Signa Vitae. 2024; 20(2): 110-114. doi: 10.22514/sv.2023.026
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Evaluation of time constant, dead space and compliance to determine PEEP in COVID-19 ARDS: a prospective observational study

Filip Depta1,2,*,, Michael A. Gentile3, Richard H. Kallet4,5, Viliam Donic6, Marko Zdravkovic7,8

1Department of Critical Care, East Slovak Institute for Cardiovascular Diseases, 04011 Košice, Slovakia

2Faculty of Medicine, Pavol Jozef Šafárik University, 04011 Košice, Slovakia

3Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA

4Department of Anesthesia, University of California, San Francisco, CA 94110, USA

5San Francisco General Hospital, San Francisco, CA 94110, USA

6Department of Physiology, Pavol Jozef Šafárik University, 04011 Košice, Slovakia

7Department of Anaesthesiology, Intensive Care and Pain Management, University Medical Centre Maribor, 2000 Maribor, Slovenia

8Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia

*Corresponding Author(s):fdepta@protonmail.com (Filip Depta)

History Submitted: 01 February 2023 | Accepted: 14 March 2023 | Published: 08 February 2024
Copyright:  ©2024  The Author(s). Published by MRE Press.
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

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Abstract

Multiple variables exist to identify optimal positive end-expiratory pressure (PEEP) to keep alveolar recruitment in acute respiratory distress syndrome (ARDS). These include increased respiratory system compliance (CRS) and decreased dead space to tidal volume fraction (Vd/Vt). Increasing CRS reflects improved lung volume, whereas decreasing Vd/Vt reflects improved ventilation/perfusion matching. An increasing expiratory time constant (RCEXP) reflects both, changes in CRS and alterations in tissue resistance. Whether RCEXP might reflect corresponding changes in Vd/Vt better than CRS during alveolar recruitment is unknown. This prospective observational study examined the correlation between these variables during ascending PEEP titration in patients with novel Coronavirus disease (COVID-19) related ARDS. PEEP titrations were performed in ten patients with COVID-19 ARDS under passive, pressure-controlled ventilation with a fixed driving pressure of 14 cmH2O. PEEP was increased stepwise between 5 and 20 cmH2O with 2 minutes allowed for Vd/Vt equilibration. RCEXP, Vd/Vt and CRS were recorded at each PEEP level and statistically assessed. The overall correlation between Vd/Vt and RCEXP was −0.72 (95% CI: −0.57 to −0.82); p < 0.0001. CRS had a weaker correlation with Vd/Vt (−0.47 (95% CI: −0.25 to −0.64); p < 0.0001). RCEXP was the highest at 12 cmH2O of PEEP whereas Vd/Vt was the lowest at 10 cmH2O of PEEP and CRS was the highest at PEEP of 15 cmH2O. Both parameters of exhalation, Vd/Vt and RCEXP, are strongly correlated which likely reflects corresponding mechanical and global ventilation/perfusion responses during ascending PEEP titration.

Keywords:Acute respiratory distress syndrome;COVID-19;Positive end-expiratory pressure;Expiratory time constant;Lung perfusion;Dead space ventilation
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Cite this article

Filip Depta, Michael A. Gentile, Richard H. Kallet, Viliam Donic, Marko Zdravkovic. Evaluation of time constant, dead space and compliance to determine PEEP in COVID-19 ARDS: a prospective observational study. Signa Vitae. 2024; 20(2): 110-114. doi: 10.22514/sv.2023.026

1. Introduction

Acute respiratory distress syndrome (ARDS) is a life-threatening condition, typically requiring mechanical ventilation due to insufficient gas exchange. Previous research has shown that the concepts of protective mechanical ventilation improve clinical outcomes in patients with ARDS [1]. There are multiple key components when delivering protective ventilation with sufficient positive end-expiratory pressure (PEEP) representing a cornerstone of strategies [2]. Although assessing lung recruitment using inspiratory variables (i.e., respiratory system compliance (CRS) or driving pressure (dP)) is well researched, assessing recruitment and PEEP levels using exhalation variables is less investigated.

Measured expiratory time constant (RCEXP), has recently been proposed to be a potential novel method to determine PEEP levels in mechanically ventilated patients [3]. With this study, we aimed to compare optimal PEEP levels determined by three different methods (RCEXP, Vd/Vt and CRS) in mechanically ventilated patients with COVID-19 related ARDS. Of those, RCEXP and Vd/Vt are both obtained during exhalation, with RCEXP reflecting dynamics (speed) of exhalation and Vd/Vt being rather a global perfusion-sensitive variable [4].

