Hypercapnia and extracorporeal carbon dioxide removal (ECCO2R) in the acute respiratory distress syndrome

As a result of technical improvements, extracorporeal techniques for carbon dioxide removal have become an attractive option in managing adults with acute respiratory failure. However, evidence to support its use is scarce, and several questions regarding the best way to implement this therapy remain unanswered, which can be associated with severe side effects. In this review, we will present the currently available knowledge on (1) ECCO2R as an adjuvant treatment to invasive mechanical ventilation, (2) the impact of hypercapnia in patients with acute respiratory distress syndrome (ARDS), (3) the pathophysiological rationale and evidence of ECCO2R in patients with ARDS.

Acute respiratory distress syndrome; Extracorporeal carbon dioxide removal; Carbon dioxide; Lung-protective ventilation; Ventilator-associated lung injury

[1] Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A , et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. The Journal of the American Medical Association. 2016; 315: 788–800.

[2] Fan E, Del Sorbo L, Goligher EC, Hodgson CL, Munshi L, Walkey AJ, et al. An official American thoracic society/European society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine. 2017; 195: 1253–1263.

[3] Slutsky AS, Ranieri VM. Ventilator-induced lung injury. New England Journal of Medicine. 2013; 369: 2126–2136.

[4] Rackley CR, MacIntyre NR. Low tidal volumes for everyone? Chest. 2019; 156: 783–791.

[5] The Acute Respiratory Distress Syndrome Network, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine. 2000; 342: 1301–1308.

[6] Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine. 2007; 175: 160–166.

[7] Bellani G, Guerra L, Musch G, Zanella A, Patroniti N, Mauri T, et al. Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury. American Journal of Respiratory and Critical Care Medicine. 2011; 183: 1193–1199.

[8] Amato MBP, Barbas CSV, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. New England Journal of Medicine. 1998; 338: 347–354.

[9] Hager DN, Krishnan JA, Hayden DL, Brower RG. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. American Journal of Respiratory and Critical Care Medicine. 2005; 172: 1241–1245.

[10] Terragni PP, Del Sorbo L, Mascia L, Urbino R, Martin EL, Birocco A, et al. Tidal volume lower than 6 mL/kg enhances lung protection: role of extracorporeal carbon dioxide removal. The Journal of the American Society of Anesthesiologists. 2009; 111: 826–835.

[11] Fanelli V, Costamagna A, Ranieri VM. Extracorporeal support for severe acute respiratory failure. Seminars in Respiratory and Critical Care Medicine. 2014; 35: 519–527.

[12] Kolobow T, Gattinoni L, Tomlinson T, Pierce J. Control of breathing using an extracorporeal membrane lung. Anesthesiology. 1977; 46: 138–141.

[13] Gattinoni L, Pesenti A, Mascheroni D, Marcolin R, Fumagalli R, Rossi F, et al. Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. The Journal of the American Medical Association. 1986; 256: 881–886.

[14] Gattinoni L, Pesenti A, Rossi GP, Vesconi S, Fox U, Kolobow T, et al. Treatment of acute respiratory failure with low-frequency positive-pressure ventilation and extracorporeal removal of CO2. The Lancet. 1980; 316: 292–294.

[15] Gattinoni L, Mascheroni D, Torresin A, Marcolin R, Fumagalli R, Vesconi S, et al. Morphological response to positive end expiratory pressure in acute respiratory failure. Computerized tomography study. Intensive Care Medicine. 1986; 12: 137–142.

[16] West JB, Dollery CT, Naimark A. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. Journal of Applied Physiology. 1964; 19: 713–724.

[17] Tomashefski JF Jr, Davies P, Boggis C, Greene R, Zapol WM, Reid LM. The pulmonary vascular lesions of the adult respiratory distress syndrome. The American Journal of Pathology. 1983; 112: 112–126.

[18] Greene R. Pulmonary vascular obstruction in the adult respiratory distress syndrome. Journal of Thoracic Imaging. 1986; 1: 31–38.

[19] Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet J, Eisner MD, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. New England Journal of Medicine. 2002; 346: 1281–1286.

[20] Kallet RH, Zhuo H, Liu KD, Calfee CS, Matthay MA. The association between physiologic dead-space fraction and mortality in subjects with ARDS enrolled in a prospective multi-center clinical trial. Respiratory Care. 2014; 59: 1611–1618.

