To the Editor: We read with great interest the article by Ahmad et al.1 about right timing for veno-venous extracorporeal membrane oxygenation (V-V ECMO) institution after noninvasive respiratory support (RS) in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). Authors claimed that patients receiving V-V ECMO after a noninvasive support period longer than 3 days have worse clinical outcomes (i.e., lower rates of ECMO liberation and discharge at home) than the ones with an earlier ECMO institution. However, this remarkable observation, consistent with lower ECMO survival rates observed by other authors in this setting after prolonged noninvasive oxygenation strategies,2 needs further confirmation due to some limits of the current study.1 First, among baseline characteristics, there are no clear biochemical or radiological markers of illness severity, such as static respiratory system compliance, PaO2/FiO2 ratio (PF ratio), D-dimer concentrations, and signs (i.e., pneumothorax or pneumomediastinum) suggestive of barotrauma at CT-scan imaging, collected within 24 hours of patient admission. The lack of triage criteria does not allow the detection of high-risk patients, which most likely benefit from early treatment with V-V ECMO. Noninvasive RS is known to have better results in mild-to-moderate ARDS treatment.3 In the subgroup of patients treated with noninvasive RS for more than 3 days, the PF ratio before endotracheal intubation (ETI) is significantly lower than that in the ones who received ECMO earlier, possibly due to higher severity of COVID-19.1 Thus, worse clinical outcomes are more likely to result from greater intrinsic aggressiveness of the disease, with a dismal prognosis, and from inadequacy of noninvasive RS for severe ARDS rather than from duration of treatment. As Ahmad et al.1 suggest, this difference in the PF ratio may also reflect lung damage due to COVID-19 disease progression, as well as delay before ETI or damage related to spontaneous breathing. They inferred that prolonged RS may promote self-induced lung injury (SILI), since spontaneous breathing in severe ARDS entails higher peak inspiratory pressure and tidal volumes.4 By the way, the association of noninvasive RS and SILI is still matter of debate,5 since both barotrauma and volutrauma are quite uncommon among noninvasive approaches. Of note, the article made no mention to peak inspiratory pressure nor to tidal volumes recorded during noninvasive support. Furthermore, authors grouped together patients receiving high-flow nasal oxygen (HFNC) and noninvasive ventilation (NIV): possibly due to the small sample size (78 patients, 33 of which treated with noninvasive RS over 3 days before V-V ECMO), they did not clearly analyze factors associated with failure of such noninvasive approach, for example, compliance to the treatment, ventilation parameters, sedation, adequate fit to interface, nor specify criteria for therapeutic upgrade (i.e., muscular weakness, diaphragm atrophy, and hemodynamic instability). The retrospective nature of the study limits the power of its results: further clinical trials, with a prospective design, carried on a population stratified for risk, are needed to confirm whether 3 days represent a critical duration for noninvasive RS.
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