The mystery of the pandemic's ‘happy hypoxia’
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1 May 2020
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- Jennifer Couzin-Frankel
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RE: Happy Hypoxia does not defy basic biology
The phenomenon of so called "Happy Hypoxia" does not defy basic biology. Breathing is regulated by a number of factors. The most powerful is the blood level of CO2, which is continuously sensed by receptors in the central nervous system. If blood CO2 increases, so do breathing efforts (in amplitude and frequency) to get rid of the excess CO2. When CO2 levels decrease, breathing efforts decrease too. The oxygen level is also sensed so that if O2 blood levels decrease (hypoxia) breathing increases to improve arterial oxygen. However, the response is much more powerful in response to changes in CO2 than to changes in O2. Several years ago we demonstrated that if CO2 levels are brought down, the inhibitory effect on the respiratory centers may be so powerful that breathing essentially ceases even if at the same time oxygen levels fall. We used noninvasive assisted ventilation in normal subjects to gradually decrease CO2 levels while spontaneous breathing efforts stopped. Once a steady state of low CO2 was obtained and maintained, we decreased the inspired level of oxygen in order to achieve low saturations (down to 64%). These normal subjects reacted at some point to hypoxia by activating their inspiratory muscles to increase respiratory volume. However, when CO2 was brought down below 30 mmHg (normal is 40 mmHg), no reaction was obtained. Thus, hypocapnia (low CO2) inhibits breathing efforts even at the price of allowing very low oxygen levels (Jounieaux et al. Effects of Hypocapnic Hyperventilation on the Response to Hypoxia in Normal Subjects Receiving Intermittent Positive-Pressure Ventilation, Chest 2002; 121: 1141-1148). We believe patients with SARS-CoV-2 infection become hypoxic, increase breathing efforts, and since CO2 is much more diffusible than O2, they get rid of large quantities of CO2, i.e. they become hypocapnic. Once they are hypocapnic, they decrease breathing efforts (at the price of accepting hypoxia) and they do not feel the intense need to breathe that characterizes dyspnea. They have thus worrying and dangerous levels of oxygen saturation but feel comfortable and unusually at ease. This is something doctors have seldom seen. We also believe, based on patient observations, that the initial hypoxia may be due not only to COVID-19 pneumonia but also to the appearance of a shunt (wasted blood in pulmonary veins flowing directly to the pulmonary artery without having been depleted of CO2 and replenished with O2 in the tiny pulmonary capillaries) as we have recently suggested (Mahjoub Y, Rodenstein DO, Jounieaux V. Severe Covid-19 disease: rather AVDS than ARDS?, Critical Care in press).
RE: COVID-19, on the edge of hypoxia
During this unprecedented global pandemic of coronavirus disease 2019 (COVID-19), an increasing number of health care workers are facing the uncommon phenomenon of "happy hypoxia", "silent hypoxia" or "silent hypoxemia".
At the initial stage of the COVID-19 outbreak, Dr. Haibo Qiu was dispatched to Wuhan, Hubei province by the National Health Commission of China. He noticed that some patients tolerated well the extremely low levels of blood oxygen content, specifically, a saturation of oxygen (SaO2) 70 - 80% and partial pressure of oxygen (PaO2) 30-40 mmHg. However, some patients' condition deteriorated in an avalanche fashion once it's triggered by mild-to-moderate physical activities such as getting off the bed, excessive cough, or strain during urination or bowel, etc. The tolerance of hypoxia could be evaluated by six minutes walking test. Three patients with COVID-19 without oxygenation therapy were evaluated with 6 minutes walking and two minutes rest in their 6 meters wards. We found the SpO2 decreased, and pulse rate increased during the patients' walking, and they were back to baseline after two minutes rest. No patient complained of respiratory distress in the test. They were silent hypoxemia when they walk. Dr. Qiu has mentioned the risk of "silent hypoxemia" and emphasized the critical role of SpO2 monitoring. And this concept has been well acknowledged nationally since his interview with China Central Television (video available at http://tv.cctv.com/2020/02/29/VIDE9zvJlgkmn7XDPw4cxuAP200229.shtml).
Although the underlying mechanisms responsible for "happy" or "silent" breathing remain unknown. Based on the observation of unmatched hypoxemia and hypercapnia, there are two potential mechanisms, firstly, COVID-19 induced lung injury is inhomogeneity, alveolar collapse in injured lung tissues and alveolar hyperinflation in normal lung tissues lead to V/Q mismatch and dead space increase, secondly, It was recently reported in up to 40% of hospitalized COVID-19 patients, reports of increased respiratory dead space suggest lung-vascular thrombosis from thrombotic microangiopathy or pulmonary embolism. we strongly suspect that the two mechanisms are the main culprit for impaired blood-gas exchange in COVID-19. However, all of which lack the supporting data, especially from in vivo microimaging or autopsy.