[21] Doorduin J, Nollet JL, Vugts MPAJ, Roesthuis LH, Akankan F, van der Hoeven JG, et al. Assessment of dead-space ventilation in patients with acute respiratory distress syndrome: a prospective observational study. Critical Care. 2016; 20: 121.

[22] Sinha P, Calfee CS, Beitler JR, Soni N, Ho K, Matthay MA, et al. Physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine. 2019; 199: 333–341.

[23] Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Critical Care. 2020; 24: 154.

[24] Kallet RH, L Lipnick MS. End-tidal-to-arterial PCO2 ratio as signifier for physiologic deadspace ratio and oxygenation dysfunction in acute respiratory distress syndrome. Respiratory Care. 2021; 66: 263–268.

[25] Morales-Quinteros L, Neto AS, Artigas A, Blanch L, Botta M, Kaufman DA, et al. Dead space estimates may not be independently associated with 28- day mortality in COVID-19 ARDS. Critical Care. 2021; 25: 171.

[26] Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Medicine. 1990; 16: 372–377.

[27] Brochard L, Roudot-Thoraval F, Roupie E, Delclaux C, Chastre J, Fernandez-Mondéjar E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The multicenter trail group on tidal volume reduction in ARDS. American Journal of Respiratory and Critical Care Medicine. 1998; 158: 1831–1838.

[28] Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. Survey of Anesthesiology. 2008; 52: 271–272.

[29] Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P, Wiener CM, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Critical Care Medicine. 1999; 27: 1492–1498.

[30] Laffey JG, Kavanagh BP. Carbon dioxide and the critically ill—too little of a good thing? The Lancet. 1999; 354: 1283–1286.

[31] Broccard A, Hotchkiss J, Vannay C, Markert M, Sauty A, Feihl F, et al. Protective effects of hypercapnic acidosis on ventilator-induced lung injury. American Journal of Respiratory and Critical Care Medicine. 2001; 164: 802-806.

[32] Contreras M, Ansari B, Curley G, Higgins BD, Hassett P, O’Toole D, et al. Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB-dependent mechanism. Critical Care Medicine. 2012; 40: 2622–2630.

[33] Cummins EP, Oliver KM, Lenihan CR, Fitzpatrick SF, Bruning U, Scholz CC, et al. NF-κB links CO2 sensing to innate immunity and inflammation in mammalian cells. The Journal of Immunology. 2010; 185: 4439–4445.

[34] Otulakowski G, Engelberts D, Gusarova GA, Bhattacharya J, Post M, Kavanagh BP. Hypercapnia attenuates ventilator-induced lung injury via a disintegrin and metalloprotease-17. The Journal of Physiology. 2014; 592: 4507–4521.

[35] Yang W, Song C, Wang N, Zhang L, Yue Z, Cui X, et al. Hypercapnic acidosis confers antioxidant and anti-apoptosis effects against ventilator-induced lung injury. Laboratory Investigation. 2013; 93: 1339–1349.

[36] O’Croinin DF, Nichol AD, Hopkins N, Boylan J, O’Brien S, O’Connor C, et al. Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury. Critical Care Medicine. 2008; 36: 2128-2135.

[37] O’Toole D, Hassett P, Contreras M, Higgins BD, McKeown ST, McAuley DF, et al. Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-κB dependent mechanism. Thorax. 2009; 64: 976–982.

[38] Vohwinkel CU, Lecuona E, Sun H, Sommer N, Vadász I, Chandel NS, et al. Elevated CO2 levels cause mitochondrial dysfunction and impair cell proliferation. Journal of Biological Chemistry. 2011; 286: 37067–37076.

[39] Bharat A, Angulo M, Sun H, Akbarpour M, Alberro A, Cheng Y, et al. High CO2 levels impair lung wound healing. American Journal of Respiratory Cell and Molecular Biology. 2020; 63: 244–254.

[40] Lecuona E, Trejo HE, Sznajder JI. Regulation of Na,K-ATPase during acute lung injury. Journal of Bioenergetics and Biomembranes. 2007; 39: 391–395.

[41] Briva A, Vadász I, Lecuona E, Welch LC, Chen J, Dada LA, et al. High CO2 levels impair alveolar epithelial function independently of pH. PLoS One. 2007; 2: e1238.

[42] Lardner A. The effects of extracellular pH on immune function. Journal of Leukocyte Biology. 2001; 69: 522–530.

[43] Lang CJ, Dong P, Hosszu EK, Doyle IR. Effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2005; 289: L96–L103.

