key: cord-0726128-txs5mr0x
authors: Tsolaki, Vasiliki S.; Zakynthinos, George E.; Mantzarlis, Konstantinos D.; Deskata, Konstantina V.; Papadonta, Maria-Eirini E.; Gerovasileiou, Efrosini S.; Manoulakas, Efstratios E.; Zakynthinos, Epaminondas; Pantazopoulos, Ioannis N.; Makris, Demosthenes A.
title: Driving Pressure in COVID-19 Acute Respiratory Distress Syndrome Is Associated with Respiratory Distress Duration before Intubation
date: 2021-03-30
journal: American journal of respiratory and critical care medicine
DOI: 10.1164/rccm.202101-0234le
sha: 749066b68b100c3cd07d35969b76e5f0b39d22b8
doc_id: 726128
cord_uid: txs5mr0x

nan

The decision on the optimal time of invasive mechanical ventilation (IMV) onset in coronavirus disease (COVID-19) acute respiratory distress syndrome (ARDS) has been debated during the current pandemic (1, 2) . Although affected by the availability of resources, timing of intubation may also affect the outcome for patients with COVID-19. In this study we investigate whether factors related to respiratory distress (RD) are associated with the driving pressure (DP) in patients with COVID-19 ARDS.

We prospectively enrolled all consecutive patients with COVID-19 ARDS who were admitted to the ICU of a tertiary hospital (April to December 2020). Patients were included if they were on IMV and had positive PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ARDS. The local ethics committee (protocol number 53398/2020) approved the study with a waiver for informed consent. The primary outcome was the identification of predictors independently associated with patients' respiratory mechanics upon ICU admission.

In all patients, a lung protective protocol (VT of 6-8 ml/kg of ideal body weight and proning [if Pa O 2 /FI O 2 , 150 mm Hg]) was adopted. Positive end-expiratory pressure was set after a recruitment maneuver at the level of the lowest DP.

Pa O 2 /FI O 2 , airway pressures, VT, respiratory system compliance (VT/DP) and elastance (Ers: DP/VT/ideal body weight), Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment score, vasopressors, laboratory tests (on ICU admission), and COVID-19 treatment received before ICU admission were recorded. RD was recorded. The monitoring protocol of patients with COVID-19 ARDS before ICU admission included 1) recordings of the RR, FI O 2 , Sp O 2 , and other vital signs (i.e., arterial blood pressure, pulse rate, temperature, urine output) once every 3 hours; 2) arterial blood gases once every 8 hours per protocol-unless the patients' condition required more frequent sampling (as decided by the attending physician); and 3) continuous digital monitoring (arterial blood pressure, ECG, Sp O 2 , RR, hourly updates by the nursing staff) for all severe cases. During their ICU stay, patients had continuous digital monitoring of all clinical variables of interest (arterial blood pressure, ECG, Sp O 2 , RR, temperature), whereas arterial blood gases were measured once every 3 hours or more often.

The cutoff values for Pa O 2 /FI O 2 and RR used in the analysis were chosen on the basis of their frequency distribution and their clinical relevance (4) .

The patients were classified in two groups according to the lowest DP achieved during the first 24 hours in ICU (after recruitment maneuvers and/or prone position): DP <14 cm H 2 O and DP .14 cm H 2 O (5). This cutoff value was chosen on the basis of its association with mortality (5, 6) .

Data are presented as mean (SD). Variables significantly associated with DP (continuous variable) in univariate analysis were entered in multivariate analyses. The linear regression model was used. Analyses were performed using RD indices and repeated using its components (time with hypoxemia and time with tachypnea) separately. Ancillary analysis was performed using Ers as a dependent variable. Receiver operating characteristic analysis evaluated the diagnostic performance of RD indices and its components to identify patients with DP .14 cm H 2 O. Two-tailed P values ,0.05 were considered significant. SPSS version 26.0 was used (SPSS Inc.).

