John Murphy, CEO The COVID-19 Long haul Foundation<\/p>\n\n\n\n
The available evidence supports three conclusions simultaneously<\/strong>:<\/p>\n\n\n\n There is, however, strong evidence that hospital mortality fell dramatically during 2020 even after adjustment for age, comorbidities and disease severity<\/strong>, while the use of invasive mechanical ventilation fell and use of noninvasive respiratory support, corticosteroids and remdesivir increased.<\/p>\n\n\n\n That is probably the most important finding.<\/p>\n\n\n\n A large U.S. analysis of 20,736 hospitalized COVID patients<\/strong> examined outcomes from March through November 2020.<\/p>\n\n\n\n The observed mortality was:<\/p>\n\n\n\n Thus, mortality fell from 19.1% to 10.8%<\/strong>, a reduction of approximately 43%<\/strong>.<\/p>\n\n\n\n More importantly, the investigators adjusted for:<\/p>\n\n\n\n The reduction remained statistically significant.<\/p>\n\n\n\n Compared with March\u2013April, adjusted odds of death were:<\/p>\n\n\n\n The authors concluded that changing patient characteristics did not fully explain the decline<\/strong>.<\/p>\n\n\n\n That is powerful evidence that something about clinical management and\/or the disease environment changed.<\/strong><\/p>\n\n\n\n The CDC’s COVID-NET surveillance system provides particularly useful evidence.<\/p>\n\n\n\n Among hospitalized U.S. adults:<\/p>\n\n\n\n March 2020:<\/strong> 37.8%<\/p>\n\n\n\n December 2020:<\/strong> 20.5%<\/p>\n\n\n\n March:<\/strong> 27.8%<\/p>\n\n\n\n December:<\/strong> 12.3%<\/p>\n\n\n\n March:<\/strong> 22.7%<\/p>\n\n\n\n December:<\/strong> 12.8%<\/p>\n\n\n\n At the same time, use of:<\/p>\n\n\n\n remdesivir:<\/strong> 1.7% \u2192 53.8%<\/p>\n\n\n\n systemic corticosteroids:<\/strong> 18.9% \u2192 74.2%<\/p>\n\n\n\n And noninvasive respiratory support increased.<\/p>\n\n\n\n This is an extremely important observation.<\/p>\n\n\n\n The medical profession did not simply stop treating COVID aggressively<\/strong>.<\/p>\n\n\n\n Rather, the treatment algorithm changed:<\/p>\n\n\n\n less invasive mechanical ventilation<\/strong><\/p>\n\n\n\n and<\/p>\n\n\n\n more noninvasive respiratory support + steroids + antiviral treatment + improved critical-care management.<\/strong><\/p>\n\n\n\n Here the scientific literature is genuinely conflicting.<\/p>\n\n\n\n One large U.S. study examined 7,597 COVID patients at 11 New York City municipal hospitals<\/strong> between March and December 2020.<\/p>\n\n\n\n After propensity-score matching, the investigators found:<\/p>\n\n\n\n intubation within 48 hours \u2192 HR 1.30 for mortality<\/strong><\/p>\n\n\n\n and<\/p>\n\n\n\n intubation at any time \u2192 HR 1.62<\/strong><\/p>\n\n\n\n compared with patients who were not intubated.<\/p>\n\n\n\n At first glance, that appears to support your hypothesis.<\/p>\n\n\n\n But there is a major limitation:<\/p>\n\n\n\n Patients who required intubation were substantially sicker.<\/p>\n\n\n\n Even sophisticated statistical adjustment cannot completely eliminate this problem.<\/p>\n\n\n\n Therefore:<\/p>\n\n\n\n Higher mortality among ventilated patients does not prove that ventilation caused the deaths.<\/strong><\/p>\n<\/blockquote>\n\n\n\n It demonstrates an association.<\/p>\n\n\n\n Researchers at Mount Sinai examined 755 mechanically ventilated patients<\/strong> admitted between January 30 and April 30, 2020.<\/p>\n\n\n\n Their median age was 65.<\/p>\n\n\n\n Among these ventilated patients:<\/p>\n\n\n\n 68% died<\/strong><\/p>\n\n\n\n by the end of follow-up.<\/p>\n\n\n\n But the study found something striking:<\/p>\n\n\n\n Each additional day between admission and intubation was associated with a 3% increase in the hazard of death.