*4.1.4 Reviews of ECCO2R in COPD*

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

catheter placement.

patients [40].

intubation in 27 patients.

*4.1.3 ECCO2R to facilitate weaning from IMV*

patient mobilization out of bed at day 6 [43].

in PaCO2, minute ventilation, and ventilator pressures.

allowed the weaning from mechanical ventilator in only 3 patients.

studies should be long-term mortality.

In the study by Burki et al. [38], 20 hypercapnic patients with COPD were treated with ECCO2R using a 15.5-Fr dual-lumen cannula allowing a mean blood flow of 430 mL/min. Of the 20 patients recruited into the trial, 7 were at risk of MV despite NIV, 2 were difficult to wean from NIV, and 11 had failed liberation from MV. None of the patients failing NIV required endotracheal intubation, and both patients with difficult weaning from NIV were weaned. However, only 3 of the 11 IMV patients were liberated successfully. Moreover, significant complications arose in a number of patients: bleeding requiring blood transfusion was reported in three patients, deep vein thrombosis was diagnosed in one patient after removal of the ECCO2R catheter, one patient experienced pneumothorax due to catheter insertion, and one died from hemorrhage when the iliac vein was perforated during ECCO2R

Del Sorbo et al. [4] examined 25 patients with NIV + ECCO2R versus NIV alone (historical controls n = 21) for prevention of intubation in aeCOPD. They reported that ECCO2R with a 14-Fr dual-lumen catheter and blood flow rates of 177–333 mL/ min not only improved respiratory acidosis but also reduced the need for intubation by 75% (12 vs. 33%; p = 0.047) and significantly reduced the in-hospital mortality (8 vs. 35%; p = 0.035). However, this came with a cost of 52% prevalence of ECCO2R-related side effects and led the authors to suggest the end point of future

In the ECLAIR study, Braune et al. [39] showed that IMV was avoided in 56% of cases treated with ECCO2R but was associated with a higher incidence of complications. However, several significant differences must be taken into account. In the latter study, there was an inclusion of patients with relative contraindications to NIV, and there was an unexpectedly high incidence of hypoxemic

Finally, Morelli et al. [41] and colleagues confirmed the efficacy of ECCO2R (with a flow rate of 250–450 mL/min through a 13-Fr dual-lumen cannula) in reducing the PaCO2 in a series of 30 patients with acute hypercapnic respiratory failure due to aeCOPD, who refused endotracheal intubation after failing NIV. The duration of ECCO2R was 2–16 days, and it was possible to prevent endotracheal

Cardenas et al. [42] made the first attempt to use modern ECLS components for VV ECCO2R in a patient with aeCOPD. They demonstrated a successful reduction

Burki et al. [38] showed that in a subgroup of 11 patients receiving IMV, ECCO2R

Abrams and colleagues [3] reported five older patients (age 73 ± 8.7 years) with aeCOPD who failed NIV, requiring IMV. After an average of 16.5 ± 5.9 h of IMV, ECCO2R was initiated. By using a dual-lumen cannula (20–23 Fr) with blood flow rates of 1–1.7 L/min and with a sweep gas flow from 1 to 7 L/min, they were able to extubate all five patients within 24 h of treatment (median duration of MV post ECCO2R = 4 h, range 1.5–21.5 h). Once extubated, patients were rehabilitated while on ECCO2R, with a mean time to ambulation of 29.4 ± 12.6 h after ECCO2R. Moreover, all patients survived to hospital

Using a pediatric VV ECMO system (with blood flow rates of 0.9 L/min through a 19 Fr dual-lumen cannula placed in the right jugular vein) in two patients with aeCOPD, Roncon-Albuquerque Jr. et al. reported early extubation after 72 h and

**98**

discharge.

Sklar et al. [44] reviewed 10 studies of ECCO2R for aeCOPD and a total of 87 patients, to examine cumulative safety and efficacy. They reported that ECCO2R was able to prevent intubation in 65 (93%) of 70 patients and assist in successful extubation of 9 (53%) of 17 patients. There were a total of 11 major complications and 30 minor complications. Half of all patients experienced complications related to ECCO2R, and half of those complications were related to bleeding (21/41). No study showed any evidence of increased mortality or increased length of intensive care unit (ICU) or hospital stay with ECCO2R.