RE: Pandemic's 'Happy Hypoxia' is no mystery
The "Happy Hypoxia" associated with COVID-19 that is a mystery to Drs. Caputo, Levitan and Strayer looks to this toxicologist like a typical case of chronic carbon monoxide (CO) poisoning.
CO cases are also reported in the literature to present with extremely low oxygen saturation and hyperventilation. Here is a collection of PubMed references I compiled on the topic:
All the other symptoms of COVID-19 reported to date are also in the CO literature , as documented in this review posted on 3/30.
The CO exposure poisoning of people with COVID-19 is not from exogenous inhaled sources, however, which most doctors are familiar with, but from CO released by the natural catabolism of heme proteins by heme oygenase-1.
This process occurs throughout the body but particularly in the lining of blood vessels. It releases equimolar concentrations of CO, iron and biliverdin plus 3 molecules of water, which causes local edema. The iron and biliverdin go to ferritin and bilirubin, which many studies report are both higher than normal in COVID-19 cases, while hemoglobin is lower. So we can infer that CO is high as well even though not yet measured (or at least not yet reported) in any COVID-19 study.
The endogenous CO produced in response to respiratory infections of all kinds is considered protective by those who study this, which is consistent with the lower than expected rates of smokers reported among people hospitalized for COVID-19 in China, France and USA. CO is so protective that a multi-center team published a successful Phase 1 trial of using inhaled CO to treat ARDS in 2018
But the gradual buildup of CO in lungs as infection worsens is not all beneficial. It also causes flu-like symptoms of fatigue, chest pain, shortness of breath, cough, nauseau and vomiting.
If this CO diffuses through blood plasma into other organs beyond lungs--which oxygen therapy makes worse--it outcompetes oxygen for binding sites on cytochromes, myoglobin, neuroglobin and other heme proteins. This causes a gradual decline in oxygen that eventually results in acutely hypoxic organ failure, targeting heart and kidney primarily because they have highest concentrations cytochrome oxidase.
This CO buildup is so gradual over 1 to 2 weeks most people habituate to their declining oxygen level much like mountain climbers can gradually habituate to low oxygen at altitude. They both adapt physiologically by becoming polycythemic which thickens their blood and leaves them at higher risk of stroke and cardiac arrest.
I believe clinicians would have detected this CO poisoning a lot sooner if they had not been relying on pulse oximetry to monitor oxygen saturation. The SpO2 these devices display is always wrong since it is not actually a measure of oxygen but of all bound hemoglobin, including Hb bound with CO as COHb and NO as MetHb.
This does not make much difference when COHb+MetHb are <2% as they usually are, but COHb may be up to 87% before death intervenes, with oxygen correspondingly decreased. The only way to see this is by measuring CO directly via blood, breath or skin. The latter can be done with a finger clip or skin patch using a "pulse CO oximeter" that most hospitals already use in their operating rooms to monitor the buildup of CO that occurs during closed loop anesthesia. But these cost over $5000 (I have no financial interest).
COVID-19 patients can monitor the CO levels diffusing from their lungs, arteries, veins and average of all tissues at home using any professional detector that displays from 1ppm. Most cost <$200. The least expensive breath CO analyzer approved by US FDA is the iCO from COvita that retails for $69 (also no interest).
Bottom line for COVID-19 cases with CO-induced hyperventilation syndrome:
the optimal treatment is not oxygen or mechanical ventilation; just prone bed rest and rebreathing carbon dioxide via a brown paper bag or some more sustainable alternative, like breathing under a T-shirt with the collar pulled up over your nose.
For more passive rebreather options, see https://www.youtube.com/watch?v=iQP3ydpJ0F8Author has a US patent for a method of measuring CO levels diffusing from lungs, arteries, veins, and the average of all tissues. It is not licensed and he derives no income from it.
RE: Moderate hypoxia: Bad for the doctor, but could it be "happy" for the patient?
I read the article with great interest. The author draws our attention to the dissonance of blood oxygen saturation and the clinical picture of COVID-19. She gives examples of ambiguous interpretations by professionals of low values of saturation of blood oxygen. Understanding the mechanisms of this phenomenon is very important for the selection of optimal therapy. I would like to draw attention to one of the possible explanations of the phenomenon of low saturation. A low value of this indicator is observed not only with CJVID-19, but also with a number of diseases and physiological conditions. In particular, it is observed with myocardial infarction with symptoms of heart failure. However, even with high saturation rates, life-threatening complications of myocardial infarction may develop. This suggests that moderate hypoxia can have not only pathological significance, but also be a manifestation of an adaptive reaction. The consequence of this would be the recommendation of a comprehensive assessment of the clinical picture of the patient. In the future, this can help with the choice of oxygen support tactics with limited use of mechanical ventilation.