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Very Low Driving-Pressure Ventilation in Patients With COVID-19 Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation: A Physiologic Study

Open AccessPublished:November 26, 2022DOI:https://doi.org/10.1053/j.jvca.2022.11.033

      Objectives

      To determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE).

      Design

      A single-center prospective physiologic study.

      Setting

      At a single university medical center.

      Participants

      Adult patients with severe COVID-19 ARDS on VV ECMO.

      Interventions

      Participants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP = 1 cmH2O), and (5) 2 hours after returning to LDPV.

      Main Measurements and Results

      Twenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged—4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p = 0.481 and p = 0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers.

      Conclusions

      Biomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

      Key Words

      ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) is a common and deadly condition for which many patients require invasive mechanical ventilation. Although mechanical ventilation may be lifesaving, the repetitive stress and strain imposed on the lung parenchyma may worsen lung injury—known as "ventilator-induced lung injury" (VILI).
      • Slutsky AS
      • Ranieri VM.
      Ventilator-induced lung injury.
      Ventilator-induced lung injury and the underlying ARDS etiology precipitate the systemic release of inflammatory mediators that worsen lung injury and contribute to multiorgan injury, a phenomenon known as "biotrauma".
      • Curley GF
      • Laffey JG
      • Zhang H
      • et al.
      Biotrauma and ventilator-induced lung injury: Clinical implications.
      Thus, decreasing VILI and the associated biotrauma is a cornerstone of ARDS treatment. Low-tidal-volume ventilation (LTVV), with 6 mL/kg (with plateau pressure [pplat] ≤30 cmH2O) compared to 12 mL/kg of predicted body weight (PBW), is associated with reduced mortality.
      • Network Acute Respiratory Distress Syndrome
      • RG Brower
      • Matthay MA
      • et al.
      Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
      The benefit of LTVV is likely greatest in patients with the highest elastance and/or lowest compliance.
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      • Costa EL V.
      • Yarnell CJ
      • et al.
      Effect of lowering VT on mortality in acute respiratory distress syndrome varies with respiratory system elastance.
      Amato et al. analyzed data from multiple ARDS studies that showed lower driving pressure (ΔP) was associated independently with improved survival. Importantly, there was no clear threshold below which further reductions in ΔP (and tidal volumes) did not result in further reductions in mortality.
      • Amato MBP
      • Meade MO
      • Slutsky AS
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      Driving pressure and survival in the acute respiratory distress syndrome.
      However, it should be noted that higher driving pressure also may reflect decreased compliance due to more severe ARDS, resulting in higher mortality.
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      • Malhotra A.
      Driving pressure and respiratory mechanics in ARDS.
      For the most severe cases of ARDS, extracorporeal membrane oxygenation (ECMO) maybe required to maintain adequate gas exchange.
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      Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
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      • Peek GJ
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      • et al.
      Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicentre andomized controlled trial.
      Extracorporeal membrane oxygenation can control the partial pressure of oxygen and carbon dioxide levels in the blood, but optimal ventilator settings during ECMO remain unclear.
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      • Slutsky AS
      • Combes A.
      Extracorporeal life support for adults with respiratory failure and related indications: A review.
      The Extracorporeal Life Support Organization (ELSO) has recommended ventilator guidelines that limit ΔP to 10-to-15 cmH2O to maintain inspiratory pplat ≤25 cmH2O, positive end-expiratory pressure (PEEP) of ≥10 cmH2O, and respiratory rates of 4-to-15 breaths/min.
      • Badulak J
      • Antonini MVS
      • Christine M
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: Updated 2021 guidelines from the Extracorporeal Life Support Organization.
      These ELSO guidelines are referred to as low-driving-pressure ventilation (LDPV). Extracorporeal membrane oxygenation could further allow clinicians to use ventilator settings lower than LDPV; for example, setting ΔP at 1 or 0 cmH2O. Such an approach may offer additional lung protection, as animal data show that very low ΔP, including “apneic” or zero ΔP, decreases histologic markers of lung injury.
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      • Alegria L
      • Garcia P
      • et al.
      Near-apneic ventilation decreases lung injury and fibroproliferation in an acute respiratory distress syndrome model with extracorporeal membrane oxygenation.
      ,
      • Pelosi P
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      Close down the lungs and keep them resting to minimize ventilator-induced lung injury.
      Multiple plasma biomarkers have been used to measure VILI and/or biotrauma.
      • Terpstra ML
      • Aman J
      • van Nieuw Amerongen GP
      • et al.
      Plasma biomarkers for acute respiratory distress syndrome: A systematic review and Meta-Analysis*.
      Some systemic proinflammatory biomarkers include interleukin-6 (IL-6) and IL-8. They also may be relatively organ-specific, such as soluble receptors for advanced glycation end-products (sRAGE), an epithelial marker of lung injury.
      • Terpstra ML
      • Aman J
      • van Nieuw Amerongen GP
      • et al.
      Plasma biomarkers for acute respiratory distress syndrome: A systematic review and Meta-Analysis*.
      Prior reports have demonstrated rapid (within 1 hour) changes in biomarkers with tidal volume (Vt) changes.
      • Stüber F
      • Wrigge H
      • Schroeder S
      • et al.
      Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury.
      Biomarkers (specifically, sRAGE, IL-6, and IL-8) have been shown to prognosticate patients with ARDS on ECMO and may be used as a surrogate for VILI and/or biotrauma to evaluate the effects of different ventilators settings.
      • Stüber F
      • Wrigge H
      • Schroeder S
      • et al.
      Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury.
      • del Sorbo L
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      • Tomlinson G
      • et al.
      Effect of driving pressure change during extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome: A randomized crossover physiologic study.
      • Rozencwajg S
      • Guihot A
      • Franchineau G
      • et al.
      Ultra-protective ventilation reduces biotrauma in patients on venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      It should be noted that there are reports of extracorporeal support (eg, ECMO, cardiopulmonary bypass, etc) inducing systemic inflammation and corresponding biomarkers, specifically IL-6.
      • Millar JE
      • Fanning JP
      • McDonald CI
      • et al.
      The inflammatory response to extracorporeal membrane oxygenation (ECMO): A review of the pathophysiology.
      ,
      • Henry BM.
      COVID-19, ECMO, and lymphopenia: A word of caution.
      The study authors sought to test the hypothesis that for patients with ARDS on ECMO, decreasing lung stretch via very LDPV (V-LDPV) would decrease blood biomarkers of inflammation and lung injury (IL-6, IL-8, and sRAGE).

