min on Day 1 at 8% InCO2,which was primarily driven by an increase in breathing frequency. By 24h at 8% InCO2, VIhad declined from the 8%‐Day 1 values and remained at or near that level thereafter. This temporal pattern of adaptation is comparable to that observed during 6% CO2. A similar pattern of adaptation in [H+] occurred during 8% as occurred at 6%, while [HCO3‐] continually increased. PaCO2remained elevated throughout the 8% InCO2 exposure, compared to 6% InCO2. Finally, when SS InCO2 was increased to 8% the acute chemoreflex remained suppressed throughout the 7d. Our results suggest that progressive worsening of chronic hypercapnia results in similar SS adaptations compared to initial hypercapnic exposure. However, more severe levels of CH, such as 8% InCO2, perturb the acute chemoreflex, creating a risk for consequences such as CO2 narcosis and cardiorespiratory failure in patients with pre‐existing CH.