Extra Corporeal Carbon Dioxide Removal

 September 7

by Jonathan Downham

Extra Corporeal Carbon Dioxide Removal

Gavin Denton gives a great breakdown on some of the recent papers on Extra Corporeal Carbon Dioxide Removal. He analyses the papers in some detail. A long post….but worth the time I think. Thanks Gavin.

Three part question.

In patients with chronic obstructive airway disease and hypercapneic acidosis, who are failing non-invasive ventilation, does extra corporeal carbon dioxide removal  compared to non-invasive ventilation alone, reduce the need for invasive mechanical ventilation?


Clinical scenario.

A patient arrives in your resuscitation room in respiratory distress and a background of chronic obstructive pulmonary disease. After administering standard medical therapy, and controlled oxygen the patient remains in respiratory acidosis. Non-invasive ventilation is instituted, but the patient continues to be acidotic and deteriorating. The patient is prepared for rapid sequence induction and ventilation, but you wonder if there is an alternative.



Invasive mechanical ventilation (IMV) is the use of a machine to inflate the lungs via an artificial airway placed in the trachea. The therapy provides support for breathing in the critically ill patient when the lung tissue and respiratory muscles are failing. IMV involves using an anaesthetic and muscle relaxants to place the breathing tube in the trachea, and continuous sedation to stop the patient from pulling the tube out and allowing the machine to take over the action of breathing. Respiratory failure occurs when the lungs and the neuromuscular system that controls them fail to provide sufficient oxygen to the pulmonary blood supply, and/or remove carbon dioxide from the blood. There are a multitude of causes of respiratory failure, but the supportive techniques used follow common themes. Despite IMV being a cornerstone of supporting the critically ill patient, the side effects of this therapy can lead to worsening damage to the lungs and to other essential organs by triggering inflammation. The acute respiratory distress syndrome network (Acute Respiratory Distress Syndrome Network (ARDSNET), 2000) established that in patients with acute respiratory distress syndrome, the larger the breath and the higher the pressure delivered by a ventilator, the more likely the patient would die. This study established the practice of using smaller breaths and lower pressure in patients with severe breathing failure requiring IMV. In many patients, this approach causes large rises in carbon dioxide in the blood, raising acid levels and negatively affecting the body’s ability to maintain homeostasis. Extra corporeal carbon dioxide removal is a method of passing blood through a filter which removes carbon dioxide and returns it to the body, bypassing the need for fully functioning lungs. This allows IMV to be used more gently and reduce the risk of causing further lung damage.


Another form of respiratory support is non-invasive ventilation (NIV). This is a method of pushing more air into the lungs through a tight-fitting face mask. It is used to make breathing easier and to increase removal of carbon dioxide. In patients with certain types of breathing failure, NIV significantly reduces the need for IMV (Ram et al, 2004). However, some patients fail to respond to this therapy and therefore need IMV, consequently, they are less likely to survive (Chandra et al, 2012). The primary problem for these patients is the inability to remove carbon dioxide. Therefore, extra corporeal carbon dioxide removal may be of benefit where patients fail to respond to NIV.

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The evidence base for the use of extra corporeal carbon dioxide removal in the context of COPD exacerbation and a failed response to NIV is very small and very recent. This is emphasised in the identified narrative reviews which cite a handful of the same papers. They extrapolate extensively from the literature surrounding extra corporeal carbon dioxide removal in the context of ARDS. In the case of ARDS, Fitzgerald et al (2014) a systematic review only elicited two RCTs, with the bulk of the literature lying within the lower hierarchy of evidence in the form of case series and case-controls. This low level evidence may be an appropriate beginning in the developing literature, given the very recent nature of the application of extra corporeal carbon dioxide removal to patients with COPD and acute exacerbations. In view of the cost of new technology and its implementation, proof of principle is a minimum requirement before expensive, large scale and multi centre RCTs can be contemplated.

The obvious conflicts of interest in the available evidence include: funding, employment, editorial assistance and provision of equipment from industry. Although these issues are clearly disclosed, there has been a history of conflicts of interest and their impact on research and clinical practice over the last fifteen years. Drugs such as COX2 inhibitors (a selective non-steroidal anti-inflammatory drug class) and hydroxyethyl starch (a fluid used in shock resuscitation) have been withdrawn from the UK market, following the incomplete publication of data or outright research fraud. This emphasises that even large multi-centre RCTs can become biased and compromised when commercial interests are heavily invested in a research process.