      Materials and Methods

      Study Design

      This was a prospective cohort study. Enrollment was from March 1, 2020 to November 1, 2020. No power calculation was performed as this study was an exploratory pilot study, and the number of participants was based on feasibility and existing literature.
      • del Sorbo L
      • Goffi A
      • Tomlinson G
      • et al.
      Effect of driving pressure change during extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome: A randomized crossover physiologic study.
      ,
      • Rozencwajg S
      • Guihot A
      • Franchineau G
      • et al.
      Ultra-protective ventilation reduces biotrauma in patients on venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      The study protocol was approved by the institutional review board. Informed consent was obtained from each participant's healthcare proxy, according to the authors’ institutional guidelines.

      Participants

      The inclusion criteria were as follows: (1) age >18 years, (2) planned initiation of VV-ECMO support, (3) severe ARDS defined by the Berlin criteria, and (4) mechanical ventilation.
      • Definition Task Force ARDS
      • Ranieri VM
      • Rubenfeld GD
      • et al.
      Acute respiratory distress syndrome: The Berlin definition.
      The exclusion criteria were as follows: (1) solid organ transplantation, (2) hemodynamic instability defined as mean arterial pressure (MAP) <65 mmHg despite vasopressors and fluid administration, or (3) expected survival <24 hours. Patients with COVID-19 with obvious cardiac dysfunction (eg, by echocardiogram or need for high-dose vasopressors) were not offered ECMO in the authors’ county due to the pandemic surge and resulting resource limitations during study enrollment (pressor requirements at ECMO initiation are shown in Table 1).
      • Odish M
      • Yi C
      • Eigner J
      • et al.
      The Southern California Extracorporeal Membrane Oxygenation Consortium During the Coronavirus Disease 2019 Pandemic.
      • Bhatia M
      • Kumar PA.
      Pro: Venoarterial ECMO should be considered in patients with COVID-19.
      • McLean DJ
      • Henry M.
      Con: Venoarterial ECMO should not be considered in patients with COVID-19.
      Table 1Patient Demographics and Outcomes
      All ParticipantsParticipants Underwent V-LDPV ProtocolV-LDPV (Survivors)V-LDPV(Non-survivors)
      Total2521912
      Patient demographics
      Male, n (%)21 (84)17 (80.9)7 (77.8)10 (83.3)
      Age, mean ± SD, y50.1 (9.5)51 (9.7)48 (9.8)53.3 (9.3)
      Race, n (%)
       White23 (92)19 (90.5)8 (88.9)11 (91.7)
       Asian1 (4)1 (4.8)1 (11.1)0
       Other/mixed race1 (4)1 (4.8)01 (8.3)
      Hispanic23 (92)20 (95.2)9 (100)11 (91.7)
      BMI, mean ± SD, kg/m231.4 (4.8)31.7 (4.7)32.2 (4.8)31.3 (4.8)
      Past medical history, n (%)
       Any respiratory disease
      Respiratory diseases included asthma and COPD.
      5 (20)5 (23.8)3 (33.3)2 (16.7)
       Type 2 diabetes8 (32)8 (38.1)3 (33.3)5 (41.7)
       Pregnant or postpartum2 (8)2 (9.5)2 (22.2)0
       Malignancy1 (4)1 (4.8)01 (8.3)
      ARDS from COVID-19, n (%)25 (100)---
      SOFA score at ICU admission, mean ± SD9.7 (2.6)9.8 (2.8)9.3 (2.7)10.2 (3)
      Norepinephrine equivalent prior to V-LDPV, µg/kg/min, mean ± SD0.09 (0.1)0.09 (0.09)0.11 (0.11)
      Pre-ECMO ventilator settings, mean ± SD
      Missing ventilator settings from 10 participants due to mobile ECMO cannulation.
      n = 15
       Respiratory rate, breaths/min28 (4.9)
       Tidal volume, mean ± SD, mL/kg of PBW6.2 (1.5)
       PEEP, cmH2O12.6 (4.1)
       Plateau pressure, cmH2O28.6 (5.5)
       Driving pressure, cmH2O16 (5.4)
       Mean airway pressure, mean ± SD, cmH2O20 (4.58)
       Mechanical power, mean ± SD, joules/min29.8 (8.57)
       FIO20.94 (0.15)
       Compliance of the respiratory system, mean ± SD, mL/cmH2O25.3 (10.7)
       PaO2/FIO2, mean ± SD93 (30)89 (27)88 (16)89 (32)
       Neuromuscular blockade, n (%)13 (86.6)6 (28.5)2 (22.2)4 (33.3)
      Intubation time prior to ECMO, mean ± SD, d6.3 (4.4)5.2 (3.3)5.4 (4.1)5 (2.7)
      ECMO time prior V-LDPV, median (IQR), h-17 (14-20)16 (14-19.3)17 (14.5-19.3)
      Mobile ECMO, n (%)10 (40)10 (47.6)5 (55.6)5 (41.7)
      ECMO circuit settings prior to V-LDPV
      ECMO settings during sample collections.
       Blood flow, mean ± SD, L/min4.8 (0.6)
       Oxygenator sweep gas, mean ± SD, L/min4.5 (2)
       Venous pressure, mean ± SD, mmHt−94.1 (28.9)
      End-expiratory transpulmonary pressure gradient, mean ± SD, cmH2O
      Nineteen of the 21 participants that underwent V-LDPV had an esophageal manometer placed.
      −0.5 (4.3)
      Clinical course
      Duration of ECMO support, mean ± SD, d25.5 (17.8)26.9 (18.2)23.1 (15.6)29.8 (20.1)
       Ventilator Associated Pneumonia, n (%)21 (84)
       Length of hospital stay, mean ± SD, d41 (21.6)40.43 (24.7)41.44 (17.2)39.7 (25.3)
       Tracheostomy placement during hospitalization, n (%)10 (40)9 (42.9)5 (55.6)4 (33.3)
       Renal replacement therapy during hospitalization, n (%)2 (8)2 (9.5)02 (16.7)
       Intracerebral hemorrhage during hospitalization, n (%)3 (12)3 (14)0 (0)3 (25)
       Survival to hospital discharge, n (%)13 (52)9 (42.9)90
      Abbreviations: ARDS, acute respiratory distress syndrome; BMI, body mass index; COPD, chronic pulmonary pulmonary disease; ECMO, extracorporeal membrane oxygenation; FIO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen; PBW, predicted body weight; PEEP, positive end-expiratory pressure; SOFA, sequential organ failure assessment; V-LDPV, verylow driving-pressure ventilation.
      low asterisk Respiratory diseases included asthma and COPD.
      Missing ventilator settings from 10 participants due to mobile ECMO cannulation.
      ECMO settings during sample collections.
      § Nineteen of the 21 participants that underwent V-LDPV had an esophageal manometer placed.
      Some participants had “mobile” ECMO, i.e., had VV-ECMO initiated at another hospital by the authors’ ECMO team prior to transfer.
      • Odish MF
      • Yi C
      • Chicotka S
      • et al.
      Implementation and outcomes of a mobile extracorporeal membrane oxygenation (ECMO) program in the United States during the coronavirus disease 2019 (COVID-19) pandemic.
      ,
      • Odish M
      • Yi C
      • Tainter C
      • et al.
      The implementation and outcomes of a nurse-run extracorporeal membrane oxygenation program, a retrospective single-center study.
      The ECMO configuration, equipment, and settings can be found in the supplement.

