Extracorporeal Membrane Oxygenation (ECMO)

Number: 0546

Policy

Extracorporeal Membrane Oxygenation (ECMO) for Neonates

Aetna considers ECMO medically necessary in neonates who meet all of the following criteria:

1. Diagnosis of any of the following:

   1. Congenital diaphragmatic hernia; or
   2. Hyaline membrane disease; or
   3. Meconium aspiration; or
   4. Persistent fetal circulation; or
   5. Possible cardiac anomaly; or
   6. Refractory neonatal septic shock; or
   7. Respiratory distress syndrome; or
   8. Uncontrollable air leak.

   and

2. Gestational age of at least 34 weeks; and

3. Birth weight of 2,000 grams or greater; and

4. Age less than 10 days (preferably less than 7 days).

Aetna considers ECMO for neonates experimental and investigational when criteria are not met because of insufficient evidence of its safety and effectiveness.

ECMO for Children and Adults

Aetna considers ECMO and extracorporeal life support (ECLS) medically necessary for children and adults with any of the following diagnoses when the risk of death is very high despite optimal conventional therapy:

1. Adult respiratory distress syndrome (ARDS); or
2. As a short-term (i.e., hours to a few days) bridge to heart, liver, lung or heart-lung transplantation; or
3. As a short-term bridge to durable mechanical circulatory support; or
4. Following heart surgery to ease transition from cardiopulmonary bypass to ventilation; or
5. Liver transplant recipients with reversible respiratory or cardiovascular failure refractory to conventional treatment; or
6. Non-necrotizing pneumonias (both bacterial and viral); or
7. Primary graft failure after heart, lung or heart-lung transplantation; or
8. Pulmonary contusion; or
9. Refractory pediatric septic shock; or
10. Smoke inhalation injury; or 
11. Other reversible causes of respiratory or cardiac failure (e.g., myocarditis, cardiogenic shock, refractory ventricular tachycardia or fibrillation) that is unresponsive to all other measures.

Aetna considers ECMO/ECLS for children and adults experimental and investigational for all other indications including the following (not an all-inclusive list) because of insufficient evidence of its safety and effectiveness:

• Acute coronary syndromes
• Acute massive pulmonary embolism
• Acute type A aortic dissection (post-operative ECMO)
• After coronary artery bypass grafting (veno-arterial ECMO)
• Coronavirus disease 2019 (COVID-19) (in persons not meeting medical necessity criteria above)
• Drug overdose (veno-arterial ECMO)
• Obesity hypoventilation syndrome (veno-venous ECMO)
• Pregnant and post-partum women with H1N1-related acute respiratory distress syndrome
• Pulmonary embolism-related cardiac arrest (veno-arterial ECMO) 
• Sepsis (other than refractory pediatric septic shock)
• Support during lung transplantation (other than as a bridge to transplant).

Related Policies

• CPB 0518 - Nitric Oxide, Inhalational (INO)

Background

ECMO in Neonates

Extra-corporeal membrane oxygenation (ECMO) is a term used to describe prolonged (days to weeks) mechanical support for patients with reversible heart or lung failure.  The technology is similar to cardiopulmonary bypass as used during cardiac surgery, only modified for prolonged use at the bedside intensive care unit.  Extra-corporeal membrane oxygenation is capable of effectively and safely supporting respiration and circulation in neonates with severe reversible respiratory failure and a moribund clinical presentation.  When applied early in the course of severe failure, newborns who would have otherwise died will regularly survive.  Contraindications to ECMO therapy in neonates include any severe diagnosis which would decrease the probability of survival of the neonate candidate.  Some of the limiting diagnoses include: intra-cerebral hemorrhage; severe brain damage; multiple congenital anomalies; irreversible brain damage; and age greater than 10 days.

In a randomized controlled study (n = 59), Griffin and colleagues (2004) concluded that dexamethasone given during the first 3 days of ECMO results in significant improvement in lung injury scores by day 3 of ECMO but does not significantly decrease the duration of ECMO or improve survival.  The preponderance of evidence would not support the use of dexamethasone in this setting.

The American College of Critical Care Medicine's clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock (Brierley et al, 2009) noted that children with septic shock, compared with adults, require ECMO for refractory shock.

