Researchers shed light on cause of 'happy hypoxia' in COVID-19 patients

While many severe cases of COVID-19 are characterised by respiratory distress and dangerously low blood oxygen levels — a condition called hypoxia — the phenomenon of “quiet or pleasant hypoxia” affecting a subset of patients has puzzled experts since the start of the pandemic.

Now, computational modeling research conducted at the New Jersey Institute of Technology (NJIT) is helping to uncover the elusive cause of “happy hypoxia” in COVID-19 patients, explaining why some individuals can experience severely decreased blood-oxygen saturation without the usual struggle to breathe.

The findings, published in the journal, stated that biological cybernetics, The researchers suggest that elevated hemoglobin levels in the blood of some patients may play an important role in enabling the respiratory system to maintain low oxygen levels without producing distress signals associated with dyspnea or shortness of breath.

“Mathematical modeling of the respiratory control system allows us to explore hypotheses about how changes in chemosensory input affect the generation of breathing rhythms,” said Casey Diekman, M.D., corresponding author of the study and associate professor of mathematics at NJIT. “We focused on imbalances in oxygen sensing as a key contributor to silent hypoxemia.”

To find out more, Diekman teamed up with Christopher Wilson of Loma Linda School of Medicine and Peter Thomas of Case Western Reserve University. The team adapted a mathematical model first developed by Diekman in 2017, described as a “closed-loop control system,” to simulate the effects of silent hypoxemia on the respiratory system.

Diekman explained that this model is a system of ordinary differential equations that represents the electrical activity of the respiratory central pattern generator (CPG) in the brain stem, which drives a group of motor neurons, resulting in changes in lung volume, oxygen in the lungs, and oxygen in the blood.

“In turn, blood oxygen levels influence the amount of excitatory input sent to the CPG via a chemosensory feedback pathway,” Diekman said. “The model includes parameters that reflect the oxygen sensing input pathway, hemoglobin binding affinity, unloaded lung volume, and the speed of oxygen flow from the lungs to the blood.”

This closed-loop control model enabled the researchers to systematically investigate how different aspects of the system affect the partial pressure of oxygen in the blood and the point at which the respiratory system collapses when metabolic demands increase. Using their model, the team manipulated various parameters, ultimately identifying hematocrit – the concentration of hemoglobin in the bloodstream – as a key factor in inducing silent hypoxemia.

“Our study suggests that COVID-19 patients with silent hypoxemia may also have elevated levels of hemoglobin in their blood, which may be a protective response to infection,” said study co-author Wilson.

“We know that increased levels of hemoglobin in populations living at high altitudes are part of the body's effort to maintain adequate oxygen supply to the muscles, organs and brain, even though there is less oxygen in the air at high altitudes,” Thomas said. “When the effects of COVID-19 make it more difficult to extract oxygen from the air and deliver it to tissues, even at sea level, it may be that raising hemoglobin levels provides a similar benefit.”

For now, the team says emergency rooms should start measuring hematocrit levels for COVID-19 patients to improve patient outcomes.

“Unfortunately, most emergency rooms do not record their patients' hemoglobin levels, although it wouldn't be too difficult to do so,” Diekman said.

“We would love to see emergency rooms treating COVID-19 patients collect data on hematocrit levels,” Thomas said. “This could tell us more about how patients are adapting to the effects of the infection.”

Going forward, the researchers also hope that their findings will spur further development of respiratory control models.

“In this study, we used a relatively simple model of the respiratory pacemaker to facilitate mathematical analysis of the system. Our results motivate the inclusion of oxygen handling dynamics in more detailed state-of-the-art models of respiratory control, most of which focus on hypercapnia — excessive carbon dioxide — rather than hypoxia,” Diekman said.