Abstract
Objectives:
To study the feasibility of integrating the nitrogen multiple breath wash-in/washout (NMBW) technique with the positive end-expiratory pressure-step (PEEP-step) method to estimate transpulmonary driving pressure (DPTP), strain, and lung-specific elastance (k).
Design:
Prospective feasibility physiology study.
Setting:
National board-affiliated 30-bed quaternary care hospital PICU.
Patients:
Invasively ventilated children from 2 months to 16 years old between December 1, 2021, and August 30, 2022.
Interventions:
In volume-control mode, functional residual capacity (FRC) was measured using the NMBW technique at zero end-expiratory pressure (ZEEP), and end-expiratory lung volume was measured during the PEEP-step method.
Measurements and Results:
Data from 33 of 63 eligible subjects were analyzed, of whom 18 of 33 had pediatric acute respiratory distress syndrome (PARDS). Median (interquartile range [IQR]) FRC normalized to body weight was 15.1 mL/kg (IQR, 10.6–20.4 mL/kg). A correlation was found between FRC and respiratory compliance at ZEEP (rho = 0.775; p < 0.001). Strain demonstrated a positive correlation with both the DPTP (rho = 0.55; p < 0.001) and plateau pressure (rho = 0.72; p < 0.001) at ZEEP. Median k was lower in PARDS than non-PARDS subjects (16.1 cm H2O [IQR, 10.8–18.6 cm H2O] vs. 19.84 cm H2O [IQR, 18.50–23.93 cm H2O]; p = 0.045), but this difference was not present when k was normalized to body weight and height.
Conclusions:
Despite technical limitations, it appears possible to estimate DPTP, strain, and k by integrating the PEEP-step and NMBW methods. Validation against the gold standard esophageal pressure manometry is warranted.
Keywords: lung-specific elastance, nitrogen multiple breath wash-in/wash-out, strain, stress, transpulmonary driving pressure, ventilator-induced lung injury
RESEARCH IN CONTEXT.
Lung stress, strain, and lung-specific elastance (k) are intimately linked to each other and ventilator-induced lung injury.
Bedside methods for estimating transpulmonary driving pressure (DPTP), strain, and k, such as nitrogen multiple breath wash-in/washout (NMBW) and positive end-expiratory pressure-step (PEEP-step), have been studied in adults but not yet in children.
In this physiologic study conducted in 2021–2022, we prospectively evaluated the feasibility of combining NMBW with the PEEP-step method to estimate DPTP, strain, and k in children receiving invasive ventilation.
WHAT THIS STUDY MEANS?
In our prospective study of pediatric acute respiratory distress syndrome patients, conducted in 2021–2022, we have integrated the NMBW and PEEP-step techniques to estimate DPTP at the bedside, strain, and k.
Our study highlights the importance of normalizing k to growth parameters in children.
Further validation in larger, multicenter pediatric cohorts is now necessary before adopting these techniques into clinical practice.
Injurious mechanical ventilation (MV) settings can increase lung stress (reflected in the transpulmonary driving pressure [DPTP]) and strain (i.e., the change in volume in relation to its resting volume) (1–3). These, in turn, cause a change in the lung parenchymal extracellular matrix, which, when above a certain harmful threshold, may trigger inflammation and cause ventilator-induced lung injury (VILI) (1–5). Lung stress and strain are intimately linked by the lung-specific elastance (k), as lung stress is k times the lung strain (1, 6, 7).
Monitoring lung stress and strain at the bedside is an important part of individualized lung-protective ventilation (1, 2, 6). Esophageal manometry, as an estimate of pleural pressure, allows quantification of DPTP and is the gold standard for estimating lung stress (6, 8, 9). However, this technique has not been widely adopted in pediatric MV practice for reasons such as dependence on balloon position, patient posture, balloon pressure, esophageal smooth muscle reactivity, intra-abdominal pressure, and limited availability of pediatric catheters (8, 10, 11). These issues underscore the need for alternative tools, alongside the problem that, in children, airway pressures are a poor surrogate of lung stress (9). In this context, the “positive end-expiratory pressure (PEEP)-step” procedure has been used experimentally and in adult patients to measure k and DPTP, with excellent correlation to esophageal measurements (11–14). The “PEEP-step” method is not validated in ventilated children, but such validation is necessary because the pediatric respiratory system during invasive MV behaves differently from that of adults (5, 15).