Eighty-five patients with COVID-19 were admitted in the ICU during the study period and were included (one patient was excluded because he was admitted because of hemorrhagic shock but did not present ARDS). Measurements (per patient/day) available for Sp O 2 , Pa O 2 , FI O 2 , and RR were 24, 3, 24, and 8, respectively; no difference was found between the two groups (DP .14 cm H 2 O and DP <14 cm H 2 O) in terms of the number of assessments. Table 1 presents baseline characteristics of participants and variables associated with DP .14 cm H 2 O.

Multiple linear regression analysis revealed that only RD 100/25 (time with Pa O 2 /FI O 2 ,100 mm Hg and RR .25/min) was independently associated with DP (R 2 = 0.265, P , 0.001; b = 0.044, P = 0.009). When RD components (time with hypoxemia and time with tachypnea) were evaluated separately, only the duration (hours) with Pa O 2 /FI O 2 ,100 mm Hg was independently associated with DP (R 2 = 0.381, b = 0.044, P , 0.0001). Figure 1 presents correlations of RD components with DP.

Ers at ICU admission was significantly correlated with both RD 100/ 25 (0.513, P , 0.0001) and Pa O 2 /FI O 2 (baseline values) (r = 20.256, P = 0.019), but it was independently associated only with RD 100/25 (R 2 = 0.263, b = 0.017, P , 0.0001).

Receiver operating characteristic analysis showed that duration of hypoxemia (expressed as either hours with RD 100/25 or hours with Pa O 2 / FI O 2 ,100 mm Hg) could identify patients with DP .14 cm H 2 O; specifically, RD 100/25 longer than 7 hours presented 83% sensitivity and 73% sensitivity to identify patients with DP .14 cm H 2 O (area under 

This study demonstrates that 1) DP was above 14 cm H 2 O in 32.6% of patients with COVID-19 ARDS; 2) DP and Ers were independently associated with the duration of RD; and 3) duration of Pa O 2 /FI O 2 ,100 Data are presented as mean 6 SD unless otherwise noted. *Note that three patients in the DP < 14 cm H 2 O group and two in the DP . 14 cm H 2 O group did not have Pa O 2 /FI O 2 ,150 mm Hg before admission. These patients were intubated because of tachypnea and tachycardia. All patients were admitted in the ICU after intubation. † APACHE II score was calculated upon ICU admission.

mm Hg longer than 21.5 hours was the most significant factor predicting DP .14 cm H 2 O. To our knowledge, this is the first study to evaluate differences between patients with COVID-19 ARDS according to DP and factors that are associated with DP. We chose DP as it represents the distending pressure applied to the lung during a tidal inflation. Moreover, DP reflects respiratory compliance and provides useful information when a lung protective ventilation protocol is adopted (5, 6) . In this respect, we found it reasonable to target and analyze patients according to the best DP that could be achieved during the first 24 hours of ICU admission.

The factors that best correlated to DP .14 cm H 2 O were the duration of hypoxemia (Pa O 2 /FI O 2 ,100 mm Hg) and its combination with tachypnea, the RD 100/25. Baseline characteristics and infection duration did not have any impact. One explanation could be the increased disease severity leading to decreased compliance and tachypnea and hypoxemia. On the other hand, prolonged RD may further compound the lung injury induced by COVID-19 pathology. Our observation is in line with clinical data suggesting that vigorous, spontaneous ventilatory efforts for extended periods can exacerbate the lung damage (7), inducing a secondary insult (patient self-induced lung injury) (1) . Experimental data show that in cases of acute lung injury, spontaneous breathing may provoke increased volumetric strain and heterogeneity in lung units (8) .

Hypoxemia duration correlated with respiratory mechanics. The majority of patients with DP <14 cm H 2 O presented hypoxemia and tachypnea, yet for a significantly shorter time interval than patients with DP .14 cm H 2 O. A duration of Pa O 2 /FI O 2 ,100 mm Hg longer than 21.5 hours or RD 100/25 longer than 7 hours predicted a DP .14 cm H 2 O. These findings could help identify thresholds for the degree and duration of hypoxemia/increased work of breathing to decide the optimal time for intubation in COVID-19 ARDS (1, 2, 9) .