2. Materials and methods

2.1 Study design and participants

This prospective, observational study was performed in February 2022 in a tertiary referral hospital at the East Slovak Institute for Cardiovascular Diseases, Slovakia and conforms to the relevant Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. All patients fulfilled the following criteria: age >18 and <80 years; COVID-19 was confirmed with the polymerase chain reaction testing; all patients were on a passive, controlled mechanical ventilation and had moderate ARDS according to the Berlin definition [5].

As per local protocol care, all patients received sedation with continuous infusion of propofol and sufentanyl and continuous neuromuscular blockade with atracurium. Parameters were measured within the first 48 hours after intubation using the Aura V mechanical ventilator (Chirana Medical, Stara Tura, Slovakia). All patients were pre-oxygenated with 100% oxygen (O2) prior and throughout the study. Ventilatory settings for all patients included: pressure-controlled ventilation mode (PCV), frequency of 18 breaths per minute and inspiratory to expiratory ratio of 1:2. PEEP levels were set in the escalating order of 5, 8, 10, 12, 15, 18 and 20 cmH2O. Each PEEP lasted for 2 minutes and a fixed inspiratory pressure of 14 cmH2O was applied on top of each PEEP. Data collected at each PEEP level included: tidal volume (Vt), RCEXP, Vd/Vt and CRS. All variables were recorded as an average of the last 10 breaths before the PEEP level changed to a higher level. After the measurements, PEEP was returned to pre-study level.

2.2 Outcomes and definitions

The primary outcome of this study was to compare optimal PEEP determined with RCEXP, Vd/Vt and CRS during ascending PEEP titration. The secondary outcomes were correlation of RCEXP with Vd/Vt and CRS at all PEEP levels.

The RCEXP was automatically measured using the method of approximate iterations by the mechanical ventilator from the previous breath as in previous studies [1, 6]. Such RCEXP represents the real measured time in seconds through which 63% of Vt was exhaled with respect to the artificial airways, breathing circuits, humidification devices and mechanical ventilator (Fig. 1).

Flow versus time waveform illustrating the method how RCEXP was measured. RCEXP corresponds to 63% of exhaled tidal volume. V’: flow; RCEXP: expiratory time constant.

Fig. 1.Flow versus time waveform illustrating the method how RCEXP was measured. RCEXP corresponds to 63% of exhaled tidal volume. V’: flow; RCEXP: expiratory time constant.

The Vd/Vt was also displayed on the ventilator using volumetric capnography, according to the Bohr equation: (PaCO2–PeCO2)/PaCO2, where PaCO2 is partial pressure of CO2 in alveolar air and PeCO2 is CO2 in mixed expired air. PaCO2 was determined from the slope of phase III of volumetric capnograph trace and corresponds to alveolar plateau [7]. The CRS was calculated as Vt/(PIP-PEEP), where PIP is peak inspiratory pressure.

The optimal PEEP level was defined as the one obtained at the longest RCEXP, the highest CRS or the lowest Vd/Vt.

2.3 Statistical analysis

Categorical data are expressed as number (percentage) (n (%)), continuous data are expressed as the median with 95% confidence intervals (95% CI). Correlations were performed with Spearman correlation. The medians of expiratory tidal volume (Vte), CRS and RCEXP across PEEP levels were tested with Friedman’s test; no further multiple comparisons were rational within the sample size. The p < 0.05 was used as the level of significance. Analyses were performed with GraphPad Prism v9 (GraphPad Software, San Diego, CA, USA).

3. Results

PEEP titrations were performed in ten patients (5 patients in supine position and 5 patients in prone position). Their age was 58 ± 9 years, BMI was 28 ± 5 kg/m2, 7 of 10 patients were men and arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) ratio for all patients was between 100–200 on mechanical ventilation with PEEP >5 cmH2O.

Median values with 95% CI for Vt, CRS, RCEXP and Vd/Vt are presented in Table 1. The correlation of RCEXP with Vd/Vt for all measurements was −0.72 (95% CI: −0.57 to −0.82; p < 0.0001) (Fig. 2A). The correlation of CRS with Vd/Vt for all measurements was −0.47 (95% CI: −0.25 to −0.64; p < 0.0001) (Fig. 2C) and the correlation of CRS with RCEXP for all measurements was not statistically significant (p < 0.302).