Two previous pediatric studies described the feasibility of using the nitrogen multiple breath wash-in/washout (NMBW) technique to estimate end-expiratory lung volume (EELV) at various levels of PEEP (16, 17).
Now, we describe our work from 2021 to 2022, in which we aimed to test the hypothesis that integrating the NMBW technique with the PEEP-step method would allow for a simultaneous estimation of DPTP, strain, and k in invasively MV children with various pulmonary conditions.
MATERIALS AND METHODS
Our study was carried out prospectively in the PICU of Rainbow Children’s Hospital, Hyderabad, India, over the period from December 1, 2021, to August 30, 2022. The Hospital Ethics Committee approved the study titled “Role of measurement of End-Expiratory Lung Volume using Nitrogen Multiple Breath wash-in-washout technique to calculate strain and PEEP-step up method to calculate Stress in invasively ventilated children” (EC/NEW/INST/2021/1536; RCHBH/02/10-2021) in November 2021. Throughout this work, all research procedures adhered to the ethical standards of our local responsible committee, and the work was in full compliance with the Helsinki Declaration of 1975.
After obtaining informed consent from the parent or legal guardian, we recruited children 2 months to 16 years old undergoing MV with a cuffed endotracheal tube (ETT) without airway leak. We excluded subjects with intrinsic PEEP or cardiovascular instability (mean arterial blood pressures < 5th percentile for age and/or needing two or more inotropes), prone positioning, thoracic or spinal deformities, neuromuscular diseases, on extracorporeal devices (renal support, extracorporeal membrane oxygenation), or those receiving inhaled nitric oxide therapy or high-frequency oscillatory ventilation. We also excluded subjects with a Fio2 greater than 0.65 to ensure the accuracy of the NMBW technique (18). Subjects in whom the plateau pressure (Pplat) exceeded 28 cm H2O during the PEEP-step maneuver, despite readjustments in higher PEEP (PEEPhigh), were also excluded from the study. We excluded subjects younger than 2 months old (or those with a body weight < 4 kg requiring ventilation on neonatal mode) because the s—single, C—carbon dioxide and nitrogen dioxide, O–patient oxygen, V—patient spirometry, and X—gas exchange analysis (s-COVX) module is not designed to work according to the manufacturer.
Study Procedures
Please see the Supplemental Digital Content for further details of the methods and definitions (Table S1, https://links.lww.com/PCC/C697). In brief, subjects were sedated and, if needed, paralyzed to prevent spontaneous breathing during data acquisition. Nutritional status was classified according to the World Health Organization child growth standards for weight-for-height assessment (19). Actual body weight was used for calculations due to the high prevalence of normal or undernourished children admitted to our PICU (20).
All subjects underwent MV using a GE Carescape R860 ventilator with a s-COVX module (GE Healthcare, Helsinki, Finland). Active humidification was replaced with a heat and moisture exchange filter (Intersurgical, Wokingham, United Kingdom) 30 minutes before the study to prevent moisture entry into the s-COVX module. Endotracheal suction was done 15 minutes before respiratory measurements.
At baseline, and at each PEEP-step, end-expiratory lung volume was measured using NMBW with a 20% increase in FiO2 during washout and a 20% decrease during wash-in, as used by others (18, 21, 22). Wash-out and wash-in data were averaged and considered valid if the difference between them was less than 20%, as recommended by the manufacturer.
Before data acquisition, the ventilator mode was switched to volume-controlled ventilation. Inspiratory time, respiratory rate (RR), and flow were adjusted based on age and lung condition to create a square-shaped flow-time scalar (23). A 10% end-inspiratory pause was maintained, creating a zero-flow state (13, 23). Baseline PEEP (PEEPstart) was set at the discretion of the attending physician to target optimal lung compliance, hemodynamics, and gas exchange (24, 25). Tidal volume (Vt) was set at 6 mL/kg, aiming for Pplat less than 28 cm H2O and a driving pressure (DP) less than 15 cm H2O (24, 26). A proximal flow sensor was used in children under 6 months.