<\/strong><\/p>\n\n\n\n Adjusted HR:<\/p>\n\n\n\n 1.03 per additional day<\/strong><\/p>\n\n\n\n The authors therefore concluded that earlier rather than later intubation might improve survival<\/strong> in appropriately selected patients.<\/p>\n\n\n\n That is directly contrary to the simplistic claim that early intubation was inherently harmful.<\/p>\n\n\n\n A study involving 68 U.S. hospitals<\/strong> examined 1,879 critically ill adults admitted between March and July 2020.<\/p>\n\n\n\n They compared:<\/p>\n\n\n\n early invasive mechanical ventilation:<\/strong> ICU days 1\u20132<\/p>\n\n\n\n with<\/p>\n\n\n\n late ventilation:<\/strong> ICU days 3\u20137.<\/p>\n\n\n\n The raw mortality was:<\/p>\n\n\n\n Early:<\/strong> 42.2%<\/p>\n\n\n\n Late:<\/strong> 51.0%<\/p>\n\n\n\n After adjustment:<\/p>\n\n\n\n HR = 0.77<\/strong><\/p>\n\n\n\n 95% CI:<\/p>\n\n\n\n 0.65\u20130.93<\/strong><\/p>\n\n\n\n That means the adjusted mortality hazard was approximately 23% lower<\/strong> in the early-intubation group.<\/p>\n\n\n\n Again, this does not prove that early intubation is universally superior. But it directly contradicts the proposition that early ventilation was demonstrably responsible for the majority of early deaths.<\/p>\n\n\n\n Putting the major U.S. studies together:<\/p>\n\n\n\n The apparent contradiction is largely explained by differences in:<\/p>\n\n\n\n The Northwell Health study examined 1,966 mechanically ventilated patients<\/strong> during March and April 2020.<\/p>\n\n\n\n 1,198 died within 28 days \u2014 61%.<\/strong><\/p>\n\n\n\n That is an extraordinarily high mortality.<\/p>\n\n\n\n But this was the period of the greatest medical uncertainty and one of the largest hospital surges in the United States.<\/p>\n\n\n\n The study also compared traditional ICUs with expanded ICUs, created because conventional ICU capacity had been overwhelmed.<\/p>\n\n\n\n This is important because health-system strain itself can influence mortality.<\/strong><\/p>\n\n\n\n A patient treated by an experienced ICU team in a conventional ICU is not necessarily equivalent to an equally sick patient treated during a catastrophic surge in an improvised ICU.<\/p>\n\n\n\n The famous Mount Sinai\/New York Presbyterian case series involved 5,700 hospitalized patients<\/strong>.<\/p>\n\n\n\n At the time of analysis:<\/p>\n\n\n\n Among patients requiring mechanical ventilation, the early reported mortality appeared extraordinarily high.<\/p>\n\n\n\n But there was an enormous statistical problem:<\/p>\n\n\n\n many ventilated patients were still hospitalized.<\/strong><\/p>\n\n\n\n The April 2020 report showed:<\/p>\n\n\n\n Therefore, the early apparent mortality among ventilated patients substantially underestimated eventual survivors<\/strong> and could not be interpreted as a final case-fatality rate.<\/p>\n\n\n\n This is an important example of why some of the frightening early ventilator statistics were misleading.<\/p>\n\n\n\n There is nevertheless a legitimate physiological basis for your concern.<\/p>\n\n\n\n Mechanical ventilation can cause:<\/p>\n\n\n\n The appropriate strategy for COVID-associated ARDS consequently became lung-protective ventilation<\/strong>, using relatively low tidal volumes and limiting plateau pressures.<\/p>\n\n\n\n Clinical recommendations subsequently emphasized low-tidal-volume ventilation, appropriate PEEP, avoidance of routine recruitment maneuvers and prone positioning for appropriate patients.<\/p>\n\n\n\n So the proposition:<\/p>\n\n\n\n “Improper ventilation can contribute to death”<\/p>\n<\/blockquote>\n\n\n\n is medically well established.<\/p>\n\n\n\n The proposition:<\/p>\n\n\n\n “Most early COVID deaths were caused by improper ventilation”<\/p>\n<\/blockquote>\n\n\n\n is not established.<\/p>\n\n\n\n Those are very different claims.