In a recent publication, Taccone et al. [45] performed a systematic review of ECCO2R in adult critically ill patients. Three of the six studies included in the review evaluated patients with COPD that developed hypercapnic respiratory failure [4, 5, 39]. In all the three studies, the reduction of PaCO2 was reported within a few hours following the initiation of ECCO2R. Median values decreased from 73 to 88 mmHg to 34–66 mmHg. Regarding the duration of mechanical ventilation, only one described no significant difference between ECCO2R and the controlled group [4]. The need for endotracheal intubation was significantly reduced from 53/67 (79%) to 16/71 (22% p < 0.001). However, neither ICU nor hospital length of stay was statistically significantly reduced.

Based on the existing data, we believe that the ideal trial for ECCO2R should be a randomized controlled trial designed such ECCO2R should be implemented within 12 h of intubation after failing to show improvement (i.e., pH < 7.25 for persistent acidosis) with conventional therapy. Given the risks associated with the technique, it should be instituted once patients fail conventional treatment and require IMV. Patients should be randomized to ECCO2R plus IMV or standard IMV. Given the high rate of mortality associated with invasive mechanical ventilation, the study should be powered to demonstrate a mortality benefit, and secondary endpoints include ventilator-free days, transfusion requirements, and rates of ventilator-associated events.

More data will be forthcoming on the application of ECCO2R in the management of patients with COPD exacerbations from a number of ongoing or planned clinical trials (**Table 3**).

#### **4.2 Severe acute asthma**

Asthma is an inflammatory disorder of the airways characterized by airway hyperactivity with bronchospasm, mucosal swelling, and mucus production.

The standard treatment of severe acute asthma consists of measures to reverse airflow obstruction. β2 agonists and steroids are the mainstays of treatment causing bronchodilation and anti-inflammatory effects, respectively [10]. Other available adjunct therapies including anticholinergics, magnesium sulfate, methylxanthines, ketamine, and heliox have been utilized with varying results [46].

Despite advances in asthma therapy, asthma mortality has remained stable in recent years. One reason is status asthmaticus, which can be unresponsive to initial treatment and may lead to hypercapnic respiratory failure despite maximal therapy.

Status asthmaticus, also known as severe acute asthma or near-fatal asthma, is a condition of progressively worsening bronchospasm and respiratory dysfunction due to asthma, which is unresponsive to standard conventional therapy and may progress to respiratory failure and the need for mechanical ventilation. The current indication of mechanical ventilation in a patient presenting with status asthmaticus is a clinical one and does not require a blood gas assessment. These include certain specific situations including alteration of consciousness, respiratory fatigue, or impending cardiopulmonary arrest.


**101**

**Table 3.**

*Extracorporeal Carbon Dioxide Removal for the Exacerbation of Chronic Hypercapnic…*

**outcome**

ECCO2R can be safely used to avoid or reduce time on invasive mechanical ventilation compared to COPD patients treated with standard-of-care mechanical

Primary outcome: ventilatorfree days at day 60 from randomization

The addition of minimally invasive ECCO2R is likely to limit dynamic hyperinflation in COPD patients requiring invasive mechanical ventilation for an acute exacerbation while improving

Primary outcome: PEEPi at baseline and after ECCO2R by the device and adjustment of ventilator settings, expressed

Test the effectiveness of a membrane gas exchange device in the veno-venous circulation of continuous renal replacement therapy for the purpose of CO2 elimination and pH compensation

The primary outcome is the modification of the PaCO2 and/or the ventilator settings (tidal volume VT and plateau

ventilation alone

gas exchange

in cmH20

**Estimated enrollment**

500 patients **Device**

Hemolung

12 patients Hemolung

20 patients Prismalung

**Title Type of study Hypothesis/primary** 

**ECCO2R as an alternative or adjunct to invasive mechanical ventilation**

Multicenter randomized controlled trial

Interventional single-group trial

Interventional single-group trial

Approximately, 4% of all patients hospitalized for acute asthma require mechanical ventilation, which is associated with increased in-hospital mortality compared

pressure Pplat)

Furthermore, mechanical ventilation may aggravate alveolar hyperinflation as it was described above. To prevent the potential side effects caused by mechanical

Extracorporeal carbon dioxide removal as an adjunct to the ventilator for refractory asthma was first reported in 1981 [48]. Subsequently, there have been several case reports (**Table 4**). In the international Extracorporeal Life Support Organization (ELSO) registry, ECMO was used for asthma in 24 out of 1257 adult patients between 1986 and 2006. Before ECMO was started, the average pH was

with patients who do not require mechanical ventilation (7 vs. 0.2%) [47].

ventilation, ECCO2R has been applied as rescue therapy.