Measurements were taken under static conditions during an inspiratory (Pplat) and expiratory hold (total PEEP) with the subject in the supine position. At baseline, this included Fio2, Pplat, DP (i.e., the difference between Pplat and PEEPstart), and respiratory compliance (Crs) at PEEPstart (Vt divided by DP at PEEPstart). Then, PEEP was decreased from PEEPstart to zero (i.e., zero end-expiratory pressure [ZEEP]). At ZEEP (Fig. S1, https://links.lww.com/PCC/C697), we recorded DP (i.e., DPzeep) and Crs (i.e., Vt at ZEEP divided by DPzeep). Then, after ventilating for 3–4 minutes to stabilize Co2 elimination (measured as exhaled Co2/min), lung volume was measured (7, 18). This volume at ZEEP reflects the functional residual capacity (FRC).
After these first measurements, we performed the “PEEP-step” maneuver by applying PEEPhigh, thereby introducing a “PEEP-volume” (Fig. S2A, https://links.lww.com/PCC/C697). PEEPhigh was set at 70% of DPzeep to generate a PEEP-volume (i.e., difference between EELV minus FRC [ΔEELV]) equal to (± 20%) of Vt. After ventilating for 3 to 4 minutes at PEEPhigh, at the same Vt and RR, DP (DPhigh) and Crs (high) were recorded, and the end-expiratory lung volume at PEEPhigh (EELV) was measured. This EELV at PEEPhigh includes FRC and the added volume (i.e., PEEP-volume) from increasing PEEP.
Data acquisition was stopped, and subjects were excluded and returned to stabilizing MV settings either if pulse oximetry desaturation (Spo2 < 88%) occurred despite increasing Fio2 up to 0.65, or if hemodynamic instability (i.e., bradycardia or tachycardia with blood pressures < 5th percentile for age) occurred during the measurements. Adjustments were only made during data acquisition if an ETT leak became apparent, for which the cuff was reinflated, an increase in end-tidal co2, for which RR was increased to a maximum of 35 breaths per minute (18), or when Pplat was greater than 28 cm H2O. In the latter case, PEEPhigh was adjusted to keep Pplat less than 28 cm H2O and PEEP-volume (i.e., ΔEELV) close to (± 20%) Vt at ZEEP in line with other studies (11, 13).
Data Analysis
Lung elastance (EL) was calculated by dividing difference between PEEPhigh minus ZEEP (ΔPEEP) by ΔEELV (Fig. S2B, https://links.lww.com/PCC/C697) (7, 12–14). Multiplying EL by FRC produced k (1, 7). Total elastance (ETOT) at PEEPhigh was calculated by dividing DPhigh by Vt at PEEPhigh. We calculated global strain at PEEPhigh as: (Vt at PEEPhigh + ΔEELV)/FRC (1, 7). Strain at ZEEP was calculated as Vt/FRC (1, 7). DPTP was obtained by multiplying k by the strain at ZEEP (1, 6, 7).
Subjects with more than a 20% difference between ΔEELV and baseline Vt at ZEEP were excluded from the analysis (13, 15, 23). Furthermore, the NMBW technique has an inherent risk of 10% variability in measuring expiratory lung volumes, which can lead to errors in the measurement of EELV (11, 13, 23). To address this problem, we calculated the difference between ΔEELV and the minimum predicted increase in volume (Crs at ZEEP times the difference between PEEPhigh and ZEEP) as described by others (27, 28). Data from subjects in whom the minimum predicted increase in volume was greater than 10% of the ΔEELV were excluded from the analysis to reduce the risk of errors due to air leaks (28).
“Although data collection was completed on August 30, 2022, with 43 participants completing the study protocol, additional time was required for thorough data validation and advanced analyses, resulting in the post hoc exclusion of ten ineligible subjects, as shown in Figure 1. Preparing and revising the article in response to detailed peer reviews also extended the timeline, while prioritizing scientific rigor and clarity.”