Moreover, patients with DP .14 cm H 2 O presented advanced multiorgan involvement in terms of APACHE II, Sequential Organ Failure Assessment scores, and vasopressors compared with patients with earlier IMV initiation.

Limitations of the study are its single-center and observational character. Therefore, the association of RD with a DP .14 cm H 2 Odoes not necessarily imply causality. Second, intrathoracic pressure swings were not directly evaluated; yet, esophageal pressure monitoring is not always feasible, especially in conscious patients with RD, and the interpretation of measurements is not always straightforward and simple (10) . RD was arbitrarily defined as it has never been definitely quantified. One might certainly argue that the optimal time for intubation/ICU admission may also impact outcomes. Such decisions during a pandemic depend on clinical assessment, end-of-life issues, and resources/bed availability. We acknowledge that these parameters were not assessed and could be the scope of a future study. 

In the present study, RD and hypoxemia duration in patients with COVID-19 ARDS were significantly associated with a DP .14 cm H 2 O on ICU admission.

Author disclosures are available with the text of this letter at www.atsjournals.org.

To the Editor:

The subset of ever-smokers with a FEV 1 to FVC ratio .0.7 and a FEV 1 ,80% predicted have been classified as preserved ratio impaired spirometry (PRISm), exhibiting respiratory symptoms similar to patients with chronic obstructive pulmonary disease (COPD), progression of airway and lung parenchymal disease, and increased risk for acute respiratory events (1) . The prevalence of PRISm is estimated to be as high as 24% in ever-smokers (2). Despite similar classification based on these criteria, PRISm remains a poorly characterized group with variable clinical phenotypes and disease courses (3). In moderate to severe COPD, the ratio of the diameters of the pulmonary artery (PA) and aorta (A) as measured on nongated, thoracic computed tomography (CT) is associated with increased risk for severe respiratory exacerbations and death (4, 5) . We hypothesized that pulmonary vascular disease, indicated by PA enlargement, will be associated with increased symptom severity, risk for acute respiratory exacerbations, and mortality within PRISm. Some of the results from this study were previously reported in the form of an abstract (6) .

The study population includes participants in COPDGene (the Genetic Epidemiology of COPD Study) who completed comprehensive clinical history, quality of life questionnaires including St. George's Respiratory Questionnaire (SGRQ), pre-and post-bronchodilator spirometry, and . The Genetic Epidemiology of COPD Program is supported by NIH grants U01 HL089897 and U01 HL089856. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the NIH. COPDGene is also supported by the COPD Foundation through contributions made to an industry advisory board comprising AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

Author Contributions: R.C.W., J.P.S., and J.M.W. all provided substantial contributions to the conception and design of the work as well as the acquisition, analysis, and interpretation of data for the work. R.C.W., J.P.S., and J.M.W. drafted the work. All authors revised the manuscript critically for important intellectual content and gave final approval of the version to be published. R.C.W., J.P.S., and J.M.W. agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Originally Published in Press as DOI: 10.1164/rccm.202103-0619LE on May 20, 2021

Management of COVID-19 respiratory distress

Caution about early intubation and mechanical ventilation in COVID-19

EPIC II Group of Investigators. International study of the prevalence and outcomes of infection in intensive care units

Use, timing and factors associated with tracheal intubation in septic shock: a prospective multicentric observational study

Driving pressure and survival in the acute respiratory distress syndrome

Effect of lowering Vt on mortality in acute respiratory distress syndrome varies with respiratory system elastance

Progression of regional lung strain and heterogeneity in lung injury: assessing the evolution under spontaneous breathing and mechanical ventilation

Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation

Emory COVID-19 Quality and Clinical Research Collaborative. Timing of intubation and mortality among critically ill coronavirus disease 2019 patients: a single-center cohort study

Pleural pressure and optimal positive end-expiratory pressure based on esophageal pressure versus chest wall elastance: incompatible results