'Silent' Presentation of Hypoxemia in COVID-19

Cardiovascular Response and Limitations During Profound Hypoxemia

Hypoxemia is well tolerated when compensated by cardiovascular responses (Figure 2). Cardiovascular adaptation is the key component of a suite of responses enabling humans to adapt to high altitude hypoxia, endure prolonged breath-hold dives, survive profound acute anemia (hemoglobin less than 5 g/100 ml^[47]) and endure other physiologic stressors.^[30] While biochemical adaptation to hypoxia is also important especially for long term adaptation,^[48,49] cardiovascular adaptation is both the component most strongly coupled to immediate clinical outcomes and the one most easily assessed by clinicians.

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Figure 2.

Cardiovascular compensation for mild (85 to 90% SaO₂), moderate (75 to 85% SaO₂), severe (50 to 75% SaO₂), and profound (<50% SaO₂) hypoxemia. Increased cardiac output, mainly mediated by increased heart rate, is the main cardiovascular response to hypoxemia, but is limited by age and cardiovascular disease. Mild to moderate hypoxemia causes increased cellular glycolysis, which generates 2,3 diphosphoglycerate and increases the P₅₀ of hemoglobin. Decreased tolerance of physical exertion or even normal activity is a sensitive indicator of the adequacy of early cardiovascular response to hypoxemia. Loss of consciousness becomes likely at saturations less than 50%. Failure of cardiovascular adaptation ultimately involves bradycardia, asystole, or pulseless electrical activity, with rapidly ensuing tissue injury and death. CO, cardiac output; HR, heart rate; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance.

The proximal cause of tissue injury in profound hypoxemia is failure of cardiovascular compensation, not hypoxia per se. A study in cats^[5] illustrates the critical importance of the circulation in predicting tissue injury during severe hypoxemia: when animals were experimentally exposed to 25 min of severe hypoxia (FIO₂ = 3.4%; PAO₂ = 17 mmHg) with adequate blood pressure (mean arterial blood pressure greater than 65 mmHg) not one animal suffered any end-organ injury. In contrast, 12 of 13 cats exposed to the same degree of hypoxemia but with reductions in mean arterial pressure to less than 45 mmHg for only 4 min developed a pattern of brain injury closely resembling that of humans surviving in a persistent vegetative state after cardiorespiratory arrest. Similarly, brain injury in hypoxemic primates only occurs when hypoxia causes low cardiac output.^[6]

Cardiovascular compensation underlies the preservation of cognitive function in well compensated profound hypoxemia. Cerebral blood flow increases during hypoxia, preserving cerebral oxygenation out of proportion to systemic hypoxemia^[50] and leaving most cognitive domains little effected by hypoxia.^[51] Other studies^[52] have reported intact executive and motor function and mild deficits in memory.

It is of critical importance for clinicians caring for COVID-19 patients to understand that, just as for respiratory system adaptation, cardiovascular compensatory responses are both variable^[53] and limited. The limits of cardiovascular compensation define increasing acidosis and impending cardiovascular collapse and death, as shown in Figure 2.

Normal compensated cardiovascular adaptation to acute hypoxemia involves increased cardiac output, mediated predominately by tachycardia, with only moderate augmentation of blood pressure. As with the breathing response to hypoxemia, this heart rate and blood pressure response to hypoxia vary enormously in healthy individuals.^[53] The heart rate response to hypoxemia parallels the ventilatory response, so that individuals who do not present with shortness of breath, may also present without significant tachycardia.^[54]

Cardiovascular compensation to hypoxemia also varies with age and coexisting disease. We expect that most younger patients with profound hypoxemia have normal or elevated cardiac output, which is one of the most important factors for tolerating hypoxemia. Aging is known to decrease sympathetic nervous system/cardiovascular responses to hypoxic stress, and thereby contribute to a decreased tolerance of hypoxia in older individuals.^[38,39,55] The highest mortality rate in COVID-19 has been reported among older patients^[12] who may be less capable of adequate cardiovascular compensation. Individuals with coexisting cardiovascular or pulmonary disease may be limited in the scope or tolerance of sympathetic nervous system activation by systemic hypoxia,^[56] resulting in elevated heart rate, and increases in pulmonary and systemic vascular resistance.

Deterioration in oxygen saturation and cardiovascular compensation can occur rapidly in hypoxemic patients, particularly in patients with profound shunt physiology. It is important to realize that deterioration in oxygenation most often is caused by a combination of factors. These factors include increasing shunt, reduced cardiac output, decreased ventilation, and gas exchange on the steep portion of the oxyhemoglobin dissociation curve. Low cardiac output also worsens pulmonary gas exchange because of decreased mixed venous PO₂,^[57] right shift of the oxyhemoglobin dissociation curve caused by acidosis, and decreased effectiveness of hypoxic/hypercapnic pulmonary vasoconstriction. In the presence of a fixed intrapulmonary shunt, a lower mixed-venous PO₂ will have a large effect on arterial saturation because of the shape of the oxyhemoglobin dissociation curve^[58] (Figure 1). Because alveolar gas exchange is on the steep portion of the oxyhemoglobin dissociation curve, small changes in cardiac output or alveolar PO ₂ result in large changes in oxygen saturation via this decrease in mixed venous PO ₂. Taken together, these effects explain the seemingly unpredictable precipitous changes in oxygenation that can occur in all severe pneumonias.