Figure 1.
Study flow. ΔEELV = difference between end-expiratory lung volume and functional residual capacity, PEEPhigh = higher positive end-expiratory pressure applied as part of positive end-expiratory pressure-step maneuver, s-COVX = s—single, C—carbon dioxide and nitrogen dioxide, O—patient oxygen, V—patient spirometry, and X—gas exchange analysis, Vt = tidal volume, ZEEP = zero end-expiratory pressure.
Statistical Analysis
For analytical purposes, subjects were divided into two groups: one with pediatric acute respiratory distress syndrome (PARDS), as defined by the 2015 Pediatric Acute Lung Injury Consensus Conference (24) and one without PARDS (non-PARDS group). Oxygenation index and the Pao2 to Fio2 ratio were calculated at the time of initiation of the study protocol.
Data were assessed for normality using the Kolmogorov-Smirnov test. Descriptive analysis was performed, reporting frequency and proportion for categorical variables. Continuous variables were presented as median (interquartile range [IQR]). The chi-square test was used to test the statistical significance of cross-tabulation between categorical variables. The Mann-Whitney U test was used to compare the median (IQR) of continuous variables between two groups. Spearman rank correlation was used to assess the correlation between two continuous variables. A p value of less than 0.05 was considered statistically significant. R-Studio Desktop, Version 4.3.0 and SPSS, Version 27 (IBM Corp, Armonk, NY) were used for statistical analysis (R-Studio Team [2023], Boston, MA; http://www.rstudio.com/).
RESULTS
During the 9-month period (2021–2022) of our study, 2748 children were admitted to the PICU, of which 492 (17.8%) were on invasive MV. Sixty-three of the MV subjects (12.8%) were potential candidates for the study (Fig. 1); 7 were excluded due to Spo2 desaturation or hemodynamic instability at the beginning of the study protocol. An additional five subjects were excluded due to calibration errors in the s-COVX module, and three had hypermetabolic states from high fever and metabolic acidosis. Another five subjects developed hemodynamic instability during the study and were excluded; seven subjects were removed post-protocol because the minimum predicted increase in volume was greater than 10% of the ΔEELV. Three subjects were excluded due to greater than 20% difference between ΔEELV and baseline Vt at ZEEP and PEEPhigh. And, in three PARDS subjects, during the PEEP-step maneuver, Pplat was greater than 28 cm H2O, where PEEP-high was successfully readjusted as per the protocol. No subjects were excluded due to leakage around the ETT. After all of the above exclusions, we were left with 33 subjects available for analysis.
In our 33 subjects, 19 of 33 were normally nourished, eight of 33 were undernourished, and six of 33 were overweight or obese. Eighteen of 33 subjects had PARDS. Table 1 summarizes the demographic characteristics and baseline respiratory system mechanics at the titrated PEEP (PEEPstart).
TABLE 1.
