Low-Flow ECCO2R for Acute Exacerbation of COPD

4 March 2014 White Papers

By ALung Technologies, Inc.

Chronic obstructive pulmonary disease (COPD) is an irreversible, progressive, lung disease caused by chronic bronchitis and emphysema, resulting in persistent expiratory airflow limitation.1 According to the World Health Organization, COPD is the fourth leading cause of death worldwide, and projected to increase by more than 30% over the next 10 years.2

Acute exacerbations are a major cause of worsened morbidity and mortality in COPD patients and can be triggered by bacterial or viral infections, air pollutants, temperature change and allergies. Typically, exacerbations in mild to moderate COPD can be treated pharmacologically and with supplemental oxygen; however, exacerbations in patients with severe COPD are often associated with acute hypercapnic respiratory failure requiring hospitalization and ventilatory support.3

For patients requiring intubation and mechanical ventilation (MV), in-hospital mortality in recent meta-analyses and observational studies has been reported to be as high as 25-39%.4-7 Furthermore, COPD patients requiring intubation and standard MV have a higher risk of prolonged weaning and failure to wean due to the underlying physiologic changes to the respiratory system caused by COPD.8-10

Noninvasive Ventilation

Randomized trials conducted in the mid-1990s established noninvasive positive pressure ventilation (NIV) as an alternative method of lung support that has been shown to reduce mortality in COPD patients by 50%.11,12 As a result, the use of NIV has increased substantially over the last decade, and is now used as a first line of defense in more than 50% of patients who require ventilatory support for acute exacerbations of COPD.4,13 However, 15%-26% fail NIV support and require intubation and MV.13-16 The mortality for patients who require intubation and MV after failing NIV has been shown to be worse than for those who are treated at the outset with MV.4 The primary reason for failure of NIV is the inability to ventilate CO2, resulting in increased hypercapnia, dyspnea and work of breathing.17,18

What are the risks of intubation and mechanical ventilation?

Endotracheal intubation and MV are associated with a long list of acute and chronic complications. MV can cause additional injury to the already compromised lungs because of the pressures and tidal volumes needed to achieve respiratory support. Complications associated with ventilator-induced lung injury include pneumothorax, pneumomediastinum, and subcutaneous or pulmonary interstitial emphysema. Other complications result from injuries to the airway caused by the endotracheal tube. In one study of risk factors associated with endotracheal intubations, at least one severe complication occurred in 28% of ICU patients requiring intubation.19 The mortality rate in the patients who experienced a severe complication due to intubation was two times the rate of those patients who did not experience a severe complication.19,20

The development of nosocomial respiratory infections resulting from long-term intubation and MV (longer than 48 hours) is one of the foremost risks of intubation and MV. The incidence of ventilator-associated pneumonia (VAP) ranges from 9%-27%,21-23 and is associated with prolonged duration of MV and ICU stay.22,24,25 The risk of ICU mortality was found to be significantly increased in studies of COPD patients who developed VAP compared to patients without COPD.26,27 In these studies, ICU mortality for COPD patients on invasive MV who developed VAP ranged from 60-64%. Other complications of endotracheal intubation and MV include aspiration, bronchospasm, inadvertent esophageal or mainstem bronchus intubation, stress gastritis/ulcers, thromboembolic disorders, gastrointestinal motility dysfunction, diaphragmatic dysfunction, and impaired swallowing.19,28-31 Avoidance of intubation and MV is also a heavily weighted, patient-centered outcome. Several studies have linked prolonged MV to depression, anxiety, and post-traumatic stress disorder.32,33 While intubated, patients are unable to communicate, mobilize, or receive oral nutrition, and often became malnourished and severely weakened.34 Most patients who are intubated require sedation or analgesics which are associated with their own complication risks.35-37

ECCO2R as an alternative to mechanical ventilation when noninvasive ventilation fails

Low-flow extracorporeal CO2 removal (ECCO2R) is a minimally invasive alternative to intubation and MV, when NIV alone is not able to adequately ventilate CO2. The approach of low-flow, or partial, extracorporeal COremoval (ECCO2R) was first explored by Gattinoni et al., and published in 1986.38 This was an important study which showed that if extracorporeal support was used to provide removal of only 33% of estimated basal COproduction in patients maintained with NIV, normalization of arterial CO2 levels and significant reduction in minute ventilation could be achieved.

Low-flow ECCO2R, by nature, is less invasive than extracorporeal membrane oxygenation, or ECMO. ECMO is used to provide cardiopulmonary life support, and must meet the full oxygenation and CO2 removal requirements of a patient. In so doing, ECMO requires the use of large-bore catheters to enable high blood flows of 3–6 liters per minute, and is often used in a venous-toarterial cannulation configuration to offload the heart. In contrast, low-flow ECCO2R provides partial CO2 removal at dialysis-like blood flows, which can be achieved through a single, dual-lumen, venous catheter.

