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• Reply to: Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.
  Lara Pisani, Stefano Nava, Tommaso Tonetti and Vito Marco Ranieri
  Published on: 11 November 2020
• Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.
  Pradipta Bhakta
  Published on: 11 November 2020

• Published on: 11 November 2020

  Reply to: Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.

  • Lara Pisani, Professor, MD Alma Mater Studiorum – Università di Bologna, Dipartimento di Scienze Mediche e Specialistiche, Respiratory and Critical Care Me
  • Other Contributors:
    • Stefano Nava, Professor; MD
    • Tommaso Tonetti, MD
    • Vito Marco Ranieri, Professor, MD

  To the Editor

  We thank Dr. Bhakta and colleagues for their interest in our article on the use of extracorporeal CO2 removal (ECCO2R) in patients with stable COPD and chronic hypercapnia (1).
  Bhakta et al. pointed out the role of non invasive ventilation (NIV) to treat chronic hypercapnic respiratory failure by improving alveolar ventilation. The Authors additionally argued that, in evaluating the efficacy of ECCO2R in hypercapnic COPD stable patients who have failed NIV therapy, we only concentrated on the hypercapnic rather than the hypoxic aspects, pointing out that in this population symptomatic relief and long-term CO2 reduction cannot occur without improved oxygenation.
  These points of discussion give us the opportunity to better explain the ECCO2R functioning and consequently the methodology of our study.
  ECCO2R refers to an extracorporeal circuit that is able to selectively extract carbon dioxide from blood with little to no effect on oxygenation. Various ECCO2R systems are now available. In addition to PaCO2 baseline level, the ability of different ECCO2R devices to eliminate CO2 is dependent upon two important determinants: 1) the surface area available for gas exchange and 2) the blood flow rate (2). Moreover, the partial pressure gradient of the gas across the membrane can be obtained by using oxygen or air as sweep gas, according to Fick’s law of diffusion. Because in minimally invasive veno-venous ECCO 2 R systems the ratio of catheter...