Baseline Characteristics at Titrated Positive End-Expiratory Pressure (n = 33)
| Variables | Whole Cohort (n = 33) | PARDS (n = 18) | Non-PARDS (n = 15) |
|---|---|---|---|
| Age (mo), median (IQR) | 60 (18–94) | 28.5 (10–92) | 83 (37.2–108) |
| Male, n (%) | 20/33 | 9/18 | 11/15 |
| Weight (kg), median (IQR) | 16 (10–27.5) | 14 (8.75–26.5) | 17 (15–30) |
| Height (cm), median (IQR) | 108 (75.5–120) | 88 (70–120) | 108 (99–122) |
| Diagnosis (n) | |||
| Neurologic disorders | 10/33 | 2/18 | 8/18 |
| Respiratory disorders | 11/33 | 11/18 | 0 |
| Infectious/systemic disorders | 8/33 | 5/18 | 3/18 |
| Gastrointestinal/hepatic/surgical | 4/33 | 0 | 4/18 |
| Respiratory system mechanics at PEEPstart | |||
| Plateau pressure (cm H2O), median (IQR) | 17 (15–19) | 18 (16–21) | 17 (16–18) |
| Driving pressure (cm H2O), median (IQR) | 10 (8.5–12) | 11 (9–12.5) | 10 (9–12) |
| PEEPstart (cm H2O), median (IQR) | 7 (6–8) | 8 (7–8) | 7 (6–7) |
| Pao2/Fio2 ratio, median (IQR) | 217 (145–405) | 147 (122–200) | 420 (255–470) |
| Oxygenation index, median (IQR) | 4.2 (1.95–7.8) | 7.5 (5.7–9.3) | 1.9 (1.7–3.1) |
| Respiratory compliance at PEEPstart normalized to body weight (mL/kg/cm H2O), median (IQR) | 0.9 (0.7–1.1) | 0.8 (0.7–1.2) | 0.9 (0.7–1) |
IQR = interquartile range, PARDS = pediatric acute respiratory distress syndrome as per Pediatric Acute Lung Injury Consensus Conference-1 definition, PEEPstart = the positive end-expiratory pressure titrated at bedside and at which normal ventilation was done before starting the study protocol of shifting to zero end-expiratory pressure and positive end-expiratory pressure-step technique.
At ZEEP, the median FRC normalized to body weight was 15.1 mL/kg (10.6–20.4 mL/kg; Table 2). There was a significant correlation between FRC and Crs (rho = 0.775; p < 0.001; Figs. S3 and S4, https://links.lww.com/PCC/C697). Median strain at ZEEP was 0.416 (0.3–0.58). Median DP at ZEEP was 12 cm H2O (10–14 cm H2O) while the median PEEPhigh, that is, ΔPEEP, was 8 cm H2O (7–9 cm H2O). Median DPTP 6.9 cm H2O (6.1–8.9 cm H2O). The strain demonstrated a strong positive correlation with DPTP (rho = 0.55; p < 0.001) and Pplat (rho = 0.72; p < 0.001) at ZEEP (Fig. 2, A and B).
TABLE 2.
Measurements at Zero End-Expiratory Pressure (n = 33)
| Variables | Whole Cohort (n = 33), Median (IQR) | PARDS (n = 18), Median (IQR) | Non-PARDS (n = 15) |
|---|---|---|---|
| Vt normalized to weight at ZEEP (mL/kg) | 6.2 (5.5–7.3) | 6.4 (5.5–7.5) | 6.0 (5.5–6.5) |
| Plateau pressure at ZEEP (cm H2O) | 12 (10–14) | 13 (12–14) | 10 (8–12) |
| Driving pressure at ZEEP (cm H2O) | 12 (10–14) | 13 (12–14) | 10 (8–12) |
| Respiratory compliance normalized to weight at ZEEP mL/kg/cm H2O | 0.6 (0.5–0.7) | 0.5 (0.4–0.6) | 0.6 (0.5–0.7) |
| FRC/kg weight (mL/kg) | 15.1 (10.6–20.4) | 12.9 (9.4–16.7) | 18.5 (15.1–23.6) |
| FRC normalized to height (mL/cm) | 2.6 (1.8–3.6) | 1.91 (1.25–3.14) | 3.25 (2.5–3.8) |
| Vt at ZEEP/FRC | 0.416 (0.3–0.58) | 0.578 (0.4–0.66) | 0.355 (0.238–0.420) |
| Transpulmonary driving pressure at ZEEP (cm H2O) | 6.9 (6.1–8.9) | 7.8 (6.50–9.10) | 6.2 (5.8–7.5) |
FRC = functional residual capacity, IQR = interquartile range, PARDS = pediatric acute respiratory distress syndrome as per Pediatric Acute Lung Injury Consensus Conference-1 definition, Vt = tidal volume, ZEEP = zero end-expiratory pressure.
Figure 2.
Correlation analysis of tidal volume at zero end-expiratory pressure/functional residual capacity (Strain) at zero end-expiratory pressure. Correlation between transpulmonary driving pressure (DPTP; A) and plateau pressure (Pplat; B) with strain at zero end-expiratory pressure (n = 33).