      Data Collection

      Demographic information, baseline characteristics, ventilator, hemodynamics and vasopressors and/or inotropes, analgesia and sedative medication doses, neuromuscular blockade (NMB) use, and laboratory values were collected at study enrollment and during protocol sample collection. The norepinephrine equivalent dose and mechanic work were calculated as previously reported (see equations in supplemental materials).
      • Russell JA
      • Walley KR
      • Singer J
      • et al.
      Vasopressin versus norepinephrine infusion in patients with septic shock.
      ,
      • Giosa L
      • Busana M
      • Pasticci I
      • et al.
      Mechanical power at a glance: A simple surrogate for volume-controlled ventilation.

      Experimental Protocol

      The study authors measured plasma biomarkers at the following time points: (1) pre-ECMO with LTVV, (2) post-ECMO with LTVV, (3) post-ECMO with LDPV, (4) post-ECMO after 2 hours of V-LDPV (main intervention), and (5) post-ECMO 2 hours after returning to LDPV from V-LDPV (main intervention) (Fig 1; Supplemental Table S1). Very low driving-pressure ventilation was performed for 2 hours with a ΔP of 1 cmH2O. The ventilators were set to pressure-control ventilation during LDPV and V-LDPV. All measurements were made with participants in the supine position, with the head of the bed elevated at 20°-to-40°. An esophageal balloon (Cooper Surgical) was placed prior to the V-LDPV protocol, as previously described.
      • Beitler JR
      • Sarge T
      • Banner-Goodspeed VM
      • et al.
      Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure-guided strategy vs an empirical high PEEP-FiO2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: A randomized clinical trial.
      Fig 1
      Fig 1Study protocol. The ventilators were set to pressure-control ventilation during low-driving-pressure ventilation and very low driving-pressure ventilation; thus, plateau pressure = positive end-expiratory pressure + driving pressure. May reference Supplementary Table S1 in Supplemental Appendix for protocol sample timing and ventilator settings. ELSO, extracorporeal life support organization; EMCO, extracorporeal membrane oxygenation; LDPV, low-driving-pressure ventilation; LTVV, low-tidal-volume ventilation; PEEP, positive end-expiratory pressure; V-LDPV, very low driving- pressure ventilation.
      Patients were frequently on NMB at the time of ECMO cannulation and deeply sedated at the time of all measurements. After the initiation of ECMO, the decision to continue or stop NMB was left to the clinical team (and was sometimes stopped to obtain a neurologic examination). No patients during the protocol (V-LDPV) had a spontaneous awaking or breathing trial or were placed in the prone position. Standard intensive care unit therapies for patients with ARDS at the authors’ institution, such as stress ulcer prophylaxis, sedation, analgesia, and restrictive fluid management, were provided and unchanged by their protocol. Given the brief duration of the protocol and the within-subjects comparisons, the authors doubt these had a major impact on their results.