ECMO in Children and Adults

ECMO and extra-corporeal life support (ECLS) are used in children and adults with irreversible heart or lung failure for prolonged (days to weeks) mechanical support.  The goal of ECMO/ECLS for pediatric or adult patients is to provide lung rest from the high levels of oxygen and higher airway pressures that are necessary to support oxygenation and ventilation.  Proper selection involves determining in which patients the disease process itself is reversible (with 1 to 2 weeks of ECMO/ECLS).  Contraindications to ECMO/ECLS in pediatric and adult patients include: necrotizing pneumonia; multiple organ failure in addition to respiratory or cardiac failure; metastatic disease; major central nervous system injury; quadriplegia; and more than 10 days on mechanical ventilation prior to the start of ECMO/ECLS.

An assessment of ECMO by the National Institute for Clinical Excellence (NICE, 2004) stated that its use is established in post-neonatal children to treat respiratory or cardiac failure that is unresponsive to all other measures, but is considered to have a reversible cause.  According to NICE guidelines, ECMO may also be used following heart surgery in post-neonatal children to ease the transition from cardiopulmonary bypass to ventilation.  National Institute for Clinical Excellence (2004) concluded that the use of ECMO for these indications in adults is currently the subject of investigation in the CESAR trial (Conventional ventilatory support versus Extracorporeal membrane oxygenation for Severe Adult Respiratory failure).

Thiagarajan et al (2007) reported on outcomes and predictors of in-hospital mortality after ECMO used to support cardiopulmonary resuscitation (E-CPR).  Outcomes for patients aged less than 18 years using E-CPR were analyzed with data from the Extracorporeal Life Support Organization, and predictors of in-hospital mortality were determined.  Of 26,242 ECMO uses reported, 695 (2.6 %) were for E-CPR (n = 682 patients).  Survival to hospital discharge was 38 %.  In a multi-variable model, pre-ECMO factors such as cardiac disease (odds ratio [OR] 0.51, 95 % confidence interval [CI]: 0.31 to 0.82) and neonatal respiratory disease (OR 0.28, 95 % CI: 0.12 to 0.66), white race (OR 0.65, 95 % CI: 0.45 to 0.94), and pre-ECMO arterial blood pH greater than 7.17 (OR 0.50, 95 % CI: 0.30 to 0.84) were associated with decreased odds of mortality.  During ECMO, renal dysfunction (OR 1.89, 95 % CI: 1.17 to 3.03), pulmonary hemorrhage (OR 2.23, 95 % CI: 1.11 to 4.50), neurological injury (OR 2.79, 95 % CI: 1.55 to 5.02), CPR during ECMO (OR 3.06, 95 % CI: 1.42 to 6.58), and arterial blood pH less than 7.2 (OR 2.23, 95 % CI: 1.23 to 4.06) were associated with increased odds of mortality.  The authors concluded that ECMO used to support CPR rescued one-third of patients in whom death was otherwise certain.  Patient diagnosis, absence of severe metabolic acidosis before ECMO support, and uncomplicated ECMO course were associated with improved survival.  This is in agreement with the observations of Alsoufi et al (2007) who noted that acceptable survival and neurological outcomes (30 %) can be achieved with E-CPR in children after prolonged cardiac arrest (up to 95 minutes) refractory to conventional resuscitation measures.

In a review and quantitative analysis, Chawlin and colleagues (2008) stated that the role of ECMO has not been formally validated for patients with adult respiratory distress syndrome (ARDS).  In anticipation of publication of the conventional ventilation versus ECMO in severe adult respiratory failure (CESAR) trial, the role of ECMO in this setting was reviewed. An electronic search for studies reporting the use of ECMO for the treatment of ARDS revealed 2 randomized controlled trials (RCTs) and 3 non-controlled trials.  Bayesian analysis on the 2 RCTs produced an odds ratio mortality of 1.28 (CI: 0.24 to 6.55) showing no significant harm or benefit.  Pooling was not possible for the non-controlled studies because of differing admission status and ECMO selection criteria and an inability to control for these differences in the absence of individual patient data.  A large number (n = 35) of case series have been published with generally more positive results.  The authors concluded that ECMO, as rescue therapy for ARDS, appears to be an unvalidated rescue treatment option.  Analysis and review of trial data does not support its application; however the body of reported cases suggests otherwise.

