Abstract
BackgroundOld age is associated with a significantly increased mortality in COVID-19 patients exposed to long-term controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection. However, our understanding of age-related differences in the response to CMV in the absence of a viral infection remains insufficient.MethodsYoung (7–8 months) and old (28–32 months) F344 BN hybrid rats were exposed to the ICU condition for 5 days, i.e., complete immobilization, mechanical ventilation, and extensive monitoring. Transcriptomic (RNA-Seq) and proteomics (Proximity Extension Assay) analyses of the diaphragm and proteomics analysis of plasma were conducted to investigate the molecular differences between young and old rats exposed to the ICU condition.ResultsAccording to multi-omics analyses, significant differences were observed in the diaphragm between young and old rats in response to 5 days CMV and immobilization. In young rats, metabolic pathways were primarily downregulated in response to immobilization (post-synaptic blockade of neuromuscular transmission). In old rats, on the other hand, dramatic immune and inflammatory responses were observed, i.e., an upregulation of specific related pathways such as “IL-17 signaling pathway”, along with a higher level of inflammatory factors and cytokine/chemokine in plasma.ConclusionsThe dramatically increased mortality in old ICU patients with COVID-19-associated hyperinflammation and cytokine storm need not only reflect the viral infection but may also be associated with the ventilator induced diaphragm dysfunction (VIDD) and hyperinflammatory responses induced by long-term CMV per se. Although mechanical ventilation is a life-saving intervention in COVID-19 ICU patients, CMV should be cautiously used especially in old age and other means of respiratory support may be considered, such as negative pressure ventilation.
Highlights
Old age is associated with a significantly increased mortality in COVID-19 patients exposed to longterm controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection
The rapid decrease in diaphragm muscle endurance and strength associated with ventilator-induced diaphragm dysfunction (VIDD) induces extubation failure, prolonged weaning from ventilator with increased duration of intensive care unit (ICU) stay and staggering negative effects on ICU mortality and healthcare expenditures, with old patients being at higher risk
Besides the viral infection, the age-related response to the CMV per se contributes to hyperinflammation and cytokine storm reported in old patients with COVID-19 responsible for the increased mortality in old age
Summary
Old age is associated with a significantly increased mortality in COVID-19 patients exposed to longterm controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection. The morbidity/mortality rate is higher in old patients with COVID-19 [2] and the hyperinflammatory response induced by SARS-CoV2 has been forwarded as the major pathological process leading to disease severity and death in infected older patients [3,4,5]. The rapid decrease in diaphragm muscle endurance and strength associated with VIDD induces extubation failure, prolonged weaning from ventilator with increased duration of ICU stay and staggering negative effects on ICU mortality and healthcare expenditures, with old patients being at higher risk. This being a major concern in the modern era of critical care during the current COVID-19 pandemic [9]. It is reported that old patients with COVID-19 may benefit less from MV compared to those who are younger and healthier at baseline [12]
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