The median values of RCEXP were the highest at 12 cmH2O of PEEP and the lowest Vd/Vt values were at PEEP of 10 cmH2O (Fig. 2B), whereas median CRS values were the highest at 15 cmH2O of PEEP (Fig. 2D). Moreover, Vt where optimal PEEP was identified for RCEXP and Vd/Vt was almost the same (600 vs. 609 mL), compared to significantly higher Vt where highest CRS was identified (Vt 663 mL, p < 0.01).

Table 1.Median values with 95% CI for tidal volume (Vt), compliance of the respiratory system (CRS), expiratory time constant (RCexp) and dead space to tidal volume ratio (Vd/Vt) during ascending PEEP titration.
PEEP (cmH2O)Vt (mL) (n = 10)CRS (mL/cmH2O) (n = 10)RCEXP (s) (n = 10)Vd/Vt (n = 10)
5540 (481–650)35 (28–42)0.63 (0.45–0.66)0.35 (0.29–0.74)
8537 (503–636)35 (31–39)0.65 (0.55–0.75)0.35 (0.27–0.49)
10600 (510–635)34 (29–45)0.67 (0.55–0.76)0.31 (0.28–0.48)
12609 (480–681)38 (27–48)0.70 (0.53–0.77)0.36 (0.32–0.51)
15663 (466–681)40 (26–48)0.67 (0.49–0.72)0.38 (0.34–0.52)
18641 (431–668)38 (24–46)0.65 (0.44–0.68)0.43 (0.34–0.52)
20623 (406–640)35 (25–44)0.62 (0.40–0.69)0.46 (0.38–0.71)
p value0.06300.12600.0020<0.0001
The Friedman’s nonparametric test was used to compare medians of Vt, CRS, RCEXP and Vd/Vt across different PEEP levels.
The correlation plots (A,C) and median values (B,C). A. Expiratory time constant (RCEXP) versus dead space to tidal volume ratio (Vd/Vt) correlation plot. B. Median values with 95% CI for RCEXP and Vd/Vt during 10 PEEP titrations (5 in supine and 5 in prone position) in 10 patients with ARDS. C. Respiratory system compliance (CRS) versus Vd/Vt correlation plot. D. Median values with 95% CI for CRS and Vd/Vt during 10 PEEP titrations (5 in supine and 5 in prone position) in 10 patients with ARDS. PEEP: positive end-expiratory pressure; ARDS: acute respiratory distress syndrome.

Fig. 2.The correlation plots (A,C) and median values (B,C). A. Expiratory time constant (RCEXP) versus dead space to tidal volume ratio (Vd/Vt) correlation plot. B. Median values with 95% CI for RCEXP and Vd/Vt during 10 PEEP titrations (5 in supine and 5 in prone position) in 10 patients with ARDS. C. Respiratory system compliance (CRS) versus Vd/Vt correlation plot. D. Median values with 95% CI for CRS and Vd/Vt during 10 PEEP titrations (5 in supine and 5 in prone position) in 10 patients with ARDS. PEEP: positive end-expiratory pressure; ARDS: acute respiratory distress syndrome.

4. Discussion

The main finding of this study is that the optimal PEEP determined by the highest RCEXP was closer to optimal PEEP by the lowest Vd/Vt compared to optimal PEEP determined by the highest CRS. Also, RCEXP was more strongly correlated with Vd/Vt at all PEEP levels than CRS which is considered the gold standard for lung recruitment during PEEP titration.

These results may be explained with pathophysiologic rationale. First, Vd/Vt and RCEXP are both parameters assessing exhalation. Second, RCEXP reflects time and all changes (regional and global) that occur in the lungs during the first 63% of Vt exhalation, including change in both, CRS and RAW, including small airways diameter change during positive pressure ventilation [8].

On the other hand, assessing recruitment with static parameters (parameters obtained from change in airway pressure and corresponding Vt) only reflects a specific time when measured. In this study, real measured RCEXP derived from expiratory flow curve was used, rather than calculated RCEXP (a product of CRS and RAW) that may be less accurate [9]. As a parameter reflecting exhalation dynamics, RCEXP might be more sensitive to reflect global overdistention than static values of CRS (i.e., progressively shorter RCEXP were recorded, while tidal volume was not significantly reduced at higher PEEP levels). As a result, the highest CRS for all patients was recorded at higher PEEP levels, compared to the PEEP levels where RCEXP was the longest.