The primary results for the CESAR trial, a multi-center randomized controlled clinical trial comparing conventional ventilation methods with ECMO for the treatment of severe acute respiratory failure in adults, has been published in the Lancet.  Peek et al (2009) examined the safety, clinical efficacy, and cost-effectiveness of ECMO compared with conventional ventilation support.  These investigators used an independent central randomization service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO.  Eligible patients were aged 18 to 65 years and had severe (Murray score greater than 3.0 or pH less than 7.20) but potentially reversible respiratory failure.  Exclusion criteria were: high pressure (greater than 30 cm H(2)O of peak inspiratory pressure) or high fraction of inspired oxygen [FiO(2)] (greater than 0.8) ventilation for more than 7 days; intra-cranial bleeding; any other contraindication to limited heparinization; or any contraindication to continuation of active treatment.  The primary outcome was death or severe disability at 6 months after randomization or before discharge from hospital.  Primary analysis was by intention-to-treat.  Only researchers who did the 6-month follow-up were masked to treatment assignment.  Data about resource use and economic outcomes (quality-adjusted life-years) were collected.  Studies of the key cost generating events were undertaken, and these researchers did analyses of cost-utility at 6 months after randomization and modelled lifetime cost-utility.  A total of 766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n = 90) or to receive conventional management (n = 90); 68 (75 %) patients actually received ECMO; 63 % (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47 % (41/87) of those allocated to conventional management (relative risk 0.69; 95 % CI: 0.05 to 0.97, p = 0.03).  Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected].  A lifetime model predicted the cost per QALY of ECMO to be 19,252 pounds (95 % CI: 7622 to 59 200) at a discount rate of 3.5 %.  The authors recommended transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a center with an ECMO-based management protocol to significantly improve survival without severe disability.  They stated that this strategy is also likely to be cost-effective in settings with similar services to those in the United Kingdom.

In a retrospective review, Tissot et al (2009) analyzed the indications and outcome of ECMO for early primary graft failure and determined its impact on long-term graft function and rejection risk.  A total of 28 (9 %) of 310 children who underwent transplantation for cardiomyopathy (n = 5) or congenital heart disease (n = 23) required ECMO support.  The total ischemic time was significantly longer for ECMO-rescued recipients compared with the authors' overall transplantation population (276 +/- 86 mins versus 242 +/- 70 mins, p < 0.01).  The indication for transplantation, for ECMO support, and the timing of cannulation had no impact on survival.  Hyperacute rejection was uncommon; 15 children were successfully weaned off ECMO and discharged alive (54 %).  Mean duration of ECMO was 2.8 days for survivors (median of 3 days) compared with 4.8 days for non-survivors (median of 5 days).  There was 100 % 3-year survival in the ECMO survivor group, with 13 patients (46 %) currently alive at a mean follow-up of 8.1 +/- 3.8 years.  The graft function was preserved (shortening fraction 36 +/- 7 %), despite an increased number of early rejection episodes (1.7 +/- 1.6 versus 0.7 +/- 1.3, overall transplant population, p < 0.05) and hemodynamically comprising rejection episodes (1.3 +/- 1.9 versus 0.7 +/- 1.3, overall transplant population, p < 0.05).  The authors concluded that overall survival was 54 %, with all patients surviving to at least 3 years after undergoing transplantation.  None of the children requiring more than 4 days of ECMO support survived.  Despite an increased number of early rejection and hemodynamically compromising rejection episodes, the long-term graft function is similar to the overall transplantation population.