[44] Oliver KM, Lenihan CR, Bruning U, Cheong A, Laffey JG, McLoughlin P, et al. Hypercapnia induces cleavage and nuclear localization of relb protein, giving insight into CO2 sensing and signaling. Journal of Biological Chemistry. 2012; 287: 14004–14011.

[45] Nakahata K, Kinoshita H, Hirano Y, Kimoto Y, Iranami H, Hatano Y. Mild hypercapnia induces vasodilation via adenosine triphosphate-sensitive K+ channels in parenchymal microvessels of the rat cerebral cortex. Anesthesiology. 2003; 99: 1333–1339.

[46] Shiota S, Okada T, Naitoh H, Ochi R, Fukuchi Y. Hypoxia and hypercapnia affect contractile and histological properties of rat diaphragm and hind limb muscles. Pathophysiology. 2004; 11: 23–30.

[47] Tang W, Weil MH, Gazmuri RJ, Bisera J, Rackow EC. Reversible impairment of myocardial contractility due to hypercarbic acidosis in the isolated perfused rat heart. Critical Care Medicine. 1991; 19: 218–224.

[48] Kregenow DA, Swenson ER. The lung and carbon dioxide: implications for permissive and therapeutic hypercapnia. European Respiratory Journal. 2002; 20: 6–11.

[49] Cullen D, Eger E. Cardiovascular effects of carbon dioxide in man. Anesthesiology. 1974; 41: 345–349.

[50] Nin N, Muriel A, Peñuelas O, Brochard L, Lorente JA, Ferguson ND, et al. Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome. Intensive Care Medicine. 2017; 43: 200–208.

[51] Tiruvoipati R, Pilcher D, Buscher H, Botha J, Bailey M. Effects of hypercapnia and hypercapnic acidosis on hospital mortality in mechanically ventilated patients. Critical Care Medicine. 2017; 45: e649–e656.

[52] Madotto F, Rezoagli E, McNicholas BA, Pham T, Slutsky AS, Bellani G, et al. Patterns and impact of arterial CO2 management in patients with acute respiratory distress syndrome: insights from the LUNG SAFE study. Chest. 2020; 158: 1967–1982.

[53] Kiiski R, Takala J. Hypermetabolism and efficiency of CO2 removal in acute respiratory failure. Chest. 1994; 105: 1198–1203.

[54] Burki NK, Mani RK, Herth FJF, Schmidt W, Teschler H, Bonin F, et al. A novel extracorporeal CO2 removal system: results of a pilot study of hypercapnic respiratory failure in patients with COPD. Chest. 2013; 143: 678–686.

[55] Wearden PD, Federspiel WJ, Morley SW, Rosenberg M, Bieniek PD, Lund LW, et al. Respiratory dialysis with an active-mixing extracorporeal carbon dioxide removal system in chronic sheep study. Intensive Care Medicine. 2012; 38: 1705–1711.

[56] Fanelli V, Ranieri MV, Mancebo J, Moerer O, Quintel M, Morley S, et al. Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress syndrome. Critical Care. 2016; 20: 36.

[57] McNamee JJ, Gillies MA, Barrett NA, Perkins GD, Tunnicliffe W, Young D, et al. Effect of lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal vs. standard care ventilation on 90- day mortality in patients with acute hypoxemic respiratory failure: the REST randomized clinical trial. The Journal of the American Medical Association. 2021; 326: 1013–1023.

[58] Zanella A, Caironi P, Castagna L, Rezoagli E, Salerno D, Scotti E, et al. Extracorporeal chloride removal by electrodialysis. A novel approach to correct acidemia. American Journal of Respiratory and Critical Care Medicine. 2020; 201: 799–813.

[59] Scaravilli V, Kreyer S, Belenkiy S, Linden K, Zanella A, Li Y, et al. Extracorporeal carbon dioxide removal enhanced by lactic acid infusion in spontaneously breathing conscious sheep. Anesthesiology. 2016; 124: 674–682.

[60] Tapia P, Lillo F, Soto D, Escobar L, Simon F, Hernández K, et al. Liquid extracorporeal carbon dioxide removal: use of THAM (tris-hydroxymethyl aminomethane) coupled to hemofiltration to control hypercapnic acidosis in a porcine model of protective mechanical ventilation. American Journal of Translational Research. 2016; 8: 3493–3502.

[61] Cove ME, MacLaren G, Federspiel WJ, Kellum JA. Bench to bedside review: extracorporeal carbon dioxide removal, past present and future. Critical Care. 2012; 16: 232.