<\/p>\n\n\n\n The RECOVERY trial provides unusually strong evidence because it was randomized.<\/p>\n\n\n\n Among hospitalized patients receiving invasive mechanical ventilation:<\/p>\n\n\n\n 29.3% mortality<\/strong><\/p>\n\n\n\n versus<\/p>\n\n\n\n 41.4% mortality<\/strong><\/p>\n\n\n\n Rate ratio:<\/p>\n\n\n\n 0.64<\/strong><\/p>\n\n\n\n 95% CI:<\/p>\n\n\n\n 0.51\u20130.81<\/strong><\/p>\n\n\n\n That’s an approximately 36% relative reduction in mortality<\/strong> among mechanically ventilated patients.<\/p>\n\n\n\n The absolute difference was approximately:<\/p>\n\n\n\n 12.1 percentage points.<\/strong><\/p>\n\n\n\n That is a very large treatment effect.<\/p>\n\n\n\n Therefore, one explanation for the later reduction in COVID mortality is straightforward:<\/p>\n\n\n\n physicians learned how to treat the inflammatory phase of severe COVID more effectively.<\/strong><\/p>\n\n\n\n Dexamethasone was not beneficial at every stage of COVID<\/strong>.<\/p>\n\n\n\n Among patients receiving no respiratory support:<\/p>\n\n\n\n 17.8% died with dexamethasone<\/strong><\/p>\n\n\n\n versus<\/p>\n\n\n\n 14.0% with usual care.<\/strong><\/p>\n\n\n\n The difference was not statistically significant and trended in the wrong direction.<\/p>\n\n\n\n This is an important lesson.<\/p>\n\n\n\n The treatment that saved lives in severe COVID was not simply “give everyone steroids.”<\/p>\n\n\n\n It was:<\/p>\n\n\n\n give appropriate anti-inflammatory treatment to patients with clinically significant oxygen requirements.<\/strong><\/p>\n\n\n\n That is precisely the type of knowledge that was unavailable in March 2020.<\/p>\n\n\n\n A much larger study encompassing:<\/p>\n\n\n\n 104,590 hospitalized patients<\/strong><\/p>\n\n\n\n across<\/p>\n\n\n\n 21 U.S. health systems<\/strong><\/p>\n\n\n\n examined the first 20 months of the pandemic.<\/p>\n\n\n\n Risk-standardized mortality fell from:<\/p>\n\n\n\n 16.4% in February\u2013April 2020<\/strong><\/p>\n\n\n\n to<\/p>\n\n\n\n 9.0% in July\u2013September 2021.<\/strong><\/p>\n\n\n\n Unadjusted mortality fell from:<\/p>\n\n\n\n 18.6%<\/strong><\/p>\n\n\n\n to<\/p>\n\n\n\n 7.3%.<\/strong><\/p>\n\n\n\n That is approximately a:<\/p>\n\n\n\n 45% reduction in risk-standardized mortality.<\/strong><\/p>\n\n\n\n This occurred despite subsequent waves containing enormous numbers of hospitalized patients.<\/p>\n\n\n\n The same general pattern appears repeatedly:<\/p>\n\n\n\n early pandemic \u2192 more invasive ventilation<\/strong><\/p>\n\n\n\n later pandemic \u2192 less invasive ventilation<\/strong><\/p>\n\n\n\n while:<\/p>\n\n\n\n noninvasive oxygenation increased.<\/strong><\/p>\n\n\n\n The CDC’s national COVID-NET data provide the clearest numerical evidence:<\/p>\n\n\n\n This is probably the strongest evidence supporting your observation that medical management changed substantially after the first wave.<\/strong><\/p>\n\n\n\n But it doesn’t establish that the ventilators were the principal cause of death.<\/p>\n\n\n\n No.<\/p>\n\n\n\n The magnitude of the decline is too large and the number of simultaneous changes too great.<\/p>\n\n\n\n The later reduction in mortality likely reflects a combination of:<\/p>\n\n\n\n It would be scientifically incorrect to assign the entire improvement to any one factor.<\/p>\n\n\n\n This is where the evidence becomes difficult to dismiss.<\/p>\n\n\n\n The 20,736-patient U.S. analysis adjusted for:<\/p>\n\n\n\n Yet mortality still declined from 19.1% to 10.8%<\/strong>.<\/p>\n\n\n\n The investigators specifically concluded that changes in patient characteristics did not fully account for the improvement.<\/p>\n\n\n\n That strongly supports the existence of a period effect<\/strong>\u2014something about the treatment environment and\/or the disease itself changed.