With regard to extra corporeal carbon dioxide removal and its effectiveness in the removal of CO2, there is little doubt. The NIV and ARDS literature show consistently that the technique is effective. Using this removal of CO2 as the surrogate endpoint does not necessarily translate into a meaningful patient centred outcome (e.g. survival) and its use must be treated with caution. There is a strong theoretical basis that reducing or avoiding the need for IMV in patients who have failed NIV may translate to an improvement in morbidity and mortality in this population. This argument combined with the effectiveness of CO2 removal with ECCO2R, is an important bench to bed side translation of research and a pertinent research question. At present, the theoretical advantage of ECCO2R seems to be the primary argument for its use, implying cause and effect. Within the limits of the available level of evidence, there is support for the notion that extra corporeal carbon dioxide removal can reduce the need for IMV in this population. Taken at face value, Del Sorbo et al (2015) found a significant treatment effect. However, it is important not to automatically assume cause and effect. Chandra et al (2012) noted increased mortality in patients who required IMV when NIV failed to stabilise COPD patients. Conversely, patients who received IMV from the outset had an improved outcome compared to patients who failed NIV later and then received IMV. There may be other factors at play with regard to morbidity and mortality in this group of patients which are not immediately apparent. It is possible that reducing IMV in this group of patients may not provide the hoped-for mortality benefit, and other confounders may be present.

VV-ECCO2R is likely to supersede the initial pump-less AV system which was designed to be a less invasive alternative to ECMO. The equivalent CO2 removal capacity of VV-ECCO2R, without the risks of large bore arterial cannulation, make AV-ECCO2R of little additional value. This is particularly pertinent when balancing the risks of ECCO2R with IMV, and could potentially switch the benefits to harm. The additional benefit of VV-ECCO2R its increased utility outside of specialist ECMO centres. If future research is to establish a firm mortality benefit, it will not be possible to transport unstable patients who are not responding to NIV around the country to regional ECMO centres. It seems that if there is to be a future for ECCO2R, it will be in its integration into the typical therapies currently available in the average intensive care unit.

There is insufficient evidence to make assumptions about the impact of ECCO2R upon mortality or morbidity. Whilst proof of principle has been established, this does not mean to say that the reduction of NIV failure should continue to be accepted as a surrogate for reduced mortality. The risks of major bleeding and even death from haemorrhage should not be downplayed. Exchanging the risk of mortality from IMV with that of major bleeding and infection should not be considered advantageous. Using a comparable therapeutic method that is expensive, invasive and not widely available is not in the best interests of the patient. There is insufficient data to draw conclusions as to whether ECCO2R is a safer alternative to IMV.

There are signals in the current body of evidence that ECCO2R may reduce the need for IMV in patients with COPD with an exacerbation which does not respond to NIV. It is unclear whether there is a mortality benefit or if there is a reduction in morbidity. The current evidence base suffers from significant conflicts of interests which may incur a high bias in the results of these studies.


Bottom line.

  1. An RCT is required which is adequately powered to detect statistically significant differences in the need for invasive ventilation, mortality and morbidity between groups. A multi-centre (possibly international) trial would be needed to recruit a sufficient number of subjects.
  2. It is important that future trials compare like for like technology. VV-ECCO2R should be used to compare with IMV to remove the potential confounding increase in complications that may be associated with AV-ECCO2R.
  3. It is difficult to justify the risks of AV-ECCO2R versus a VV approach. VV-ECCO2R should be the mode of choice, particularly in the context of use outside of the domain of an ECMO centre.
  4. Patients who receive extracorporeal support should have data submitted to the Extracorporeal Life Support Organisation (ELSO, accessed July 2016). ELSO compiles an international registry of patients who receive extracorporeal life support. This is an organisation that is independent of industry and may be able to provide large volume cohort or case series data in the future.
  5. Any future research should aim for the greatest independence possible from commercial companies involved in the manufacture of ECCO2R This may require the use of government grants in order to maintain independence from corporate interests.
  6. There is insufficient evidence to recommend the routine use of ECCO2R in any population. In centres where a system of training and clinical governance is in place, ECCO2R is a potential option in individual cases.