      Blood Analysis

      All blood samples were drawn into heparin plasma separator tubes (Becton, Dickinson and Co) and centrifuged within 2 hours of collection at 2,000 × g for 15 minutes. Plasma was aliquoted and stored at -80°C within 2.5 hours of collection. The IL-6, IL-8, sRAGE, chemokine ligand-5 (CCL-5), angiopoietin-2, angiopoietin-1, interferon γ-inducible protein-10, tumor necrosis factor α, CCL-2, CCL-9, interleukin 10 (IL-10), and vascular endothelial growth factor levels were measured in 2-fold diluted plasma using a BioLegend Legendplex multiplex custom cytokine panel. Biomarker values were calculated using Biolegend's cloud-based analysis software.

      Outcomes

      The primary outcome was the changes in plasma IL-6, IL-8, and sRAGE between periods of LDPV and V-LDPV. The secondary outcomes included the following: tolerability and safety of V-LDVP as assessed by MAP, heart rate, pulse oximetry, norepinephrine equivalent dose, ECMO circuit blood flow rate, and ECMO sweep gas flow rate, and changes in additional biomarker levels (ie, CCL-5, angiopoietin-2, angiopoietin-1, interferon-inducible protein-10, tumor necrosis factor α, CCL-2, CCL-9, IL-10, and vascular endothelial growth factor).

      Statistical Analysis

      Descriptive statistics were calculated using mean (SD) or median (IQR) for the continuous variables and frequency (percentage) for the categorical variables.
      The primary analyses assessed the change in Vt and each biomarker level from LDPV (protocol sample 3) to V-LDPV (protocol sample 4) and from V-LDPV back to LDPV (protocol sample 5). Linear mixed- effects models were used with Vt or biomarker levels (in log scale) at each time point as the outcome, sampling time as the fixed effect, and random intercept and slope. The authors also studied whether spontaneous breathing affected the change in Vt or biomarker levels by including the interaction term of spontaneous breathing and sampling time as a fixed effect in the models. Spearman's correlations were calculated to assess whether a change in Vt from LTVV to LDPV (protocol sample 1 to 3), LDPV to V-LDPV (protocol sample 3 to 4), and from V-LDPV to LDPV (protocol sample 4 to 5) was associated with the change in biomarkers.
      To determine if the initiation of ECMO impacted biomarker levels, paired t tests were used to assess the change in biomarker levels between protocol samples 1 and 2. To study the effects of ECMO over the first 16-to-24 hours, the authors looked at the change in biomarker levels between protocol samples 1 (on LTVV) and 3 (on ECMO for participants who performed V-LDVP protocol), or 6 (on ECMO for participants who did not perform V-LDVP protocol). Given the number of biomarkers the authors examined, the Benjamini-Hochberg method was used to adjust for multiple testing. Statistical analysis was performed with SPSS (version 27.0; IBM SPSS, Inc, Armonk, NY) and R (version 3.6.1; R Foundation for Statistical Computing) statistics software.

      Results

      Participants

      Twenty-six participants were enrolled. One participant was discovered to have an intracerebral hemorrhage immediately after ECMO initiation, and support was withdrawn shortly thereafter and not included in the analysis. Sixteen patients were initiated on ECMO at the authors’ institution; whereas 10 were begun prior to transfer to their institution (mobile ECMO), and most (9 of 10 [90%]) of these participants did not have protocol samples 1 and 2 (Supplemental Figure S1). Twenty-one participants underwent the V-LDPV intervention. Four participants only had protocol samples 1, 2, and 6 collected (without V-LDPV), due to the initial COVID-19 pandemic restrictions on the biosafety level-2 laboratory operating hours and staff availability. One participant's V-LDPV protocol used a ΔP of 5 cmH2O due to the specific ventilator model limitations on minimal ΔP.

      Patient Demographics and Clinical Course

      Baseline demographics are reported in Table 1. All participants had ARDS due to SARS-CoV-19. Three participants had intracerebral hemorrhages and did not survive to hospital discharge. Thirteen (13 of 25 [52%]) participants survived to hospital discharge; of the participants (n = 21) who underwent the V-LDPV protocol, 9 (9 of 21 [43%]) survived (Table 1).