*DOI: http://dx.doi.org/10.5772/intechopen.84936*

CO2 removal for mechanical ventilation avoidance during acute exacerbation of COPD (VENT-AVOID)

**ClinicalTrials. gov number**

NCT03255057 Extracorporeal

**ECCO2R physiological studies** NCT02586948 Physiological

NCT02590575 "Low Flow"

RRT

*Ongoing clinical studies of ECCO2R in COPD.*

CO2 removal on

study of minimally invasive ECCO2R in exacerbations of COPD requiring invasive mechanical ventilation (EPHEBE)


*Extracorporeal Carbon Dioxide Removal for the Exacerbation of Chronic Hypercapnic… DOI: http://dx.doi.org/10.5772/intechopen.84936*

#### **Table 3.**

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

**Title Type of study Hypothesis/primary** 

Randomized, controlled trial

Interventional, randomized with parallel assignment

Interventional single-group trial

Prospective cohort study

Interventional single-group trial

Multicenter, randomized, controlled trial **outcome**

of intubation

6 h without NIV

severe disability

severe disability

intubation

intubation

ECCO2R

Addition of ECCO2R to NIV will shorten the duration of NIV and reduce the likelihood

Primary outcome: time to cessation of NIV defined as from NIV commencement to

Advantage of VV-ECCO2R in severe acute exacerbation of COPD requiring invasive mechanical ventilation (IMV) to facilitate early extubation in terms of reducing mortality or

Primary outcome: death or

Retrospectively assess the efficacy and safety of noninvasive ventilationplus-extracorporeal CO2 removal in patients who fail NIV and refuse endotracheal

Primary outcome: number of patients who avoided endotracheal intubation

Primary outcome: incidence of avoiding endotracheal

Weaning success avoiding reintubation after removal of

To evaluate the clinical effect of PALP in reducing the time on invasive ventilation in patients with an exacerbation of COPD requiring invasive mechanical ventilation

**Estimated enrollment** **Device**

24 patients Hemolung RAS

202 patients Not specified

35 patients ProLUNG [Estor]

30 patients Not specified

12 patients ProLUNG [Estor]

120 patients PALP

**ClinicalTrials. gov number**

**ECCO2R to avoid mechanical ventilation**

CO2 removal as an adjunct to noninvasive ventilation in acute severe exacerbations of COPD

extubation by ECCO2R compared to IMV in patients with severe acute exacerbation of COPD (X-COPD)

CO2 removal in hypercapnic patients

carbon dioxide removal in severe chronic obstructive pulmonary disease exacerbation

**ECCO2R to facilitate liberation from mechanical ventilation**

NCT02086084 Extracorporeal

NCT03584295 Early

NCT02564406 Extracorporeal

NCT03692117 Extracorporeal

NCT02259335 Weaning from

NCT02107222 The PALP™-

mechanical ventilation using extracorporeal CO2 removal (WeanPRO)

COPD trial (low flow CO2-removal (ECCO2-R) in exacerbated COPD) (PALP-COPD)

**100**

*Ongoing clinical studies of ECCO2R in COPD.*

Approximately, 4% of all patients hospitalized for acute asthma require mechanical ventilation, which is associated with increased in-hospital mortality compared with patients who do not require mechanical ventilation (7 vs. 0.2%) [47].

Furthermore, mechanical ventilation may aggravate alveolar hyperinflation as it was described above. To prevent the potential side effects caused by mechanical ventilation, ECCO2R has been applied as rescue therapy.

Extracorporeal carbon dioxide removal as an adjunct to the ventilator for refractory asthma was first reported in 1981 [48]. Subsequently, there have been several case reports (**Table 4**). In the international Extracorporeal Life Support Organization (ELSO) registry, ECMO was used for asthma in 24 out of 1257 adult patients between 1986 and 2006. Before ECMO was started, the average pH was

7.17 ± 0.16, PaCO2 119.7 ± 58 mmHg, and PaO2/FiO2 244 ± 180 despite mechanical ventilation. Complications were described in 19 of 24 patients (79.2%) with a remarkable number of hemodynamic, hemorrhagic, and mechanical complications [49]. These data show that in patients treated with ECMO for status asthmaticus, hypercapnia, rather than hypoxemia, was the central exchange derangement, suggesting that a less invasive technique like ECCO2R will be suitable, with fewer complications. Although most of the clinical applications of ECCO2R for the treatment of obstructive lung diseases have been reported in patients with COPD, several cases describe ECCO2R in patients with near-fatal asthma [50–54] (**Table 4**).