<\/p>\n\n\n\n This is the critical limitation.<\/p>\n\n\n\n There is no national database containing:<\/p>\n\n\n\n COVID death = 1 Nor does the NCHS mortality database contain ventilator settings.<\/p>\n\n\n\n Consequently, a calculation such as:<\/p>\n\n\n\n 400,000 COVID deaths \u00d7 20% = 80,000 ventilator deaths<\/strong><\/p>\n\n\n\n would be completely speculative.<\/p>\n\n\n\n It would not be an analysis.<\/p>\n\n\n\n It would be an assumption.<\/p>\n\n\n\n The evidence supports several levels of certainty.<\/p>\n\n\n\n COVID itself caused substantial mortality.<\/p>\n\n\n\n Hospital mortality fell substantially during 2020.<\/p>\n\n\n\n Clinical management changed substantially during the same period.<\/p>\n\n\n\n Use of mechanical ventilation declined.<\/p>\n\n\n\n Use of corticosteroids increased dramatically.<\/p>\n\n\n\n Dexamethasone reduced mortality among patients requiring oxygen or mechanical ventilation.<\/p>\n\n\n\n Mechanical ventilation can cause lung injury when improperly applied.<\/p>\n\n\n\n Timing of intubation was associated with mortality, but studies disagree about whether earlier or later intubation was preferable.<\/p>\n\n\n\n The number of U.S. deaths specifically caused by inappropriate mechanical ventilation.<\/p>\n\n\n\n That the majority of 2020 COVID deaths were actually caused by ventilators rather than SARS-CoV-2 disease.<\/p>\n\n\n\n The evidence suggests that the most productive question is not<\/strong>:<\/p>\n\n\n\n “Did ventilators kill COVID patients?”<\/p>\n<\/blockquote>\n\n\n\n It is:<\/p>\n\n\n\n “How much of the extraordinary early COVID mortality was preventable with the medical knowledge that subsequently became available?”<\/strong><\/p>\n<\/blockquote>\n\n\n\n That question is answerable.<\/p>\n\n\n\n It can be approached by comparing:<\/p>\n\n\n\n March\u2013April 2020<\/strong><\/p>\n\n\n\n with<\/p>\n\n\n\n May\u2013December 2020<\/strong><\/p>\n\n\n\n while controlling for:<\/p>\n\n\n\n The Atlanta study, for example, incorporated many of these variables and still found substantial variation in mortality across successive surges.<\/p>\n","protected":false},"excerpt":{"rendered":" John Murphy, CEO The COVID-19 Long haul Foundation Executive finding The available evidence supports three conclusions simultaneously: There is, however, strong evidence that hospital mortality fell dramatically during 2020 even […]<\/p>\n","protected":false},"author":2,"featured_media":15918,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1537,332,333,929,621],"tags":[],"class_list":["post-15877","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-mechanical-ventilation","category-mortality","category-mortality-morbidity","category-respiration","category-ventilation-2"],"_links":{"self":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/15877","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=15877"}],"version-history":[{"count":1,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/15877\/revisions"}],"predecessor-version":[{"id":15878,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/15877\/revisions\/15878"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/media\/15918"}],"wp:attachment":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=15877"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=15877"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=15877"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}\n
\n\n\n\n1. The strongest U.S. evidence: mortality fell by roughly 40% during 2020<\/h5>\n\n\n\n
Admission period<\/th> Mortality<\/th><\/tr><\/thead> March\u2013April 2020<\/td> 19.1%<\/strong><\/td><\/tr> May\u2013June<\/td> 11.9%<\/strong><\/td><\/tr> July\u2013August<\/td> 11.0%<\/strong><\/td><\/tr> September\u2013November<\/td> 10.8%<\/strong><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n \n