      Very Low Driving-Pressure Ventilation

      In 21 participants, the mean Vt going from LDPV to V-LDPV and back to LDPV was 3.4 ± 2.6 to 2.7 ± 3.2 to 4.0 ± 2.9 mL/kg PBW (p = 0.075 from LDPV to V-LDPV; p < 0.001 from V-LDPV back to LDPV; Fig 2). Four patients were on NMB during V-LDPV and did not have spontaneous respirations based on esophageal manometry changes and respiratory rate. Additionally, 5 patients not on NMB also had no evidence of spontaneous respiration. The Vt of these 9 participants was changed significantly from LDPV to V-LDPV (p < 0.001) and from V-LDPV back to LDPV (p < 0.001) with Vt of 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg PBW, respectively.
      Fig 2
      Fig 2Tidal volume changes during experimental ventilator protocol. Left panel, tidal volumes per kg of predicted body weight in all participants (n = 21) undergoing very low driving-pressure ventilation. Blue dashed lines are spontaneously breathing participants (n = 12). Green solid lines are nonspontaneously breathing participants (n = 9). Right panel, average tidal volumes per kg of predicted body weight. The Red line is all participants, blue line is spontaneously breathing participants, and green line is nonspontaneously breathing participants. Error bars represent 95% CI. LDPV, low-driving-pressure ventilation; PBW, predicted body weight; V-LDPV, very low driving-pressure ventilation.
      Twelve participants (12 of 21 [57%]) had spontaneous respirations. The Vt in these participants did not significantly change from LDPV to V-LDPV (p = 0.481) and from V-LDPV back to LDPV (p = 0.065) with Vt of 4.5 ± 3.1 to 4.7 ± 3.1 to 5.6 ± 2.9 mL/kg PBW.
      There were no significant changes in safety parameters, including MAP, heart rate, pulse oximetry, norepinephrine equivalent dose, ECMO circuit blood flow rate, and ECMO sweep gas flow rate during the V-LDPV protocol (Supplemental Table S2).

      Biomarker Outcomes

      There were no significant changes in primary biomarkers (sRAGE, IL-6, IL-8) from LDPV (protocol sample 3) to V-LDPV (protocol sample 4) and back to LDPV (protocol sample 5) (Table 2; Fig 3). Patients who were spontaneously breathing had higher biomarkers levels, although this was not statistically significant (Fig 3). There was no significant association between changes in Vt and biomarkers (sRAGE, IL-6, IL-8) from LTVV to LDPV and from LDPV to V-LDPV (Supplemental Figure S2).
      Table 2Biomarkers Measurements at Protocol Samples 1-6
      PlasmaBiomarkerProtocol Sample 1: Pre-ECMO With LTVV(n = 16)Protocol Sample 2:Post-ECMO With LTVV (n = 14)Protocol Sample 3:Post-ECMO With LDPV(n = 22)Protocol Sample 4:

      Post-ECMOAfter 2 Hours of V-LDPV(n = 21)
      Protocol Sample 5:Post-ECMO With LDPV(n = 20)Protocol Sample 6: 24 Hours Post-ECMO(LDPV) (n = 4)
      sRAGE1,654.1 (929.9–2,753.6)2,301.8 (1,035.2–3,168.6)1,978.4 (800.2–4,362.2)1,066.3 (679.6–4,645.3)1,220.7 (836.1–7,298.3)3,712.1 (1,907.6–4,432)
      IL–6338.2 (166–627.5)348.6 (187.3–580.6)587.8 (250–1,166.7)520.8 (197.6–700.6)388.2 (261.7–976.5)1,939.5 (249.8–2,624.5)
      IL–8305.1 (187.4–396.6)355.1 (204.3–510.3)293.3 (170.9–436)258 (149.3–406)257.9 (133.5–450.4)548.5 (319–560.6)
      IL–1030.3 (26.4–36.5)24.7 (22.6–36.5)28.5 (21.2–42.4)29.7 (20.9–38.1)30.2 (20.2 – 38.6)28.8 (19.8–37.1)
      CCL2900.3 (814.8–1,711.5)879.8 (778–1,224.1)1,422.6 (711.3–2,077.7)1,187.5 (809.5–2,403)1,123.3 (654.6–2,031.4)1,802.4 (1,207.6–2,421)
      CCL57,574.8 (2,772.3–14,469.7)6,561 (1,982–11,871.4)2,825.1 (1,982.3–6,851.3)2,112.9 (1,052.4–9,842.7)2,499.2 (1,211.7–6,882.54,204.5 (4,045.4–6,144.3)
      CXCL9
      p ≤ 0.05 between protocol samples 1 and 2 (pre-ECMO with LTVV v post-ECMO with LTVV).
      p ≤ 0.05 between protocol samples 1 and 3 or 5 (pre-ECMO with LTVV v post-ECMO 16-24 hours).
      p ≤ 0.05 between protocol samples 3 and 4 (post-ECMO LDPV v V-LDPV) when associated with change in tidal volume.
      2,928.7 (1,590–5,108)6,024.1 (4,066.3–9,537.5)4,328.1 (1,967.7–6,384.7)4,002.8 (1,803.5–6,322.3)4,069.5 (1,796.1–5,392.8)5,650.4 (3,114.5–6,036.8)
      Ang–12,540.6 (1,320.5–4,898.8)3,033.3 (694.7–4,238.8)1,769.7 (982.7–4,300.1)2,054.3 (1,161.6–2,712.3)1,702.1 (450.6–2,506.9)2,148.1 (1,515.9–2,998.6)
      Ang–22,202.5 (1,448.2–2,756)2,028.9 (1,412.7–2,850)2,174.3 (1,523.6–3,240.1)2,275 (1,533.6–3,386)2,035.4 (1,472.9–2,691.5)1,674.4 (1,114.1–2,041.3)
      IP–101,811.8 (1,419–3,423.9)2,121.7 (1,792.8–3,038.8)2,764.3 (1,435.5–5,188.5)2,892.4 (1,477.5–5,123.9)2,817.1 (1,532.2–4,405.4)1,415.9 (1,137.2–2,222.4)
      IFN–α
      p ≤ 0.05 between protocol samples 1 and 2 (pre-ECMO with LTVV v post-ECMO with LTVV).
      p ≤ 0.05 between protocol samples 1 and 3 (pre-ECMO with LTVV v post-ECMO with LDPV) when associated with change in tidal volume.
      499.3 (378.6–616.8)494.9 (337.5–674.3)353.1 (235.2–719.5)300.3 (199.5–519.6)305.3 (169–631.7)575 (563–624.2)
      TNF–α27.4 (21.6–37.2)38 (30.4–54.9)22.2 (14.6–71.2)21.1 (9.1–30.2)19.5 (7.3–45.5)83.3 (58.2–102.2)
      VEGF
      p ≤ 0.05 between protocol samples 1 and 2 (pre-ECMO with LTVV v post-ECMO with LTVV).
      p ≤ 0.05 between protocol samples 3 and 4 (post-ECMO LDPV v V-LDPV). ‡p ≤ 0.05 between protocol samples 4 and 5 (post-ECMO V-LDPV v LDPV).
      98.5 (75.3–119.4)42.5 (26.4–55.8)72.1 (42.6–95.6)53.9 (41.6–71.3)54.8 (38–76.3)50 (49.3–58.7)
      NOTE. All values are median (IQR). Biomarker units in pg/mL.
      Abbreviations: Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; CCL, chemokine ligand; CXCL9, chemokind ligand-9; IFN-α, interferon-α; IL, interleukin; IP-10, interferon γ-inducible protein-10; LDPV, low-driving-pressure ventilation; LTVV, low-tidal-volume ventilation; sRAGE, soluble receptor for advanced glycation end-products; TNF-α, tumor necrosis factor α; V-LDPV, very low driving-pressure ventilation; VEGF, vascular endothelial growth factor levels.
      low asterisk p ≤ 0.05 between protocol samples 1 and 2 (pre-ECMO with LTVV v post-ECMO with LTVV).
      p ≤ 0.05 between protocol samples 3 and 4 (post-ECMO LDPV v V-LDPV).‡p ≤ 0.05 between protocol samples 4 and 5 (post-ECMO V-LDPV v LDPV).
      § p ≤ 0.05 between protocol samples 1 and 3 or 5 (pre-ECMO with LTVV v post-ECMO 16-24 hours).
      || p ≤ 0.05 between protocol samples 1 and 3 (pre-ECMO with LTVV v post-ECMO with LDPV) when associated with change in tidal volume.
      p ≤ 0.05 between protocol samples 3 and 4 (post-ECMO LDPV v V-LDPV) when associated with change in tidal volume.
      Fig 3
      Fig 3Biomarker changes during experimental ventilator protocol. Biomarker levels for all patients who underwent very low driving-pressure ventilation (n = 21). Left panels, average biomarker levels (with 95% CI) for soluble receptor for advanced glycation end-products, interleukin-6, and interleukin-8. Red for all patients, blue for spontaneously breathing patients, and green for patients with nonspontaneous breaths. Right panel, red for spontaneously (n = 9) and teal for non-spontaneous breathing (n = 12) patients. IL-6, interleukin 6; IL-8, interleukin 8; LDPV, low-driving-pressure ventilation; V-LDPV, very low driving-pressure ventilation; sRAGE, soluble receptor for advanced glycation end-products.
      The primary biomarkers (sRAGE, IL-6, IL-8) did not have significant changes from pre-ECMO (protocol sample 1: LTVV) to immediately post-ECMO (protocol sample 2: LTVV) for the 14 patients who had both samples (Table 2; Supplemental Table S3).
      In addition, sRAGE, IL-6, and IL-8 did not significantly change from pre-ECMO (protocol sample 1: LTVV) compared to 16 hours and 24 hours post-ECMO (protocol sample 3: LDPV and protocol sample 6: LDPV, respectively) (Table 2; Supplemental Table S4). Sixteen participants with protocol sample 1 were included in this analysis. The study authors found no relationship among their main biomarkers (IL-6, IL-10, and sRAGE) and survivors versus nonsurvivors in a logistic regression (p = 0.280, p = 0.086, p = 0.357, respectively). All other biomarkers that did change significantly during the authors’ protocol are noted in Table 2.

