Modern medicine combines the traditional approach to treat syndromes with recent advances in translational research to improve understanding of the pathophysiology of the patient response. Integration of biomarkers with routinely measured clinical variables may offer information on how patients respond to a treatment and their final outcome.1 Therefore, integration and understanding the different pathophysiological information of critical illness will improve treatment decisions and outcomes at bedside.
In patients with ARDS, an elevated measured pulmonary dead space, measured as deadspace to tidal volume ratio (VD/VT) is a predictor of death and is one of the respiratory physiomarkers independently associated with mortality.2-5 However, determination of dead space at the bedside requires extra equipment for the measurement of the PCO2 in mixed expired air, which is a limitation for its routine clinical use. Other ventilator efficiency indices using partial pressure of end-tidal CO2 as a function of PaCO2 also have value to predict optimal recruitment,6 greater likelihood of weaning from venovenous extracorporeal membrane oxygenation (ECMO),7 or to be independently associated with mortality risk8,9 although their implementation is not generalized. Since CO2 is highly more diffusible across tissues than oxygen, impaired CO2 excretion reflects profound vascular and alveolar injury.
In recent years, the ventilatory ratio (VR), an index of impaired efficiency of ventilation, has been proposed as an easily acquired bedside index of impaired ventilation that can be computed using routinely measured respiratory variables.10 VR is an index of lung efficiency reflecting the relationship between measured and predicted PaCO2 and minute ventilation being physiologically related to VD/VT. Since VR is probably influenced by large shunt fractions and the volume of CO2 elimination, it constitutes a good global index of the efficiency of lung gas exchange.
In patients with ARDS, the VR correlates well with VD/VT11,12 and is independently associated with increased risk of mortality.3,8,11 In addition, VR discriminates the need for ECMO,13 and Villalbla et al14 found that alveolar vascular congestion determined in postmortem lung histology in subjects with COVID-19 ARDS was closely correlated with VR and higher alveolar vascular congestion was also associated with worse survival.
Two investigations in this issue of the Journal confirm VR as one of the physiologic biomarkers to monitor at the bedside that could enhance bedside estimation of patient prognosis. Siegel and co-workers15 identified variables specific to respiratory failure that might add prognostic value to indicators of systemic illness severity in an observational cohort of subjects with ARDS and multiple comorbidities. In 50 subjects, they tested the contribution of respiratory variables (oxygenation index, VR, and the radiographic assessment of lung edema score) to logistic regression models of 28-d mortality adjusted for indicators of systemic illness severity (Acute Physiology and Chronic Health Evaluation [APACHE] III score) or severity of shock as measured by the number of vasopressors required at baseline. Interestingly, they found that VR significantly improved discrimination for mortality, and the number of vasopressors required at baseline and APACHE III had similar discrimination for mortality when combined with VR. Therefore, VR captures a domain of ARDS severity and lung injury that is not reflected by APACHE III alone. These findings are also consistent with the existing literature demonstrating that VR is independently associated with mortality even after adjusting for oxygenation, PEEP, and severity of illness with APACHE III.11 Moreover, these findings have been found in a modest-sized cohort with only a few exclusion criteria, thus supporting a wide use of VR in almost all patients with ARDS.
Tisminetzky and co-workers16 aimed to determine the association between relative changes in physiological parameters at 24 h of prone positioning and ICU mortality in adult subjects with moderate to severe ARDS receiving prone position and included in the VENTILA database. In 156 subjects with ARDS, they found that a relative decline in VR at 24 h of prone position was associated with lower ICU mortality (odds ratio 0.80 [95% CI 0.66–0.97]) (every 10% decrease in VR after 24 h was associated with 20% decrease in the odds of mortality), whereas variations in PaO2/FIO2, PaCO2, or dynamic driving pressure were not. Robustness of these results was confirmed by appropriate sensitivity analysis.
Prone position increases gas-exchanging blood flow and decreases shunted blood flow by mechanisms related with increasing of lung recruitment of dorsal part of the lungs and preventing de-recruitment in the ventral regions, leading to a global increase in recruitment and prevention of ventilator-induced lung injury.17-19 Prone position is strongly associated with improved survival in severe ARDS,20,21 and its use is highly recommended in all guidelines for the management of adult patients with ARDS. Despite the fact that all clinical evidence favors early use of prone position in ARDS, there is still some reluctance, and there is no generalized application. Furthermore, changes in oxygenation to track the response to prone position in routine practice are not consistently associated with improvement in outcomes. In a recent study on COVID-19–associated ARDS, dead space measured by electrical impedance tomography was reduced in the ventral regions of the lungs; and the dead-space/shunt ratio also decreased significantly, leading to an improvement in ventilation-perfusion matching during prone position.22
Provided that prone position re-aerates previous atelectatic lung regions by a mechanism different than PEEP, prone position could benefit ventilatory efficiency even with, a small improvement in oxygenation. In fact, seminal studies in subjects with ARDS on the combined effects of inhaled nitric oxide and prone position found that non-responders to inhaled nitric oxide became responders in the prone position, with improved oxygenation, likely because nitric oxide reached previously shunted pulmonary vessels without causing overdistention.23 Although mechanistic explanations fit with the findings of Tisminetzky and co-workers,16 further investigations are warranted.
All clinicians try to estimate mortality of a critically ill patient. The two originial studies15,16 commented on in this editorial teach us that use of respiratory variables alone is not sufficient. The integration of severity variables, the intensity and response to vasopressor treatment, and the VR response during the first 24 h of prone position are powerful new information to add in the armamentarium to understand and treat ARDS.
Electronic medical records should allow calculation of VR routinely and add this physiomarker to the constellation of data generated by critically ill patients. Including ventilator efficiency indices in new designed or re-analyzed clinical trials or using real-world data captured around the critically ill patient,1,24 if verified and valid, will constitute real evidence to facilitate research to narrow the gap between patient care and clinical investigations and redefine complex multifactorial syndromes such as ARDS.
Footnotes
- Correspondence: Lluís Blanch MD PhD, Critical Care Department, Parc Tauli Universitary Hospital, Sabadell, Spain; Institut d'Investigació i Innovació Parc Taulí, Sabadell, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona, Bellaterra, Spain. E-mail: lblanch{at}tauli.cat
See the Original Study on Page 1067
Dr Haro reported no conflict of interest. Dr Blanch is inventor of one CS Parc Taulí owned US patent: “Method and system for managed related patient parameters provided by a monitoring device,” US Patent No. 12/538,940. Dr Blanch is founder of BetterCare S.L. a spin off of Corporació Sanitária Parc Taulí. Dr Roca reported a research grant from Hamilton Medical AG, speaker fees from Hamilton Medical AG, Fisher & Paykel Healthcare Ltd, Aerogen Ltd and Ambu, and non-financial research support from Timpel; all outside the submitted work.
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