At PEEPhigh, the median volume generated by the PEEPhigh (ΔEELV) was 111 mL (80–175 mL), which was within the ± 20% range of the median Vt of 109 mL (78–180 mL). At PEEPhigh, the median global strain was 0.865 (0.671–1.244; Table 3).
TABLE 3.
After Application of a Higher Positive End-Expiratory Pressure Applied As Part of Positive End-Expiratory Pressure-Step Maneuver (n = 33)
| Variables | Whole Cohort (n = 33), Median (IQR) | PARDS (n = 18), Median (IQR) | Non-PARDS (n = 15) |
|---|---|---|---|
| PEEPhigh (cm H2O) | 8 (7–9) | 8 (7–10) | 8 (6–8) |
| Difference between PEEPhigh and ZEEP (cm H2O) | 8 (7–9) | 8 (7–10) | 8 (6–8) |
| Plateau pressure measured at PEEPhigh (cm H2O) | 18 (15–21) | 19 (18–21) | 15 (14–16) |
| Vt normalized to body weight at PEEPhigh (mL/kg) | 6.2 (5.7–7.2) | 6.6 (5.9–7.8) | 6 (5.6–6.5) |
| EELV at PEEPhigh (mL) | 420 (242–563) | 287 (156–502) | 459 (400–663) |
| EELV normalized to body weight at PEEPhigh (mL/kg) | 21.6 (18.2–27.9) | 21.7 (18.3–29) | 21.6 (14.4–28) |
| Vt (mL) | 109 (78–180) | 110 (64–180) | 110 (88–179) |
| ΔEELV (mL) | 111 (80–175) | 84 (56–189.7) | 124 (97–175) |
| (Vt at PEEPhigh + ΔEELV)/FRC | 0.865 (0.671–1.244) | 1.013 (0.837–1.666) | 0.723 (0.590–0.893) |
| EL (cm H2O/mL) | 70.4 (42.8–109.8) | 95.2 (42.8–135.4) | 64.5 (42.4–79.2) |
| ETOT (cm H2O/mL) | 75.6 (50.8–116.6) | 112.5 (53.3–243.7) | 66.7 (50.2–83.3) |
| EL/ETOT ratio | 0.857 (0.741–0.954) | 0.750 (0.617–0.896) | 0.883 (0.857–0.972) |
| k (cm H2O) | 18.2 (13.9–21.4) | 16.1 (10.8–18.6) | 19.8 (18.5–23.9) |
| “k” normalized to body weight (cm H2O/kg) | 1.1 (0.56–1.92) | 1.14 (0.50–2.31) | 1.065 (0.593–1.595) |
| “k” normalized to body height/length (cm H2O/cm) | 0.185 (0.130–0.246) | 0.154 (0.112–0.281) | 0.191 (0.150–0.224) |
| “k” normalized to FRC (cm H2O/L) | 70.4 (42.8–109.8) | 95.2 (42.8–135.4) | 64.5 (42.4–79.2) |
EELV = end-expiratory tidal volume measured after applying a higher positive end-expiratory pressure applied as part of positive end-expiratory pressure-step maneuver, EL = lung elastance, ETOT = total elastance, FRC = functional residual capacity, IQR = interquartile range, k = lung-specific elastance, PARDS = pediatric acute respiratory distress syndrome as per Pediatric Acute Lung Injury Consensus Conference-1 definition, PEEPhigh = a higher positive end-expiratory pressure applied as part of positive end-expiratory pressure-step maneuver, Vt = tidal volume, ZEEP = zero end-expiratory pressure, ΔEELV = difference between EELV and FRC.
Comparison Between PARDS and Non-PARDS
At ZEEP, FRC, FRC normalized to body weight (FRC/kg), and height (FRC/cm) were significantly lower among PARDS compared with non-PARDS (p = 0.023, 0.25, and 0.005, respectively; Tables S2–S4, https://links.lww.com/PCC/C697). At PEEPhigh, median “k” was lower in PARDS vs. non-PARDS subjects (16.1 cm H2O [IQR, 10.8–18.6 cm H2O] vs. 19.84 cm H2O [IQR, 18.5–23.9 cm H2O; p = 0.045]; Table S3, https://links.lww.com/PCC/C697). However, k was similar between groups after normalizing to body weight, FRC, and height (Table S3, https://links.lww.com/PCC/C697). There was a correlation between FRC and Crs in PARDS (rho = 0.791; p < 0.001) and non-PARDS subjects (rho = 0.754; p < 0.001).
