**2. ECMO as a bridge to recovery for acute respiratory failure in patients with advance lung disease**

Treating patients with interstitial lung disease (ILD) and acute respiratory failure (ARF) is challenging. Lung transplantation is the only definitive therapy for patients with severe and meaningful recovery. Unfortunately, acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of idiopathic pulmonary fibrosis (IPF).

Mechanical ventilation is a significant problem in advanced interstitial lung disease patients as the lung parenchyma is susceptible to ventilator-induced lung injury and oxygen toxicity [2, 3]. This likely triggers further disease progression [4]. Also, these patients often have secondary pulmonary hypertension and right ventricular dysfunction, increasing ventilation strategies' challenges [5]. Patients with advanced lung disease who developed respiratory failure and required mechanical ventilation have high mortality (70–90%) [6]. On the other hand, ECMO support might prevent ventilator-induced lung injury and worsening right ventricular dysfunction. However, the value of ECMO in patients with acute respiratory failure due to underlying lung fibrosis has not yet been well studied.

Kreuter *et al*. [7] published an international survey from 66 countries and 509 pulmonologists to assess the global variability in the prevention, diagnostic, and treatment of AE-IPF and reported that in case of respiratory failure, invasive ventilation was offered only to 45% to patients suitable for lung transplantation (LTx), as a BTT or in

*ECMO for Respiratory Failure in the Patient with Advance Lung Disease: A Bridge to Recovery… DOI: http://dx.doi.org/10.5772/intechopen.106824*

very selected other cases. Extracorporeal membrane oxygenation was offered to 44% of patients suitable for LTx as a bridge-to-transplant, mainly in Europe (57%) and the fewest in Oceania (24%). Palliative care was considered by 65% of the pulmonologist. The differences in these approaches were again significant between continents. Some of the differences in approaches might be related to center protocols, ICU resources, and ECMO expertise team experiences. Technology and resources also vary among countries.

#### **2.1 ECMO for acute respiratory distress syndrome**

Several landmark trials of venovenous (VV)—ECMO for acute respiratory distress syndrome (ARDS) are often referenced when discussing the potential benefits of ECMO for respiratory failure. Key studies supporting the efficacy of ECMO include the Australian and New Zealand study on H1N1-induced ARDS patients treated with ECMO having greater than 70% survival [8]. Around this time, major improvements were made to the ECMO devices, including more efficient oxygenators, fewer thrombotic centrifugal pumps, and improved percutaneous vascular access cannulas.

Peek *et al.* [9] conducted a multicenter randomized control trial based in the UK called the CESAR trial, where patients with ARDS were randomized to conventional therapy or ECMO, showing that patients with ARDS who were referred to an ECMO center had significantly improved survival 6 months from discharge than those who were not referred and treated with medical management alone. Severe ARDS was defined as a Murray score above three or an arterial pH below 7.20. Essential exclusion criteria were prolonged high oxygen requirement or high-pressure mechanical ventilation for more than 7 days before considering enrollment. The results of the CESAR trial showed improved survival without severe disability in the patients considered for ECMO. 63% of the ECMO consideration group was alive at 6 months, whereas only 47% of the conventional therapy group survived that timeframe. Most deaths in the ECMO group were from multi-system organ failure, whereas 60% of the standard therapy patients died of respiratory failure. The release of the data from the CESAR trial and the treatment successes from the 2009 Influenza pandemic has propagated ECMO use in various clinical settings.

The REVA study group published their results using ECMO for H1N1-associated ARDS and identified at 1-year post-ICU discharge that 83% of patients treated with ECMO had returned to work vs. 64% of non-ECMO treated patients [10].

The ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) clinical trial randomized patients to VV ECMO based on blood gas and ventilator criteria similar to CESAR [11]. However, its results further clouded the data regarding the benefits of ECMO for refractory ARDS. In total, 249 patients were randomized in the study, and there were no significant differences between the two groups. At the primary endpoint of 60 days, 35% of the ECMO group had died, whereas 46% of the control group was dead. The highest sub-group mortality was those patients who crossed over from the control group to ECMO, as 57% of them were dead by 60-days. They concluded that among patients with very severe ARDS, 60-day mortality was not significantly lower with ECMO than with a strategy of conventional mechanical ventilation that included ECMO as rescue therapy. Despite what appears to be trending toward better survival with earlier ECMO, the data did not reach statistical significance.