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  To the Editor

  We thank Dr. Bhakta and colleagues for their interest in our article on the use of extracorporeal CO2 removal (ECCO2R) in patients with stable COPD and chronic hypercapnia (1).
  Bhakta et al. pointed out the role of non invasive ventilation (NIV) to treat chronic hypercapnic respiratory failure by improving alveolar ventilation. The Authors additionally argued that, in evaluating the efficacy of ECCO2R in hypercapnic COPD stable patients who have failed NIV therapy, we only concentrated on the hypercapnic rather than the hypoxic aspects, pointing out that in this population symptomatic relief and long-term CO2 reduction cannot occur without improved oxygenation.
  These points of discussion give us the opportunity to better explain the ECCO2R functioning and consequently the methodology of our study.
  ECCO2R refers to an extracorporeal circuit that is able to selectively extract carbon dioxide from blood with little to no effect on oxygenation. Various ECCO2R systems are now available. In addition to PaCO2 baseline level, the ability of different ECCO2R devices to eliminate CO2 is dependent upon two important determinants: 1) the surface area available for gas exchange and 2) the blood flow rate (2). Moreover, the partial pressure gradient of the gas across the membrane can be obtained by using oxygen or air as sweep gas, according to Fick’s law of diffusion. Because in minimally invasive veno-venous ECCO 2 R systems the ratio of catheter blood flow rate to cardiac output is relatively low, the application of oxygen sweep gas is not sufficient to improve oxygenation (3,4).
  However, hypercapnic respiratory failure is not necessarily associated with severe hypoxemia, especially in stable hypercapnic COPD patients in whom the presence of hypercapnia has been shown to be a determinant of mortality (5-7).
  Actually, the main mechanisms of NIV effectiveness in such population include the impact of the reduced lung hyperinflation on respiratory muscle workload and the increased ventilatory chemo-sensitivity to CO2 (8). In addition, most of the evidences on the use of NIV in patients with stable COPD compared the effects of domiciliary NIV+ long long-term oxygen therapy (LTOT) to LTOT alone (9).
  In our study we included 10 severe stable COPD patients with hypercapnia refractory to chronic NIV in terms of arterial blood gases. As mentioned, IPAP was set at 19.3±1.7 and EPAP 4.2±0.02 cmH20. NIV average use was 5.8±1.1hours/night, so the compliance was rather good. Most of patients used LTOT (70%). Obviously, during ECCO2R trial additional oxygen therapy was added if needed and FiO2 was adjusted to maintain SaO2 between 88 and 92%.
  The second point concerns how to capitalize the benefits derived from the observed transiently improvement in the arterial blood gas values. In fact, in the cohort of patients able to complete the 24 hours treatment, the effect on CO2 reduction was retained for 48–96 hours after ECCO2R discontinuation (1). We hypothesized that removing CO2 through the extracorporeal circuit may empty parts of the tissue CO2 stores, allowing transient normocapnia during spontaneous breathing. The mechanism of alveolar hypoventilation, as unique factor for the development and maintenance of chronic hypercapnia, is clearly not the only physiological explanation. Moreover, we are often led to translate the physiopathology of COPD exacerbation, for which we are more confident, to the chronic stable condition of the disease. The truth is that the mechanisms underlying this response are not yet identified.
  About the third point, we regret that the Authors did not notice the HCO3- baseline values ​​in table 1. In addition, bicarbonates remained stable during the time course of the trial (figure 2). In fact, ECCO2R is not aimed to “normalize” CO2, but just to lower its levels, keeping it reduced for a long period of time.
  Finally, we strongly agree that in severe COPD patients, CO2 load is not the sole mediator of improved outcomes. Our manuscript did not touch any patient-related outcomes. However being a proof of concept feasibility study, we focused exclusively to detect a signal whether ECCO2R may provide a time window “free” from hypercapnia in this population. However, the study demonstrated the feasibility of the hypothesis that ECCO2R may improve CO2 clearance in patients with chronic hypercapnia unresponsive to NIV.
  To conclude, ECCO2R could have important implications for the care of stable COPD patients and for the design of future investigations aiming to assess how many hours of ECCO2R are needed to provide the longest time window “free” from hypercapnia, detecting the ideal target population ( ECCO2R responders) and clinical benefits such as number of disease-related hospitalisations, improvement of dyspnea, exercise tolerance and health-related quality of life.

  References

  1. Pisani L, Nava S, Desiderio E, Polverino M, Tonetti T, Ranieri VM. Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: a proof-of-concept study Thorax. 2020;75(10):897-900.

  2. Karagiannidis C, Strassmann S, Brodie D, Ritter P, Larsson A, Borchardt R, Windisch W. Impact of membrane lung surface area and blood flow on extracorporeal CO2 removal during severe respiratory acidosis. Intensive Care Med Exp. 2017;5(1):34

  3. Schmidt M, Tachon G, Devilliers C, Muller G, Hekimian G, Brechot N, Merceron S, Luyt CE, Trouillet JL, Chastre J, Leprince P, Combes A: Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults. Intensive Care Med 2013, 39: 838-846.

  4. Karagiannidis C, Kampe KA, Sipmann FS, Larsson A, Hedenstierna G, Windisch W, Mueller T.Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations. Crit Care. 2014;18(3):R124

  5. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT Investigators (Study to understand prognoses and preferences for outcomes and risks of treatments). Am J Respir Crit Care Med 1996; 154: 959–967.

  6. Costello R, Deegan P, Fitzpatrick M, et al. Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis. Am J Med 1997; 102: 239–244.

  7. Foucher P, Baudouin N, Merati M, et al. Relative survival analysis of 252 patients with COPD receiving long-term oxygen therapy. Chest 1998; 113: 1580–1587

  8. Turkington PM, Elliott MW. Rationale for the use of non-invasive ventilation in chronic ventilatory failure. Thorax 2000; 55: 417–423.

  9. Begum E, Oczkowski S, Rochwerg B et al. European Respiratory Society guidelines on long-term home non-invasive ventilation for management of COPD. European Respiratory Journal 2019 54: 1901003

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  Conflict of Interest:
  None declared.

