key: cord-0698395-ttoodtl4
authors: Somers, Virend K.; Kara, Tomas; Xie, Jiang
title: In Reply –Does Hypoxia Itself Beget Worsening Hypoxemia in COVID-19?
date: 2021-01-19
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2021.01.008
sha: deae734d6faf5504a73409256a08ad0ae1f02525
doc_id: 698395
cord_uid: ttoodtl4

nan

To the Editor: We appreciate the interest of Chan and Sharma in our Perspective proposing the early use of oxygen in patients with COVID-19 pneumonia.

First, in the setting of a global pandemic with widespread fatalities and severely limited therapeutic options, it is important to consider all possible alternative therapies. Here it is relevant that four potential pharmacologic interventions tested on hospitalized patients with COVID-19 in the WHO Solidarity Trial showed no evidence of improvement in mortality, initiation of ventilation or duration of hospitalization. 1 In this regard, other investigators have also proposed early oxygen therapy as a possible option for prevention of COVID-19 disease progression. 2 Second, Chan and Sharma place great emphasis on distinguishing between hypoxia and hypoxemia. In the context of tissue hypoxia possibly potentiating COVID-19 pathophysiology, this is a distinction without a difference. They belabor the point of how one should determine hypoxia -should we measure lactate or central venous oxygen saturation? This would certainly be an admirable exercise in more 'normal' academic environments. However, in less elevated settings, such as in the midst of overwhelming patient need as was initially experienced in Wuhan 3 and is more recently ongoing in the Czech Republic and elsewhere, we suggest a very simple approach -if the oxygen saturation is low or falling, then proceed as if the patient has tissue hypoxia. Regarding target oxygen levels, this awaits the conduct of pilot interventional proof-of principle J o u r n a l P r e -p r o o f studies, but we believe a goal oxygen saturation of ≥96% and even a range of 94 to 98% is very reasonable, especially in light of the comparative benefit of more aggressive oxygen supplementation in ARDS reported by Barrot et al. 4 Regarding hyperbaric therapy, Chan and Sharma misrepresent our stance, which more correctly stated is that "If aggressive oxygen supplementation is beneficial in more comprehensive health care settings, hyperbaric oxygen as a further step may possibly alleviate advanced cases of COVID-19-pneumonia." They cite studies in suggesting that hyperbaric oxygen may reduce lymphocyte proliferation, as an argument for its avoidance. Remarkably, they also cite work by Ackermann and colleagues 5 which reports widespread pulmonary lymphocytic inflammation with perivascular lymphocyte infiltration as a significant component of COVID-19 pulmonary pathophysiology. Chan and Sharma make no mention of this seeming disconnect in their logic. We further submit that potential exacerbation of inflammation by hypoxia 6 is a strong rationale for trying to prevent tissue hypoxia in COVID-19. Similarly, risks of aerosol spread with hyperbaric therapy are real, but are also present in COVID-19 patients treated with CPAP. ICU therapy of COVID-19 pneumonia is also "fraught with infection control issues", but certainly not a reason to shrink from therapy. In the very ill patient with no other recourse, one should at least consider an empirical and/or individualized case-bycase approach to the risks and benefits of less traditional therapeutic options.

Third, Chan and Sharma cite other viruses which may not proliferate in hypoxic conditions. It is certainly no surprise that biology is not uniform across organisms, and obvious that any effects of oxygen versus hypoxia on COVID-19 replication needs in vivo testing to more definitively answer this question. However the concept of oxygen Given their nuanced and critical analysis of our Perspective paper, we are bemused at their somewhat simplistic approach to understanding COVID-19 in conditions of altitude.

We strongly encourage them to consult the website of their own institution, National Jewish Health, under the section "Coronavirus: Information and Resources", subsection "COVID-19 (Coronavirus) and Altitude". 7 Here it is clearly explained that individuals who are acclimated to high altitude may actually be protected from severe effects of COVID-19 because of lower levels of ACE2 expression. By contrast, those who travel from low to high altitude are "at higher risk of severe complications from COVID-19, as they have higher levels of ACE2". We would argue that this 'hypoxic preconditioning' as possible protection against COVID-19 provides further support for the concept of hypoxia as a potential pathophysiologic mediator in COVID-19 disease. One of their colleagues in fact points out that COVID-19 patients at altitude need more aggressive oxygen therapy, and have been transferred to hospitals at lower elevation "to help the recovery process", presumably because of richer oxygen levels. The National Jewish Health website includes a link to a paper by Arias-Reyes and colleagues 8 proposing that "higher tissue oxygenation…could be explored for potential therapy for acute respiratory distress associated with COVID-19".

Finally, Chan and Sharma emphasize the adaptive benefits of hypoxic pulmonary vasoconstriction (HPV). While in conditions of regional reductions in partial pressure of oxygen, HPV is an adaptive mechanism that diverts perfusion to better ventilated areas of the lung, in acute diffuse inflammatory lung injury where alveolar hypoxia is widespread, such as "in ARDS, both HPV and pulmonary vascular damage can lead to pulmonary hypertension and right ventricular dysfunction." 9 In COVID-19 pneumonia, pulmonary hypertension may represent an important target for disease amelioration. 10 HPV may contribute significantly to the increased pulmonary vascular resistance due to the rapid progression of lung injury and hypoxia. However, whether the HPV response is amplified or attenuated in COVID-19 remains to be resolved. 9 Chan and Sharma further reference the interesting phenomenon of pulmonary vascular microthrombi in COVID-19 5 but seem incurious as to the important and compelling potential role for hypoxia in promoting thrombosis. 11, 12 Virend K Somers, MD, PhD Mayo Clinic, Rochester, Minnesota Tomas Kara, MD, PhD, Mayo Clinic, Rochester, Minnesota Brno Municipal Hospital, School of Medicine of Masaryk University, Masaryk , Czech Republic

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