Bermudez and colleagues (2009) analyzed outcomes after ECMO use for primary graft dysfunction (PGD) after lung transplantation at a single center over a 15-year period and assessed long-term survival.  From March 1991 to March 2006, 763 lung or heart-lung transplants were performed at the authors' center.  A total of 58 patients (7.6 %) required early (0 to 7 days after transplant) ECMO support for PGD.  Veno-venous or veno-arterial ECMO was implemented (32 and 26 cases) depending on the patient's hemodynamic stability, surgeon's preference, and the era of transplantation.  Mean duration of support was 5.5 days (range of 1 to 20).  Mean follow-up was 4.5 years.  Thirty-day and 1-year and 5-year survivals were 56 %, 40 %, and 25 %, respectively, for the entire group.  Thirty-nine patients were weaned from ECMO, 21 veno-venous and 18 veno-arterial (53.8 % and 46.2 %), with 1-year and 5-year survivals of 59 % and 33 %, inferior to recipients not requiring ECMO (p = 0.05).  Survival at 30 days and at 1 and 5 years was similar for the patients supported with veno-arterial or veno-venous ECMO (58 % versus 55 %, p = 0.7; 42 % versus 39 %, p = 0.8; 29 % versus 22 %, p = 0.6).  The authors concluded that ECMO can provide acceptable support for PGD irrespective of the method used.

Hammainen and colleagues (2011) examined early outcome in patients with end-stage pulmonary disease bridged with ECMO with the intention of lung transplantation (LTx) in 2 Scandinavian transplant centers (n = 16).  Most patients were late referrals for LTx, and all failed to stabilize on mechanical ventilation.  A total of 13 patients (7 men) with a mean age of 41 +/- 8 years (range of 25 to 51 years) underwent LTx after a mean ECMO support of 17 days (range of 1 to 59 days).  Mean follow-up at 25 +/- 19 months was 100 % complete.  Three patients died on ECMO while waiting for a donor, and 1 patient died 82 days after LTx; thus, by intention-to-treat, the success for bridging is 81 % and 1-year survival is 75 %.  All other patients survived, and 1-year survival for transplant recipients was 92 % +/- 7 %.  Mean intensive care unit stay after LTx was 28 +/- 18 days (range of 3 to 53 days).  All patients were doing well at follow-up; however, 2 patients underwent re-transplantation due to bronchiolitis obliterans syndrome at 13 and 21 months after the initial ECMO bridge to LTx procedure.  Lung function was evaluated at follow-up, and mean forced expiratory volume in 1 second was 2.0 +/- 0.7 l (62 % +/- 23 % of predicted) and forced vital capacity was 3.1 +/- 0.6 l (74 % +/- 21 % of predicted).  The authors concluded that ECMO used as a bridge to LTx results in excellent short-term survival in selected patients with end-stage pulmonary disease.

Haneya et al (2011) describes the successful use of different extra-corporeal circulatory systems as a bridge to LTx at remote centers.  Between January 2003 and December 2009, these investigators had 10 requests for implantation of extra-corporeal circulatory systems (pumpless extra-corporeal lung assist [PECLA] or ECMO) in patients decompensating on the waiting list to bridge to LTx at 3 different transplant centers between 150 km and 570 km apart.  Cannulas were inserted percutaneously with Seldinger's technique.  The median patient age was 36 years (range of 24 to 53).  Three patients were supported with PECLA and 7 with ECMO.  The median duration of support was 23 days (range of 5 to 73).  Two patients were initially provided with ECMO and then changed to PECLA after hemodynamic stabilization in the face of persisting pulmonary failure.  Two patients died of multi-organ failure on ECMO while on the waiting list.  One PECLA patient was successfully weaned and waiting for LTx.  Before transplantation, 5 patients (4 PECLA and 1 ECMO) were successfully weaned from mechanical ventilation, and 3 PECLA patients were successfully weaned from the system.  Seven patients were successfully bridged and transplanted; 5 of 7 patients were discharged from the transplant centers.  The authors concluded that these findings suggested that implantation of extra-corporeal circulatory systems is a safe method to bridge patients decompensating on the waiting list for LTx.  Support intervals of several weeks are possible.