      Discussion

      The authors tested the hypothesis that V-LDPV would lead to decreased levels of biomarkers of lung injury and inflammation in participants with COVID-19 ARDS on ECMO. They found that V-LDPV was feasible and safe, but it did not uniformly result in very low Vt (<4 mL/kg of PBW) due to spontaneous respiratory efforts. Perhaps, as a result, there were no significant changes in the main biomarkers, IL-6, IL-8, and sRAGE. Even when controlling for spontaneous breathing and Vt change, the authors did not find consistent changes in plasma biomarkers in the first 24 hours post-ECMO.
      This study demonstrated that V-LDPV and the sometimes-resulting apneic oxygenation were feasible and safe for the duration of the study period. Similar studies also reported no safety issues.
      • del Sorbo L
      • Goffi A
      • Tomlinson G
      • et al.
      Effect of driving pressure change during extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome: A randomized crossover physiologic study.
      ,
      • Rozencwajg S
      • Guihot A
      • Franchineau G
      • et al.
      Ultra-protective ventilation reduces biotrauma in patients on venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      However, there may be tradeoffs with V-LDPV and apneic oxygenation. All participants in the studies by Rozencwajg et al. (n = 16) and Del Sorbo et al. (n = 10) were paralyzed using NMB, compared to only 19% of the participants in this study. Neuromusclar blockade and resulting sedation have associated risks, such as delirium, weakness, and ventilatory-associated pneumonia (VAP).
      • Price D
      • Mikkelsen M
      • Umscheid C
      • et al.
      Neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness: A systematic review and meta-analysis.
      ,
      • Klompas M.
      Potential strategies to prevent ventilator-associated events.
      One series of participants with COVID-19 requiring ECMO had VAP rates of 86%, similar to the authors’ rate of 84%.
      • Luyt C-E
      • Sahnoun T
      • Gautier M
      • et al.
      Ventilator-associated pneumonia in patients with SARS-CoV-2-associated acute respiratory distress syndrome requiring ECMO: A retrospective cohort study.
      Although there are many possible explanations (eg, altered antimicrobial pharmacokinetics due to extracorporeal circuits, immunosuppression due to treatment with corticosteroids, and long duration of intubation), it is also possible that low Vt, atelectasis, and higher sedation requirements impair secretion clearance and therefore increase the risk of VAP.
      The RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19.
      • Duceppe M-A
      • Kanji S
      • Do AT
      • et al.
      Pharmacokinetics of commonly used antimicrobials in critically ill adults during extracorporeal membrane oxygenation: A systematic review.
      • Ramanathan K
      • Shekar K
      • Ling RR
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis.
      • Abrams D
      • Agerstrand C
      • Beitler JR
      • et al.
      Risks and benefits of ultra–lung-protective invasive mechanical ventilation strategies with a focus on extracorporeal support.
      Although speculative, there may be Vt (∼2-4 mL/kg PBW) that is low enough to minimize VILI and/or biotrauma but high enough to avoid atelectasis, VAP, and require less sedation and/or NMB. This speculative Vt will likely need to be personalized to each patient.
      A primary finding was that V-LDPV by itself did not reliably reduce Vt, even with deep sedation and normal serum pH levels from ECMO support. Setting low ΔP in deeply sedated patients falsely may reassure clinicians that they are minimizing VILI and/or biotrauma; however, as the authors’ study revealed, it may not consistently lower Vt if participants are spontaneously breathing (ie, higher transpulmonary pressure).
      • Dianti J
      • Fard S
      • Wong J
      • et al.
      Strategies for lung- and diaphragm-protective ventilation in acute hypoxemic respiratory failure: A physiological trial.
      Mechanically ventilated patients may still have high respiratory drive (measured with P0.1) despite deep sedation.
      • Dzierba A
      • Khalil A
      • Derry K
      • et al.
      Discordance between respiratory drive and sedation depth in critically ill patients receiving mechanical ventilation.
      For patients with ARDS on ECMO, even high sweep gas rates do not reliably suppress respiratory drive, in contrast to those on ECMO for other indications.
      • Crotti S
      • Bottino N
      • Ruggeri G
      • et al.
      Spontaneous breathing during extracorporeal membrane oxygenation in acute respiratory failure.
      Thus, although retrospective analysis has shown that lower ΔP may have a survival benefit for ARDS patients on ECMO, the authors caution that lower ΔP alone may not confer benefit.
      • Amato MBP
      • Meade MO
      • Slutsky AS
      • et al.
      Driving pressure and survival in the acute respiratory distress syndrome.
      ,
      • Neto AS
      • Schmidt M
      • Azevedo LCP
      • et al.
      Associations between ventilator settings during extracorporeal membrane oxygenation for refractory hypoxemia and outcome in patients with acute respiratory distress syndrome: A pooled individual patient data analysis: Mechanical ventilation during ECMO.
      Although they recommend following the ELSO ECMO guidelines on ARDS ventilator settings, they do not discuss the use of NMB.
      • Tonna JE
      • Abrams D
      • Brodie D
      • et al.
      Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO).
      Patients who are spontaneously breathing or have increased work of breathing during LDPV, with resulting harmful or unwanted Vt a may require increasing sedation (if it successfully lowers respiratory drive) and/or NMB to minimize transpulmonary pressure (TPP). In short, TPP is likely more reflective of VILI and/or biotrauma than ΔP or mechanical power.
      The study authors found no significant change in plasma biomarkers of lung injury and inflammation among the 3 studied ventilator strategies (LTVV, LDPV, and V-LDPV), possibly because they did not reliably change Vt. Even when investigating changes in Vt (rather than ventilator ΔP) with changes in biomarkers, contrary to the authors’ hypothesis, they did not see a reliable correlation. These results were similar to Rozencwajg et al. who observed no difference between different combinations of ΔP and PEEP, some of which should be more protective (eg, high PEEP and low ΔP) in their cohort of 16 ECMO participants.
      • Rozencwajg S
      • Guihot A
      • Franchineau G
      • et al.