Hemodynamic compromise, due to inappropriately high PEEP levels as the result of increased right ventricular afterload is well documented [10]. Under such circumstances, the distending pressure of the alveoli, rather than pulmonary venous pressure, serve as a backward pressure for the pulmonary flow [11]. Inappropriately high PEEP levels compromising the pulmonary circulation in our cohort, have likely caused reduction in perfusion (manifesting as increasing Vd/Vt) and the dynamics of measured RCEXP reflected that phenomenon sooner than CRS.

The positive correlation of RCEXP with Vd/Vt may be clinically important as the Vd/Vt has been associated with mortality [12], effectiveness of prone positioning [13], and successful extubation [14]. Having RCEXP as a measured variable may provide insight into adequacy of PEEP settings in terms of ventilation and indirectly also optimal global perfusion. Therefore, identifying ventilation variable (RCEXP) that estimates PEEP levels causing recruitment close to the global lung perfusion may have some advantage in addition to Vd/Vt as it can be assessed on the breath-to-breath basis and is not complicated by the excessive humidity or secretions in the circuit associated with Vd/Vt measurement.

Our study is limited by short evaluation time for possibly manifesting full lung recruitment, the low sample size and its observational nature. Because PCV was used without an end-inspiratory pause, plateau pressure used to calculate static compliance was not obtained and therefore dynamic compliance was used instead as a gold standard. Dynamic compliance underestimates true (static) compliance due to the resistive pressure, although it was reported in previous studies that also used dynamic compliance during descending PEEP trial, that correlation between dynamic and static compliance was very high (r = 0.92) [15]. Stahl also suggested that application of dynamic respiratory mechanics as a diagnostic tool in ventilated patients should be more appropriate than using static pressure-volume curves [16].

Due to inability to obtain partial pressure of carbon dioxide (PaCO2) during short intervals between changes in PEEP levels, we decided to use ventilator displayed values of calculated Vd/Vt using Bohr instead of Enghoff formula. Despite Enghoff method is preferred to estimate Vd/Vt, it also tends to overestimate true dead space [17]. What is more, measurement of Bohr dead space returns a more accurate reflection of ineffective ventilation and perfusion in the lungs and are not impacted by the shunt or low ventilation/perfusion inequalities that are common in ARDS patients [17].

Lastly, possible technical limitations could be obtaining all data from a single device. However, all mechanical ventilators were calibrated prior to measurements and operated according to the manufacturer’s instructions.

5. Conclusions

In conclusion, the measured RCEXP seems to better correlate with Vd/Vt than CRS during ascending PEEP trial. Further controlled studies are needed to correlate RCEXP with other methods of assessing lung perfusion and with optimal PEEP levels to achieve personalization of the protective mechanical ventilation.

Abbreviations

ARDS, acute respiratory distress syndrome; CRS, compliance of the respiratory system; CO2, carbon dioxide; PaCO2, partial pressure of carbon dioxide in alveolar air; PeCO2, partial pressure of carbon dioxide in mixed expired air; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; RCEXP, measured expiratory time constant; Vd/Vt, ratio of dead space ventilation to tidal volume; Vt, tidal volume; 95% CI, 95% confidence interval.

Availability of data and materials

Data are accessible upon reasonable request from the corresponding author.

Author contributions

FD—Conceptualization, Methodology, Writing—original draft; MAG—Writing—review & editing; RHK—Writing—review & editing; VD—Review & editing; MZ—Formal Analysis, Writing—review & editing. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was approved by the East Slovak Institute for Cardiovascular Diseases ethics committee (IEC No. N.A 201/2022) and confirms that all methods were performed in accordance with the relevant guidelines and regulations. IEC waived the need for informed consent due to a recognized and frequently used PEEP titration method to determine optimal PEEP levels in routine clinical practice.

Acknowledgment

This publication is the result of the project: “Design and implementation of advanced methods of lung ventilation treatment and diagnosis of viral pneumonia including COVID-19 with the possibility of their rapid adoption”, ITMS2014+: 313011ASX1 supported by the Operational Program Integrated Infrastructure funded by European Regional Development Fund (ERDF).

Funding

Funding was provided in part from European Regional Development Fund (ERDF), project identifier: ITMS2014+: 313011ASX1.

Conflict of interest

The authors declare no conflict of interest.

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