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• Published on: 11 November 2020

  Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.

  • Pradipta Bhakta, Anaesthesiologist and Intensivist Consultant, Department of Anaesthesia and Intensive Care, University Hospital Kerry, Tralee, Kerry, Ireland.

  Title: Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.
  Pradipta Bhakta, Antonio M. Esquinas, Brian O’Brien.
  Authors:
  1. Dr. Pradipta Bhakta (MD, MNAMS, FCAI, EDRA, EDIC)
  Consultant,
  Department of Anaesthesia and Intensive Care,
  University Hospital Kerry, Tralee, Kerry, Ireland.
  Phone: 00353894137596.
  Email: bhaktadr@hotmail.com
  2. Dr. Antonio M. Esquinas (PhD, MD)
  Consultant,
  Department of Intensive Care,
  Hospital Morales Meseguer,
  Murcia, Spain.
  Phone: 0034609321966
  Email: antmesquinas@gmail.com
  3. Dr. Brian O’Brien [FCARCSI, FJFICMI, FCICM (ANZ)]
  Consultant and Chair,
  Department of Anaesthesia and Intensive Care,
  Cork University Hospital, Cork, Ireland.
  Mobile: 00353877931656
  Email: drbobrien@hotmail.com
  Authors and their role:
  1. Dr. Pradipta Bhakta: Was involved analysis of the article, writing and editing the letter.
  2. Dr. Antonio M. Esquinas: Was involved analysis of the article, writing and editing the letter.
  3. Dr. Brian O’Brien: Was involved analysis of the article, writing and editing the letter.
  Corresponding Author: Dr. Pradipta Bhakta,
  Consultant,
  Departm...

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  Title: Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.
  Pradipta Bhakta, Antonio M. Esquinas, Brian O’Brien.
  Authors:
  1. Dr. Pradipta Bhakta (MD, MNAMS, FCAI, EDRA, EDIC)
  Consultant,
  Department of Anaesthesia and Intensive Care,
  University Hospital Kerry, Tralee, Kerry, Ireland.
  Phone: 00353894137596.
  Email: bhaktadr@hotmail.com
  2. Dr. Antonio M. Esquinas (PhD, MD)
  Consultant,
  Department of Intensive Care,
  Hospital Morales Meseguer,
  Murcia, Spain.
  Phone: 0034609321966
  Email: antmesquinas@gmail.com
  3. Dr. Brian O’Brien [FCARCSI, FJFICMI, FCICM (ANZ)]
  Consultant and Chair,
  Department of Anaesthesia and Intensive Care,
  Cork University Hospital, Cork, Ireland.
  Mobile: 00353877931656
  Email: drbobrien@hotmail.com
  Authors and their role:
  1. Dr. Pradipta Bhakta: Was involved analysis of the article, writing and editing the letter.
  2. Dr. Antonio M. Esquinas: Was involved analysis of the article, writing and editing the letter.
  3. Dr. Brian O’Brien: Was involved analysis of the article, writing and editing the letter.
  Corresponding Author: Dr. Pradipta Bhakta,
  Consultant,
  Department of Anaesthesia and Intensive Care,
  University Hospital Kerry, Tralee, Kerry, Ireland.
  Phone: 00353894137596
  Email: bhaktadr@hotmail.com
  Category of the article: Correspondence in response to article by Pisani L et al.
  Running Title: Letter replying to Pisani L et al.
  Financial support: No funding other than personal was used in conducting the audit as well as writing the manuscript. We declare that we have no financial and/or personal relationships with other people or organizations that could inappropriately influence (bias) our work.
  Conflict of Interest: The authors report no conflicts of interest.
  Ethical Approval: Not applicable.
  Word Count: 500.
  Figure no: 0.
  Table No: 0.

  Keywords: Chronic Obstructive Pulmonary Disease; Hypercapnia; Extracorporeal CO2 Removal, Non-Invasive Ventilation.