      Ultra-protective ventilation reduces biotrauma in patients on venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      For example, in their study, IL-6 and sRAGE were unchanged 12 hours post-ventilator changes. However, prior to their ventilator interventions, biomarkers (IL-6 and sRAGE) decreased after 24 hours of protective ventilation (pplat <24) while on ECMO, compared to pre-ECMO baseline. The decrease in biomarkers compared to pre-ECMO could reflect NMB (as all 16 patients were paralyzed) and/or changes over time. It should be noted that the Rozencwajg et al. and Del Sorbo et al. studies were performed prior to the COVID-19 pandemic. Recently, in 22 patients with ARDS due to COVID-19, Lebreton et al. similarly found that IL-6 levels decreased on ECMO over 48 hours.
      • Lebreton G
      • Dorgham K
      • Quentric P
      • et al.
      Longitudinal cytokine profiling in patients with severe COVID-19 on extracorporeal membrane oxygenation and hemoadsorption.
      Consistent with these prior reports and in contrast to older literature, the authors herein did not find a significant increase in biomarkers with ECMO initiation in their participants.
      • Millar JE
      • Fanning JP
      • McDonald CI
      • et al.
      The inflammatory response to extracorporeal membrane oxygenation (ECMO): A review of the pathophysiology.
      Compared to older ECMO circuits, current circuits are smaller and more biocompatible, possibly decreasing the effects on systemic inflammation and biomarkers.
      • Willers A
      • Arens J
      • Mariani S
      • et al.
      New trends, advantages and disadvantages in anticoagulation and coating methods used in extracorporeal life support devices.
      The authors’ results differed from Del Sorbo et al., who also tested apneic oxygenation in 10 participants in crossover fashion; from standard ELSO-recommended LDPV to no ΔP (ie, only PEEP) to increased ΔP (ΔP = 20 cmH2O) for 2 hours at each setting.
      • del Sorbo L
      • Goffi A
      • Tomlinson G
      • et al.
      Effect of driving pressure change during extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome: A randomized crossover physiologic study.
      All patients were paralyzed, and the range of Vt during the experiment was about 4 mL/kg. With this change in Vt, there were small, though statistically significant changes in some biomarkers, notably IL-6. There are several possible explanations. First, the Vt does impact biomarker profile, but the authors’ study and Rozencwajg did not have large enough changes in Vt or ΔP (ie, TPP).
      • Rozencwajg S
      • Guihot A
      • Franchineau G
      • et al.
      Ultra-protective ventilation reduces biotrauma in patients on venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      Second, the authors’ patients with COVID-19 ARDS might have had more lung injury than ARDS from other etiologies, and the changes in biomarkers with changes in ventilation strategy might have been difficult to detect. For example, some IL-6 levels reported by Lebreton et al. were 5- to 10-fold higher (similar to this study) than in the Del Sorbo et al. study. Third, the authors studied their participants in the first 24 hours post-ECMO, although both the protocols of Del Sorbo et al. and Rozencwajg et al. started 24-to-48 hours post-ECMO. Thus, it is possible that the decrease in biomarkers could have been time-dependent. Finally, most of the authors’ patients were not on NMB, which might have additional antiinflammatory effects.
      • Slutsky AS.
      Neuromuscular blocking agents in ARDS.
      This study had a few limitations, primarily as a single-center study with a modest sample size. However, the authors’ sample size was larger than in recent studies.
      • del Sorbo L
      • Goffi A
      • Tomlinson G
      • et al.
      Effect of driving pressure change during extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome: A randomized crossover physiologic study.
      ,
      • Rozencwajg S
      • Guihot A
      • Franchineau G
      • et al.
      Ultra-protective ventilation reduces biotrauma in patients on venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      They did not routinely investigate cardiac function, which may be important. As previously noted, patients with known cardiac dysfunction were not offered ECMO due to resource limitations from the ongoing COVID-19 pandemic. The authors’ population exclusively had ARDS due to COVID-19, whereas many other ECMO and ARDS studies had different etiologies of lung injury. However, due to the severe lung injury in COVID-19 ARDS, the authors’ findings may not be generalizable to other etiologies of ARDS. Furthermore, to minimize confounding factors, their protocol did not alter PEEP or the respiratory rate, both of which may have biomarker implications. The TPP was measured only at one time during the authors’ protocol; had it been measured continuously across all time points, the study could have assessed the association between lung stretch and biomarker concentration, which is more biologically relevant. As a physiologic study, the authors were not powered to detect clinical outcomes such as mortality. Finally, the study intervention was relatively brief by design (although biomarkers have been shown to have significant changes as quickly as 1-hour postventilator changes), as a longer duration of intervention may have further increased difficulty in data interpretation in the setting of the vicissitudes of critical illness.
      • Stüber F
      • Wrigge H
      • Schroeder S
      • et al.
      Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury.

      Conclusions

      V-LDPV is feasible and safe for patients on ECMO for ARDS. However, Vt was not uniformly reduced by ΔP adjustments alone due to spontaneous respiratory efforts. The study authors did not find that changes in ΔP or Vt correlated with ARDS biomarker levels within the relatively modest (but typical) Vt studied. Their results suggested that, for patients on ECMO, additional sedation (if effective) and/or NMB might be needed to maintain low Vt that is considered protective. Future studies are needed to evaluate if there is a protective effect of NMB in patients with severe ARDS who require VV-ECMO and persist with large Vt despite deep sedation and low ΔP. Further studies with clinical outcomes of early V-LDPV are also needed.

      Acknowledgments

      The authors gratefully acknowledge the family members who agreed to permit patient participation, and their perfusionists, nurses, respiratory therapists, nurse practitioners, and physicians who care for their patients at UC San Diego Health. The authors acknowledge Robert Abbott, PhD supported by National Institutes of Health (grant #K99AI145762), and Shane Crotty, PhD supported by Cooperative Centers for Human Immunology (grant #AI142742) from the La Jolla Institute of Immunology for help with biomarker measurement.

      Appendix. Supplementary materials

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