Noah et al (2011) compared the hospital mortality of patients with H1N1-related ARDS referred, accepted, and transferred for ECMO with matched patients who were not referred for ECMO.  A cohort study in which ECMO-referred patients were defined as all patients with H1N1-related ARDS who were referred, accepted, and transferred to 1 of the 4 adult ECMO centers in the United Kingdom during the H1N1 pandemic in winter 2009 to 2010.  The ECMO-referred patients and the non-ECMO-referred patients were matched using data from a concurrent, longitudinal cohort study (Swine Flu Triage study) of critically ill patients with suspected or confirmed H1N1.  Detailed demographic, physiological, and co-morbidity data were used in 3 different matching techniques (individual matching, propensity score matching, and GenMatch matching).  Main outcome measure was survival to hospital discharge analyzed according to the intention-to-treat principle.  Of 80 ECMO-referred patients, 69 received ECMO (86.3 %) and 22 died (27.5 %) prior to discharge from the hospital.  From a pool of 1,756 patients, there were 59 matched pairs of ECMO-referred patients and non-ECMO-referred patients identified using individual matching, 75 matched pairs identified using propensity score matching, and 75 matched pairs identified using GenMatch matching.  The hospital mortality rate was 23.7 % for ECMO-referred patients versus 52.5 % for non-ECMO-referred patients (relative risk [RR], 0.45 [95 % confidence interval (CI): 0.26 to 0.79]; p = 0.006) when individual matching was used; 24.0 % versus 46.7 %, respectively (RR, 0.51 [95 % CI: 0.31 to 0.81]; p = 0.008) when propensity score matching was used; and 24.0 % versus 50.7 %, respectively (RR, 0.47 [95 % CI: 0.31 to 0.72]; p = 0.001) when GenMatch matching was used.  The results were robust to sensitivity analyses, including amending the inclusion criteria and restricting the location where the non-ECMO-referred patients were treated.  The authors concluded that for patients with H1N1-related ARDS, referral and transfer to an ECMO center was associated with lower hospital mortality compared with matched non-ECMO-referred patients.

In an editorial that accompanied the afore-mentioned study, Checkley (2011) stated that "the study by Noah et al was an observational, prospective study ... does not replace a randomized clinical trial .... the current study may have been underpowered to determine if ECMO was associated with a survival advantage when using hospitals as the unit of analysis .... despite several decades of investigation into potential treatment strategies, use of low tidal volumes remains the only proven therapy to decrease mortality in ARDS.  In light of the large observed differences in mortality with and without ECMO, large consortia of trialists may be enticed to consider ECMO as a potential target for a randomized controlled trial early in the course of severe ARDS from all causes".

Moran et al (2010) noted that the role of ECMO in the treatment of the acute respiratory distress syndrome (ARDS) is controversial, notwithstanding the recent publication of the results of the CESAR (Conventional Ventilation or ECMO for Severe Adult Respiratory Failure) trial.  Using Bayesian meta-analytic methods from 3 randomized controlled trials (RCTs) of ECMO in ARDS, these researchers estimated the mortality odds ratio (OR) to be 0.78 (95 % credible interval, 0.25 to 3.04), p (OR > 1) = 30 %.  Thus, a null effect of ECMO is not excluded and there appears only weak evidence of efficacy.  These investigators surveyed particular problems associated with the conduct of the "pragmatic" CESAR trial: composite endpoints, sample size estimation under uncertainty of baseline mortality rates, the generation of unbiased treatment comparisons, the impact of treatment non-compliance, and the uncertainty associated with cost-effectiveness and cost-utility analysis.  The authors concluded that the CESAR trial is problematic in terms of both the clinical and economic outcomes, although observational series suggested plausible efficacy.  They suggested that ECMO finds rationale as rescue therapy and that the current uncertainty of its role mandates a further RCT.

Park et al (2011) stated that the role of ECMO in supporting adult refractory respiratory failure continues to evolve.  Technical advances and the clinical challenges of H1N1 associated severe ARDS have spurred a resurgence of interest in ECMO.  Published systematic review and pooled analyses pointed out the limitations of available studies, however, a growing body of evidence suggested potential for benefit. 

Wong and Vuylsteke (2011) noted that a large proportion of critically ill H1N1/2009 patients with respiratory failure subsequently developed ARDS and, to date, about 400 patients receiving ECLS have been accounted for globally, with a reported survival rate from 63 % to 79 %.  The survival rates of patients with ARDS due to non-H1N1/2009 infections are similar.  There is no definite evidence to suggest that patient outcomes are changed by ECLS, but its use is associated with serious short-term complications.  Extra-corporeal life support relies on an extra-corporeal circuit, with ECMO and pumpless interventional lung assist (ILA) being the 2 major types employed in ARDS.  Both have the potential to correct respiratory failure and related hemodynamic instability.  There are only a very limited number of clinical trials to test either and, although ECLS has been used in treating H1N1/2009 patients with ARDS with some success, it should only be offered in the context of clinical trials and in experienced centers.