  To The Editor,
  We read with interest the proof-of-concept by Pisani and colleagues and congratulate them on this important work.1 We believe that several methodological details warrant analysis to facilitate extrapolation of their findings into the clinical context.
  In particular, it appears the authors characterise non-invasive ventilation (NIV) entirely as a mode of carbon dioxide (CO2) removal. We would emphasize its value as a modality to improve oxygenation. Many patients with chronic obstructive pulmonary disease (COPD) are hypoxic in part because of alveolar displacement of oxygen by expired CO2.2 The consequent type 2 respiratory failure, characteristic of advanced COPD with alveolar hypoventilation, by definition incorporates accompanying hypoxia.3 In evaluating the efficacy of ECCO2R in such patients, they only concentrated on the hypercapnic rather than the hypoxic aspect. NIV however offers both benefits.4 In selecting hypercapnic patients who have failed NIV therapy for the ECCO2R group, we would suggest that in such severe cases symptomatic relief and long-term CO2 reduction cannot occur without improved oxygenation. Effectively oxygen (O2) replaces CO2 eliminated from the alveoli, haemoglobin and cells. But if this aspect is ignored, the use of ECCO2R for 24 hours cannot contribute in the longer term. If we have understood correctly, in the ECCO2R rather than use additional O2, air flow was used to eliminate CO2. Patients in the ECCO2R group, having failed NIV trials in the preceding 6 months, were spontaneously breathing room air. This raises the question of how they were able to tolerate this. In this context we also wonder if the cases were matched for disease severity. Is it possible that milder cases were included, perhaps who were intolerant of NIV due to claustrophobia, discomfort or asynchrony? These points might be clarified further.
  A second broad point we would raise is the acceptance of normalized pH in chronic COPD patients with chronic acid-base disturbances, which are typically compensated by the kidney and by buffers in the circulation.5 We agree that in patients with severely diseased functional lung tissue the elimination of CO2 can provide temporary improvement in the arterial blood gas values, but wonder how the authors might speculate on future innovations to extend or capitalise on these benefits.
  Thirdly, while studying severe cases of COPD, the study included patients with pH levels above 7.35 while their PaCO2 exceeded 50 mmHg. There is no value given for HCO3 which is clearly important. Ideally full data might be provided to allow categorisation as per the GOLD staging classification.6
  Fourthly, in highlighting the role of ECCO2R in severe COPD patients, they have emphasised the failure of NIV. It ought to be observed that ECCO2R has similarly failed to benefit patients with acute respiratory distress syndrome.7 In severe cases of COPD, CO2 load is not the sole mediator of improved outcomes nor of symptomatic benefit, although it is a major issue with multiple adverse effects.3 We would welcome the authors’ views on these points and their thoughts on how their findings may become relevant to clinical practice in the future.
  Pradipta Bhakta,
  Antonio M. Esquinas,
  Brian O’Brien.
  References
  1. Pisani L, Nava S, Desiderio E, Polverino M, Tonetti T, Ranieri VM. Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: a proof-of-concept study [published online ahead of print, 2020 Aug 5]. Thorax. 2020;thoraxjnl-2020-214744. doi:10.1136/thoraxjnl-2020-214744.
  2. Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis. 2011;6:199-208.
  3. Agustí A, Hogg JC. Update on the Pathogenesis of Chronic Obstructive Pulmonary Disease. N Engl J Med. 2019;381(13):1248-1256.
  4. Coleman JM 3rd, Wolfe LF, Kalhan R. Noninvasive Ventilation in Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc. 2019;16(9):1091-1098.
  5. Bruno CM, Valenti M. Acid-base disorders in patients with chronic obstructive pulmonary disease: a pathophysiological review. J Biomed Biotechnol. 2012;2012:915150.
  6. Singh D, Agusti A, Anzueto A, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019;53(5):1900164.
  7. Fitzgerald M, Millar J, Blackwood B, et al. Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to the acute respiratory distress syndrome: a systematic review. Crit Care. 2014;18(3):222.

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  Conflict of Interest:
  None declared.

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