The first cases reported were by using a pumpless extracorporeal life assist (pECLA) device. Although no complications were described in these case series, a possible major complication may arise as a consequence of the arterial cannulation, such as lower limb ischemia [53]. Brenner et al. reported two cases using a venous double lumen catheter with successful survival results.


**103**

*Extracorporeal Carbon Dioxide Removal for the Exacerbation of Chronic Hypercapnic…*

Taking into account the deleterious effects of mechanical ventilation and sedation, and the advantages of keeping the patient awake, recently, an awake approach using a double lumen cannula has been described [51]. NIV was used as ventilatory support. Thirty-four hours after starting the ECCO2R system, the patient was weaned entirely from NIV, and the cannula was removed without complications. The patient was discharged from the ICU on day 4 without supplemental oxygen and left the hospital on day 10. Although this is a tempting approach, several issues should be taken into account. Unexpected cannula displacement may be provoked by an interactive patient, resulting in significant hemorrhage and lethal shock, as a time to react is short. Patient discomfort, pain, and anxiety in the "awake" approach might be in such extent that starting deep sedation and mechanical ventilation is

Although ECCO2R seems to be effective in improving or mitigating hypercapnic

Arterial cannulation is associated with higher risk than venous catheterization, with specific complications including distal limb ischemia, compartment syndrome of the lower limb requiring fasciotomy, or limb amputation as devastating conse-

Thrombocytopenia and heparin-induced thrombocytopenia are also commonly

Conversely, thrombus formation is higher at lower blood flow rates because of increased exposure time to the membrane lung and circuit. Clots may detach and enter the patient's bloodstream, plugging the membrane or obstructing the cannula

In the past, ECCO2R was a complex technique requiring intensive monitoring and surgical expertise. Due to a high rate of complications, it was avoided by all but a few high expertise centers. With newer simplified system, devices are placed like

In summary, minimally invasive ECCO2R appears very promising for patients with acute exacerbation of obstructive diseases refractory to conventional treatment, but systemic evaluation is needed to prove its efficacy and determine the

We want to acknowledge Eduardo Radicy for creating the figure for this manu-

temporary dialysis catheters and can be inserted by most intensivists.

acidosis and possibly in reducing the rate of endotracheal intubation, its use is associated with a range of vascular, hematological, and other complications.

The occurrence of bleeding events is the most frequent complications of ECCO2R. The low flow renders systemic anticoagulation mandatory, increasing the risk of significant bleeding including cerebral, gastrointestinal, and nasopharyngeal bleeds. In the studies of ECCO2R to date, the rate of clinically significant hemor-

*DOI: http://dx.doi.org/10.5772/intechopen.84936*

inevitable, losing all the advantages described before.

rhagic complications ranges between 2 and 50% [44].

if anticoagulation is not achieved.

**5. Complications**

quences [16].

observed.

**6. Conclusions**

actual risks.

**Acknowledgements**

script. He was not compensated for this work.

*IMV, invasive mechanical ventilation; NIV, noninvasive mechanical ventilation.*

#### **Table 4.**

*Case series of ECCO2R for near-fatal asthma.*

*Extracorporeal Carbon Dioxide Removal for the Exacerbation of Chronic Hypercapnic… DOI: http://dx.doi.org/10.5772/intechopen.84936*

Taking into account the deleterious effects of mechanical ventilation and sedation, and the advantages of keeping the patient awake, recently, an awake approach using a double lumen cannula has been described [51]. NIV was used as ventilatory support. Thirty-four hours after starting the ECCO2R system, the patient was weaned entirely from NIV, and the cannula was removed without complications. The patient was discharged from the ICU on day 4 without supplemental oxygen and left the hospital on day 10. Although this is a tempting approach, several issues should be taken into account. Unexpected cannula displacement may be provoked by an interactive patient, resulting in significant hemorrhage and lethal shock, as a time to react is short. Patient discomfort, pain, and anxiety in the "awake" approach might be in such extent that starting deep sedation and mechanical ventilation is inevitable, losing all the advantages described before.