The risks of low-flow ECCO2R are most similar to those associated with continuous renal replacement therapy (CRRT), which is also used in the critical care setting and operates at similar blood flows and with similar sized catheters. Like CRRT, the risks of low-flow ECCO2R are associated with central venous cannulation, a commonly performed procedure for a variety of indications, and the need for anticoagulation. However, unlike CRRT, low-flow ECCO2R does not put the patient at risk for electrolyte depletion or excessive volume removal, since the only molecule being removed from the blood is CO2.

Clinical evidence for using low-flow ECCO2R for acute exacerbations of COPD

There have been no randomized, controlled trials evaluating the efficacy of ECCO2R in patients experiencing an acute exacerbation of COPD. However, there have been several recent studies and case reports which support use of partial ECCO2R in this patient population.

In 2013, Burki et al. reported on the results of a clinical feasibility study of the Hemolung Respiratory Assist System (RAS) in patients with COPD.39 In addition, case reports of patients from this study were described in detail in articles by Mani et al. and Bonin et al.40,41 The Hemolung RAS (Pittsburgh, PA, USA) is a minimally invasive, low-flow, ECCO2R device which utilizes a 15.5 Fr single, dual-lumen, venous catheter to provide CO2 removal using blood flows of 350–550 mL/min. The Hemolung feasibility study included eight evaluable patients who were experiencing a COPD exacerbation and were failing support with NIV. All eight of these patients successfully avoided intubation with Hemolung therapy. Bonin et al. describes one of the eight patients who experienced an acute exacerbation of COPD while awaiting a lung transplant. For this patient in particular, avoidance of intubation and MV was paramount to maintaining the patient’s status on the lung transplant list. Use of the Hemolung was effective in achieving avoidance of intubation, and ultimately, the patient was successfully transplanted and discharged.

In a separate study reported by Kluge et al. in 2012, partial ECCO2R with the Novalung interventional lung assist (iLA) device was used to treat 21 patients suffering from acute hypercapnic respiratory failure who were failing support with NIV.42 The Novalung iLA (Heilbronn, Germany) is a pumpless extracorporeal therapy that utilizes arterial pressure to drive blood flow through a hollow fiber membrane cartridge at blood flows between 1-2 L/min via femoral artery to femoral vein cannulation. The outcomes of these patients were compared retrospectively with patients treated with MV after failing support with NIV. Fourteen of the 21 patients had an underlying diagnosis of COPD. The results of this study showed that 90% of the patients treated with the Novalung iLA avoided intubation and MV. While there was a trend for reduced hospital length-of-stay using partial ECCO2R, the study was not powered to evaluate differences in mortality, and the matched control group was found to have statistically less severe hypercapnia compared to the group treated with ECCO2R.

An interesting pilot study was recently reported by Abrams et al. in which ECCO2R with the Maquet Cardiohelp (Hirrlingen, Germany) was used in 5 patients experiencing an acute exacerbation of COPD who required intubation and invasive MV after failing support with NIV.44 In this study it was shown that ECCO2R could be used soon after intubation to facilitate rapid extubation. All 5 patients were extubated within 24 hours of ECCO2R initiation, were successfully mobilized, and all were discharged from the hospital. These encouraging results support further exploration of using partial ECCO2R in patients experiencing an acute exacerbation of COPD early after the need for intubation and MV, in addition to the use of partial ECCO2R to avoid intubation when timing permits.

Paradigm for use of low-flow ECCO2R

Results of the studies reported by Burki et al. and Kluge et al. are evidence that low-flow ECCO2R can be used to avoid intubation in patients experiencing an acute exacerbation of COPD for whom:

  • Support with NIV is failing after 1-2 hours of use, and
  • Endotracheal intubation has a high risk of secondary complications associated with prolonged invasive MV.

Figure 1 represents a treatment algorithm for using low-flow ECCO2R which is based on the indications of NIV failure utilized in these studies.


Mounting clinical evidence supports the use of low-flow, partial ECCO2R for patients experiencing an acute exacerbation of COPD who are failing support with NIV, as indicated by increased or refractory hypercapnia, respiratory acidosis, dyspnea and/or work of breathing. Low-flow ECCO2R is a minimally invasive alternative to intubation and MV when the risks associated with MV are undesirable. The risks of low-flow ECCO2R are similar to the cannulation and anticoagulation risks of CRRT, a common therapy in the critical care setting.

ECCO2R in COPD Algorithm

Other Notes

Hemolung RAS Intended Use

The Hemolung RAS is intended to be used for partial extracorporeal respiratory support in the treatment of acute hypercapnic respiratory failure. Oxygen is supplied and carbon dioxide is removed from blood circulated through the Hemolung RAS. The utilization period of this device has been validated for up to 7 days.

Hemolung RAS Indications for Use (EU)

The Hemolung Respiratory Assist System is indicated for severe COPD patients failing non-invasive ventilation where no alternative established therapy is available.

The Hemolung Respiratory Assist System is indicated for the application of lung protective ventilation strategies for patients who are invasively mechanically ventilated.

The Hemolung Respiratory Assist System is not indicated for patients needing assistance in weaning from invasive mechanical ventilation, patients with severe asthma, and patients preparing for and following lung transplantation.

Caution: Federal law (USA) restricts this device for sale by or on the order of a physician. Not for sale in the USA.


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