Physiological loads | COVID-induced physiological changes | Ventilatory drive modulation |
Hypoxemia | In early infection, arterial hypoxemia is primarily caused by V/Q mismatches and increases in P(A-a)O2 gradients. As a result of local interstitial edema, acute inflammation, endothelial injury, and intrapulmonary shunting, oxygen diffusion is decreased [20] . | In mild hypoxemia (PaO2 between 60 - 70 mmHg), the respiratory drive is typically unaffected, often presenting as “happy hypoxemia” without dyspnea. Due to hypoxemia worsening as PaO2 decreases, respiratory drive increases gradually. |
Hypercapnia and acidosis | Peripheral chemoreceptors sense changes in arterial blood directly, while central chemoreceptors sense changes in chronic hypercapnia through the pH of CSF [1] . | Respiratory rate and arterial pCO2 have inverse associations [81] . |
Intrapulmonary shunting and V/Q mismatching | Dead space can be caused by thrombosis in hypercoagulable states (an elevated level of D-dimer, fibrinogen, or interleukin-6 markers) [82] . | The ratio of dead space to tidal volume (VD/VT) may cause endothelial injury and microvascular coagulation [30] [83] . |
Decreased respiratory compliance | An index of rapid shallow breathing (Respiratory rate divided by tidal volume). Ventilatory demand may not be met by excessive drive [84] . | When drive increases, respiratory rate increases, resulting in a decrease in respiratory time. |
Anemia | An infection with this virus can result in a greater production of immature RBCs, followed by their release into the bloodstream and a consequent drop in Hb levels [85] . | A greater respiratory drive is induced when hypoxemia occurs due to chemoreceptor sensitivity to PaCO2. |
Impairment in respiratory muscle strength (muscle fatigue) | The reduction of forced vital capacity (FVC) and lung diffusing capacity in survivors of COVID-19 [5] . | Resulting in a reduced tidal volume and an increased work of breathing due to neuromechanical dissociation. |
Pulmonary vasoconstriction | Hypertension is etiologically linked to RAAS dysfunction. The cellular receptor for COVID-19 is ACE2. ACE converts angiotensin I into Ang II and degrades bradykinin. When ACE2 levels are low, RAAS is activated, resulting in pulmonary vasoconstriction [86] . | ACE2 plays a role in neuroinvasion, as it is expressed in the brain on neurons and glial cells, particularly in the brainstem, in the paraventricular nucleus, and in the rostral ventrolateral medulla [7] . The drive may be blunted. |
Decreased diffusion capacity and rise in P(A–a) O2 gradient | An infection results in moderate interstitial edema and surfactant loss. Alveolar collapse results in intrapulmonary shunting, resulting in non-aerated alveoli being perfused [32] [87] . | Carotid body chemoreceptors are stimulated by low PO2 resulting in increased drive |
Shift in oxygen dissociation curve or increased P50 values | An oxygen dissociation curve shift caused by fever may result in lower arterial oxygen saturation levels. | Silent hypoxemia is believed to occur due to this phenomenon, combined with the carotid bodies’ response to decreased PaO2 rather than SaO2 [18] . |
Autonomic dysfunction | The neuro-vagal anti-inflammatory reflex may be impaired by hypoxemia-induced reductions in parasympathetic activity and sympatho-excitation. There is a possibility that this impairment could contribute to the emergence of a cytokine storm [4] . | Tachypnea may be caused by pro-inflammatory cytokines in the brainstem [57] . |