Abrams, D.C., Brenner, K., Burkart, K.M., et al. (2013) Pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Annals of the American Thoracic Society, 10 (4): 307–314

ARDS Definition Task Force (2012) Acute respiratory distress syndrome [online]. JAMA, 307 (23). http://jama.jamanetwork.com/article.aspx?articleID=1160659&utm_source=Silverchair%20Infor [Accessed 16 July 2015] .

Bartosik, W., Egan, J.J. and Wood, A.E. (2011) The Novalung interventional lung assist as bridge to lung transplantation for self-ventilating patients – initial experience. Interactive cardiovascular and thoracic surgery, 13 (2): 198–200

Bonin, F., Sommerwerck, U., Lund, L.W., et al. (2013) Avoidance of intubation during acute exacerbation of chronic obstructive pulmonary disease for a lung transplant candidate using extracorporeal carbon dioxide removal with the Hemolung. The Journal of Thoracic and Cardiovascular Surgery, 145 (5): e43–e44

Braune, S.A. and Kluge, S. (2013) Extracorporeal lung support in patients with chronic obstructive pulmonary disease. Minerva anestesiologica, 79 (8): 934–943

Burki, N.K., Mani, R.K., Herth, F.J.F., et al. (2013) A novel extracorporeal CO(2) removal system: results of a pilot study of hypercapnic respiratory failure in patients with COPD. Chest, 143 (3): 678–686

Cardenas, V.J., Jr, Lynch, J.E., Ates, R., et al. (2009) Venovenous Carbon Dioxide Removal in Chronic Obstructive Pulmonary Disease. ASAIO Journal, 55 (4): 420–422

Chandra, D., Stamm, J.A., Taylor, B., et al. (2012) Outcomes of noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease in the United States, 1998-2008. American Journal of Respiratory and Critical Care Medicine, 185 (2): 152–159

Cole, S., Barrett, N.A., Glover, G., et al. (2014) Extracorporeal carbon dioxide removal as an alternative to endotracheal intubation for non-invasive ventilation failure in acute exacerbation of COPD. Journal of the  …, 15 (4)

Del Sorbo, L., Pisani, L., Filippini, C., et al. (2015) Extracorporeal Co2 Removal in Hypercapnic Patients At Risk of Noninvasive Ventilation Failure. Critical Care Medicine, 43 (1): 120–127

Kluge, S., Braune, S.A., Engel, M., et al. (2012) Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing noninvasive ventilation. Intensive Care Medicine, 38 (10): 1632–1639

Lund, L.W. and Federspiel, W.J. (2013) Removing extra CO2 in COPD patients. Current respiratory care reports, 2: 131–138

Mani, R.K., Schmidt, W., Lund, L.W., et al. (2013) Respiratory Dialysis for Avoidance of Intubation in Acute Exacerbation of COPD. ASAIO Journal, 59 (6): 675–678.

Ram, F.S.F., Picot, J., Lightowler, J., et al. (2004) Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane database of systematic reviews, (3): CD004104

Terragni, P., Maiolo, G. and Ranieri, V.M. (2012) Role and potentials of low-flow CO(2) removal system in mechanical ventilation. Current Opinion in Critical Care, 18 (1): 93–98

Terragni, P.P., Maiolo, G., Tenaglia, T., et al. (2011) Extracorporeal CO2 removal and O2 transfer: A review of the concept, improvements and future development. Trends in Anaesthesia and Critical Care, 1 (3): 123–127

Gavin Denton @dentongavin – Current role: Critical care practitioner, critical care, West Midlands. Roles include; assessment and management of the critically ill patient, insertion of invasive lines, advanced airway management (under supervision), transfer of the critically ill patient, resuscitation (from airway, to team leader to post resus care). Trenching and support of junior doctors of the above.
Graduated from the University of Birmingham with BN(hons). BSc from Birmingham City University. About to complete MSc in health sciences from the University of Warwick.
Working background: 15 years working within various aspects of critical care. 7 years in critical care, 6 years in critical care outreach, 2 years as a critical care practitioner. Adult life support instructor. Independent non-medical prescriber.
Future aims: faculty of critical care medicine affiliation. FEEL course, POCUS training.
Clinical interests: USS, airway management.


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