The EL/ETOT ratio was higher in non-PARDS compared with PARDS subjects: (0.883 [0.857–0.972] vs. 0.741 [0.617–0.853]; p < 0.001; Table S3, https://links.lww.com/PCC/C697). In both groups, the median EL/ETOT ratio was greater than 0.7, indicating the overall prevalence of normal chest wall elastance in these groups.
DISCUSSION
In this feasibility study, we have shown that it is possible to noninvasively estimate lung stress (i.e., DPTP) and strain when using a combination of the PEEP-step and NMBW method. Nevertheless, assessment of our findings against the gold standard (i.e., esophageal pressure manometry) is necessary to establish clinical validity. Although esophageal manometry has been used in pediatric patients to optimize lung-protective ventilation (29–31), it presents many technical and logistical challenges in children (29, 32, 33). The attractiveness of our approach is that it explores ways to overcome the limitations of esophageal pressure manometry (8, 10, 11, 29) and describes various technical challenges of combining NMBW with the PEEP-step technique to estimate DPTP at the bedside in children. These findings can guide future research. Of note, the PEEP-step method used in the current study was developed in adults and showed a strong correlation with esophageal manometry (11, 13, 14). This method is based on the observation that an increase in PEEP results in a less than expected increase in end-expiratory esophageal pressure, indicating that the chest wall and abdomen can gradually accommodate changes in lung volume induced by introducing a PEEPhigh (11, 14). As a result, if ΔEELV is within ± 20% of the Vt, a change in transpulmonary pressure, as measured by esophageal manometry, is equal to a change in PEEP (11, 13, 14).
Nonphysiologic stress and strain levels exceeding 1.5–2 occur when lung volumes reach total lung capacity and are known to cause VILI (1, 2, 34). A linear relationship between stress and strain has been described in the adult patient population (6). In our study, we also observed a positive correlation between DPTP and strain.
The EL/ETOT ratio was higher in the non-PARDS group, which could be attributed to four subjects exhibiting poor chest wall elastance (three with severe dengue and one with nephrotic syndrome and septic shock) in the PARDS subgroup. The median EL/ETOT ratio was above 0.70 in both groups, indicating the overall prevalence of normal chest wall elastance consistent with other studies (9, 35, 36).
In our study, k was lower in PARDS subjects compared with non-PARDS subjects. Since ΔPEEP and ΔEELV were similar, we surmise that the lower FRC explains the lower k in PARDS subjects. Contrary to our findings, a study of ten PARDS patients in 2009–2014 found higher k in PARDS compared with those with healthy lungs (9). This difference in observation may be because we measured FRC at ZEEP, whereas the 2009–2014 study assessed FRC at a titrated PEEP (9). For example, the addition of PEEP can affect the measurement of FRC (6, 16, 37). Also, in adults, there were no differences in k between normal and abnormal lungs (6). Thus, there may be an age-dependent effect on how the lungs respond to stress and strain (5, 9, 15, 38, 39). And, since k is EL times FRC, and there is a close correlation between FRC and age, height, and weight in children, we normalized k to body weight and height and found that the normalized k was similar across PARDS and non-PARDS subjects, as others have reported (40). Our findings are in agreement with data from over 50 years ago, which showed that respiratory-specific compliance can be affected by growth and development in the pediatric population (41).
We used the NMBW technique to quantify lung volumes, and it has been demonstrated that this technique can be more reliable than the Helium-dilution method for measuring lung volumes without interrupting MV (16, 22). A significant correlation between Crs and strain with EELV, measured at titrated PEEP, has been reported in a single-center pediatric study conducted in 2022, in which FRC was measured at titrated PEEP (42). We observed a significant correlation between Crs and FRC, with FRC measured at ZEEP. A “decremental-PEEP trial” to calculate ΔEELV has also been described in the adult population, but this approach has not been tested in children to date (27, 43).