#### **2.2 ECMO for hypercapnic respiratory failure**

The treatment of acute exacerbations of chronic obstructive lung disease (COPD) resulting in hypercapnic respiratory failure refractory to medical treatment has been

invasive mechanical ventilation (IMV). In the most severe cases, these may be refractory to conventional therapies and mechanical ventilation, becoming life-threatening. Invasive mechanical ventilation develops a considerable reduction in respiratory muscle strength, having a higher risk of prolonged weaning and failure to wean compared to other causes of acute hypercapnic respiratory failure and a more increased need for early tracheostomy. These patients also have a higher risk of developing complications such as ventilator-associated pneumonia (VAP), ventilator-induced lung injury (VILI), ventilator-associated diaphragmatic dysfunction (VIDD), and critical illness myopathy and neuropathy associated with steroids and neuromuscular blockade agents often used during their critical ICU admission [12]. Extracorporeal carbon dioxide removal (ECCO2R) represents an attractive approach in this setting for carbon dioxide removal options to avoid and possibly prevent worsening respiratory failure and respiratory acidosis and shorten the duration of IMV.

In 2009, Dr. Zwischenberger's group successfully used venovenous-ECMO for carbon dioxide removal (ECCO2R) in a hypercarbic patient with COPD. They successfully reduced PaCO2, minute ventilation, and ventilator pressures [13]. In 2013, the Columbia University group used ECCO2R to facilitate extubation in five patients with COPD, all of whom had failed to wean from the ventilator. These patients were extubated in a median time of 4 h and most were ambulatory within 24 h of venovenous ECMO initiation. Once extubated, patients were rehabilitated while on ECCO2R, with a mean time to ambulation of 19.4 ± 12.6 hours after ECCO2R. Moreover, all patients survived hospital discharge [14]. Since that time, multiple reports have supported the efficacy of venovenous ECMO in treating hypercapnic respiratory failure in COPD and reducing intubation time or preventing it all together [15, 16]. In the ÉCLAIR study, Braune *et al.* [16] showed that IMV was avoided in 56% of cases treated with ECCO2R but was associated with a higher incidence of complications.

Although ECCO2R seems effective in improving or mitigating hypercapnic acidosis and possibly reducing the rate of endotracheal intubation, its use is associated with a range of vascular, hematological, and other complications. Thrombocytopenia and heparin-induced thrombocytopenia are also commonly observed. Other serious complications associated with arterial cannulation include distal limb ischemia, compartment syndrome of the lower limb requiring fasciotomy, or limb amputation [17]. Bleeding is the most common complication of ECCO2R. The need for anticoagulation increases the risk of significant bleeding, including cerebral, gastrointestinal, and nasopharyngeal bleeds. The published incidence of substantial bleeding complications is between 2 and 50% [18].

#### **2.3 ECMO for pulmonary arterial hypertension**

Patients with group 1 pulmonary arterial hypertension (PAH) and decompensated right ventricular failure (RHF) were not previously considered for ECMO as a BTT or BTR because options were limited by the idea that PAH patients would not be able to weaned from ECMO as a BTR from an acute decompensation and by long transplantation wait times and perceived inability to weaned from ECMO. Rosenzweig *et al.* [19] published a retrospective review of ECMO as a BTR for PAH. A total of six patients (age 32 ± 11 years) underwent ECMO bridging. Two patients who were considered good candidates for lung transplantation underwent successful ECMO-BTT. Four patients who were not regarded as promising candidates for lung transplantation experienced ECMO-BTR with the escalation of targeted medical therapies before weaning off ECMO. Three of four ECMO-BTR patients survived ECMO

*ECMO for Respiratory Failure in the Patient with Advance Lung Disease: A Bridge to Recovery… DOI: http://dx.doi.org/10.5772/intechopen.106824*

decannulation (duration 7–23 days). This single-institution experience demonstrated the beneficial use of upper body configuration ECMO strategy without mechanical support in PAH patients as a BTR or BTT when they failed to respond to medical therapy. In addition, this strategy facilitates mobility with physical therapy, thereby optimizing transplant candidacy.

Chicotka *et al.* [20] published a retrospective review of 50 patients with interstitial lung disease and pulmonary hypertension treated initially with either VV or venoarterial (VA) ECMO as a bridge-to-transplant. They found that patients with early VA ECMO initiation had significantly better survival to transplantation than those with early VV ECMO (*p* = 0.03). In addition, there was a 59% reduction in risk of death for VA compared with VV ECMO (HR 0.41, 95% confidence interval: 0.18 to 0.92, *p* = 0.03) shown by cox proportional hazards modeling. Also, there was an 80% reduction in the risk of death when ambulating on ECMO before lung transplant (HR 20, 95% confidence interval: 0.08 to 0.48, *p* < 0.01). In this single-institution experience, they found that combined ECMO with targeted PAH therapies was successfully used as BTT or BTR for acute right heart failure in group 1 PAH patients leading to significant improvement in gas exchange and end-organ function. Unfortunately, only 10 patients in this series of 50 were IPAH and 5 Eisenmenger. This approach needs further assessment, and as experience grows, we may anticipate earlier instituting ECMO in suitable group 1 PAH patients.