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\n\n\n\n2. Respiratory management changed dramatically<\/h5>\n\n\n\n
ICU admission<\/h5>\n\n\n\n
Mechanical ventilation<\/h5>\n\n\n\n
Vasopressors<\/h5>\n\n\n\n
\n\n\n\n3. Was early intubation actually harmful?<\/h5>\n\n\n\n
Confounding by indication<\/h5>\n\n\n\n
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\n\n\n\n4. Another major U.S. study produced the opposite result<\/h5>\n\n\n\n
\n\n\n\n5. A much larger U.S. multicenter study again favored earlier ventilation<\/h5>\n\n\n\n
\n\n\n\n6. The 2020 literature therefore does NOT support one simple ventilation narrative<\/h5>\n\n\n\n
Study<\/th> Population<\/th> Finding concerning timing<\/th><\/tr><\/thead> NYC municipal hospitals<\/td> 7,597<\/td> Early intubation associated with higher<\/strong> mortality<\/td><\/tr> Mount Sinai<\/td> 755 ventilated<\/td> Later intubation associated with higher<\/strong> mortality<\/td><\/tr> 68-hospital U.S. cohort<\/td> 1,879 ICU patients<\/td> Later ventilation associated with higher<\/strong> mortality<\/td><\/tr> New York Northwell<\/td> 1,966 ventilated<\/td> 61% 28-day mortality during first wave<\/td><\/tr> Atlanta<\/td> 217 ICU patients<\/td> 35.7% mortality among ventilated patients<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n \n
\n\n\n\n7. The New York experience demonstrates just how sick the ventilated population was<\/h5>\n\n\n\n
\n\n\n\n8. The 5,700-patient New York study must also be interpreted cautiously<\/h5>\n\n\n\n
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\n\n\n\n9. Mechanical ventilation itself can injure lungs<\/h5>\n\n\n\n
\n
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\n\n\n\n10. One of the clearest signs of improved treatment: corticosteroids<\/h5>\n\n\n\n
Dexamethasone<\/h5>\n\n\n\n
Usual care<\/h5>\n\n\n\n
\n\n\n\n11. The timing of dexamethasone matters<\/h5>\n\n\n\n
\n\n\n\n12. The overall U.S. trajectory strongly supports a treatment-learning effect<\/h5>\n\n\n\n
\n\n\n\n13. What happened to ventilation during this period?<\/h5>\n\n\n\n
Treatment indicator<\/th> March 2020<\/th> December 2020<\/th><\/tr><\/thead> ICU admission<\/td> 37.8%<\/td> 20.5%<\/td><\/tr> Mechanical ventilation<\/td> 27.8%<\/td> 12.3%<\/td><\/tr> Vasopressors<\/td> 22.7%<\/td> 12.8%<\/td><\/tr> Remdesivir<\/td> 1.7%<\/td> 53.8%<\/td><\/tr> Corticosteroids<\/td> 18.9%<\/td> 74.2%<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n
\n\n\n\n14. Could inappropriate ventilation explain the entire mortality decline?<\/h5>\n\n\n\n
Treatment<\/h5>\n\n\n\n
\n
Medical knowledge<\/h5>\n\n\n\n
\n
Population factors<\/h5>\n\n\n\n
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Health-system factors<\/h5>\n\n\n\n
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\n\n\n\n15. A particularly important finding: mortality declined even after statistical adjustment<\/h5>\n\n\n\n
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\n\n\n\n16. But the data cannot tell us “X deaths were caused by ventilators”<\/h5>\n\n\n\n
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Ventilator caused death = 0\/1<\/p>\n<\/blockquote>\n\n\n\n
\n\n\n\n17. What we can estimate with reasonable confidence<\/h5>\n\n\n\n
Very strong evidence<\/h5>\n\n\n\n
Very strong evidence<\/h5>\n\n\n\n
Very strong evidence<\/h5>\n\n\n\n
Very strong evidence<\/h5>\n\n\n\n
Very strong evidence<\/h5>\n\n\n\n
Randomized evidence<\/h5>\n\n\n\n
Strong physiological evidence<\/h5>\n\n\n\n
Observational evidence<\/h5>\n\n\n\n
Insufficient evidence<\/h5>\n\n\n\n
No credible evidence<\/h5>\n\n\n\n
\n\n\n\n18. A more interesting hypothesis emerges<\/h5>\n\n\n\n
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