[62] Flörchinger B, Philipp A, Klose A, Hilker M, Kobuch R, Rupprecht L, et al. Pumpless extracorporeal lung assist: a 10-year institutional experience. The Annals of Thoracic Surgery. 2008; 86: 410–417.

[63] Karagiannidis C, Kampe K, Sipmann F, Larsson A, Hedenstierna G, Windisch W, et al. Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations. Critical Care. 2014; 18: R124.

[64] Abrams D, Roncon-Albuquerque R, Brodie D. What’s new in extracorpo-real carbon dioxide removal for COPD? Intensive Care Medicine. 2015; 41: 906–908.

[65] Fitzgerald M, Millar J, Blackwood B, Davies A, Brett SJ, McAuley DF, et al. Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to the acute respiratory distress syndrome: a systematic review. Critical Care. 2014; 18: 222.

[66] Combes A, Fanelli V, Pham T, Ranieri VM. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Medicine. 2019; 45: 592–600.

[67] Goligher EC, Combes A, Brodie D, Ferguson ND, Pesenti AM, Ranieri VM, et al. Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design. Intensive Care Medicine. 2019; 45: 1219–1230.

[68] Bein T, Weber-Carstens S, Goldmann A, Müller T, Staudinger T, Brederlau J, et al. Lower tidal volume strategy (≈3 mL/kg) combined with extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 mL/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Medicine. 2013; 39: 847–856.

[69] Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld DA, et al. Driving pressure and survival in the acute respiratory distress syndrome. New England Journal of Medicine. 2015; 372: 747–755.

[70] Grasso S, Stripoli T, Mazzone P, Pezzuto M, Lacitignola L, Centonze P, et al. Low respiratory rate plus minimally invasive extracorporeal CO2 removal decreases systemic and pulmonary inflammatory mediators in experimental Acute Respiratory Distress Syndrome. Critical Care Medicine. 2014; 42: e451–e460.

[71] Gattinoni L. Ultra-protective ventilation and hypoxemia. Critical Care. 2016; 20: 130.

[72] Gattinoni L, Kolobow T, Tomlinson T, Iapichino G, Samaja M, White D, et al. Low-frequency positive pressure ventilation with extracorporeal carbon dioxide removal (LFPPV-ECCO2R): an experimental study. Anesthesia & Analgesia. 1978; 57: 470–477.

[73] Diehl J, Mercat A, Pesenti A. Understanding hypoxemia on ECCO2R: back to the alveolar gas equation. Intensive Care Medicine. 2019; 45: 255–256.

[74] Sklar MC, Beloncle F, Katsios CM, Brochard L, Friedrich JO. Extra-corporeal carbon dioxide removal in patients with chronic obstructive pulmonary disease: a systematic review. Intensive Care Medicine. 2015; 41: 1752–1762.

[75] Campbell EJ, O’Byrne V, Stratford PW, Quirk I, Vick TA, Wiles MC, et al. Biocompatible surfaces using methacryloylphosphorylcholine laurylmethacrylate copolymer. American Society for Artificial Internal Organs. 1994; 40: M853–M857.

[76] Combes A, Auzinger G, Capellier G, du Cheyron D, Clement I, Consales G, et al. ECCO2R therapy in the ICU: consensus of a European round table meeting. Critical Care. 2020; 24: 490.

[77] Terragni P, Del Sorbo L, Mascia L, Urbino R, Martin E, Birocco A, et al. Tidal volume lower than 6 mL/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology. 2009; 111: 826–835.

[78] Augy JL, Aissaoui N, Richard C, Maury E, Fartoukh M, Mekontso-Dessap A, et al. A 2-year multicenter, observational, prospective, cohort study on extracorporeal CO2 removal in a large metropolis area. Journal of Intensive Care. 2019; 7: 45.

[79] Schmidt M, Jaber S, Zogheib E, Godet T, Capellier G, Combes A. Feasibility and safety of low-flow extracorporeal CO2 removal managed with a renal replacement platform to enhance lung-protective ventilation of patients with mild-to-moderate ARDS. Critical Care. 2018; 22: 122.

[80] Ding X, Chen H, Zhao H, Zhang H, He H, Cheng W, et al. ECCO2R in 12 COVID-19 ARDS patients with extremely low compliance and refractory hypercapnia. Frontiers in Medicine. 2021; 8: 654658.