Our study has some limitations. First, a significant limitation is that we had to exclude a substantial number of subjects due to various technical reasons. Subjects with severe PARDS were excluded because it was unclear how they would respond to lung volume measurements at ZEEP. For example, during the NMBW technique, the main issue with both oxygen and nitrogen as tracer gases is that changes in Fio2 of more than 0.2 fractions are required for accurate measurements of FRC (18, 21, 22). Thus, if a subject is on Fio2 of 0.8, then during the NMBW step, the subject may not tolerate a fall in Fio2 by 0.2. Others have found that measurements are imprecise when Fio2 is greater than 0.70 at a respiratory quotient of 0.8 (18). Hence, to avoid measuring FRC at ZEEP in the adult patient population, a one-breath derecruitment maneuver from 5 cm H2O PEEP to ZEEP has been tested (38). This approach has not been used in the pediatric population, but in those with normal lungs, an FRC normalized to weight by a factor of 19.6 mL/kg (± 5.1 mL/kg) (16) produces results similar to our non-PARDS subgroup, which supports the reliability of our measurements at ZEEP.
Second, the NMBW technique carries a risk of measurement error of 10% variability in expiratory lung volumes, which can lead to errors in determining EELV (11, 13, 23). Three previous studies in adult patients have calculated the difference between the “change in end-expiratory lung volumes” and the “minimum predicted increase in volume” (27, 28, 38), If the “minimum predicted increase” in volume is greater than 10% of “change in end-expiratory lung volumes” (difference between EELV measured at PEEPhigh and the FRC), data errors are likely, mainly due to circuit leaks (28). In our study, we excluded seven subjects for this reason.
One important limitation of our study is the lack of esophageal pressure manometry to validate the measurements. Fourth, it is a single-center cohort, which potentially limits the study’s generalizability, and our measurement of EELV using the NMBW technique was limited to one specific ventilator.
In conclusion, our prospective lung physiology study, conducted in 2021–2022, estimated DPTP, strain, and k at the bedside by integrating the PEEP-step and NMBW methods. Future validation against the gold standard of esophageal pressure manometry is now warranted.
Supplementary Material
Footnotes
Dr. Shaikh conceived the study and designed the study protocol; acquired, analyzed, and interpreted the data; drafted the work and wrote the main article, including the compilation of the bibliography and supplementary file. Dr. Venugopal participated in the study design, acquired data, drafted the article, and gave final approval of the work. Dr. Bhaskaran analyzed the data, drafted the article, including the bibliography, and obtained final approval of the work. Dr. Ramaswamy participated in the study design; was involved in data acquisition, analysis, and interpretation; drafted the article; and gave final approval of the work. Dr. Reddy analyzed the data, organized the bibliography, drafted the article, and gave final approval of the work. Dr. Chirla analyzed and interpreted the data, drafted the article, and gave final approval of the work. Dr. Venkatraman interpreted the data, guided the drafting of the article, reviewed, and gave final approval of the work. Dr. Kneyber guided the study design, interpreted the data, drafted and reviewed the article, and gave final approval of the work. All the authors agree to be accountable for all aspects of the study and ensure that questions related to its accuracy and integrity are appropriately investigated and resolved.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal).
Dr. Kneyber received funding from Getinge, Metran, Chiesi, and the National Heart, Lung, and Blood Institute. The remaining authors have disclosed that they do not have any potential conflicts of interest.
Contributor Information
Monesh Kethineni Bhaskaran, Email: moneshbhaskaran02@gmail.com.
Karthik Narayanan Ramaswamy, Email: narayanankarthik86@gmail.com.
Venkat Sandeep Reddy, Email: kvsandeepreddy@gmail.com.
Dinesh Kumar Chirla, Email: dchirla@gmail.com.
Shekhar Venkatraman, Email: venkataramanst@gmail.com.
Martin C. J. Kneyber, Email: m.c.j.kneyber@umcg.nl.
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