Combes et al (2012) reviewed case series and trials that evaluated ECMO for respiratory failure and describes patient and circuit management in the modern era of ECMO support.  In recent years, pivotal progress has been made in the conception and construction of ECMO circuits.  They are now simpler, safer, require less anticoagulation and are associated with fewer bleeding complications.  The encouraging results of the efficacy and economic assessment of conventional ventilatory support versus ECMO for severe adult respiratory failure (CESAR) trial performed in the United Kingdom and good outcomes of patients who received ECMO as rescue therapy during the recent H1N1 influenza pandemic, in which the latest generation of ECMO technology was used, reignited interest in ECMO for severe ARDS.  The authors concluded that the latest generation of ECMO systems is more biocompatible, better performing and longer lasting.  Although recent studies suggested that veno-venous ECMO might improve the outcomes of patients with ARDS, indications for ECMO use remain uncertain.  They stated that future trials of ECMO for severe ARDS should strictly control for standard-of-care mechanical ventilation strategies in the control group and early transportation on ECMO for patients in the intervention arm.

Cai and colleagues (2012) evaluated the effects of ECMO on mortality in adult patients with ARDS.  Literature concerning RCTs, case-control studies and prospective cohort studies from January 1966 to July 2011 on ECMO for the treatment of ARDS patients was retrieved by electronic and manual search.  Meta-analysis of the use of ECMO in the treatment of ARDS patients was conducted using the methods recommended by the Cochrane Collaboration's software RevMan 5.0.  A total of 3 papers reporting RCTs and 6 papers concerning observational cohort studies of using ECMO in patients with severe ARDS were enrolled for analysis.  Meta-analysis of the 3 RCTs (310 patients, 159 of them treated with ECMO) revealed ECMO did not decrease the mortality of ARDS patients [OR = 0.75, 95 % CI: 0.45 to 1.24, p = 0.27].  Meta-analysis of the all 9 studies (1,058 patients, 386 of them treated with ECMO) revealed ECMO increased the mortality of ARDS patients (OR = 1.58, 95 % CI: 0.94 to 2.67, p = 0.08).  The authors concluded that there is no evidence to prove that ECMO is beneficial in adult patients with ARDS, therefore further investigation with a large sample of high quality RCT is warranted.

Chou et al (2012) presented their experience of heart transplantation (HTx) using ECMO with Thoratec pneumatic ventricular assist device (TpVAD).  From May 1996 to June 2011, among 410 patients who underwent HTx, 23 required mechanical circulatory support (MCS) with implantation of the TpVAD and 15 (65 %) of them received grafts.  The 23 patients included 4 female and 19 male patients (age range of 10 to 80 years).  Eighteen (78 %) of them needed ECMO before TpVAD implantation.  Twelve (67 %) were implanted with a TpVAD double bridge to HTx.  The demand for MCS among patients with acute hemodynamic collapse has led to major improvements in the existing systems such as ECMO with double bridge to TpVAD.  These researchers used ECMO as a rescue procedure for acute hemodynamic deterioration.  However, during ECMO support, left ventricular afterload increased.  If prolonged support is required, TpVAD might be required: 15 (65 %) of patients supported by ECMO with TpVAD needed to a wait a suitable donor.  The authors recommended the application of ECMO for short-term support (within 1 week), and TpVAD as a bridge for medium- or long-term support.

Asmussen et al (2013) performed a systematic review and meta-analysis to evaluate the level of evidence for the use of ECMO in hypoxemic respiratory failure resulting from burn and smoke inhalation injury.  These investigators searched any article published before March 01, 2012.  Available studies published in any language were included.  Five authors rated each article and assessed the methodological quality of studies using the recommendation of the Oxford Centre for Evidence Based Medicine (OCEBM).  The search yielded 66 total citations but only 29 met the inclusion criteria of burn and/or smoke inhalation injury.  There were no available systematic reviews/meta-analyses published that met inclusion criteria.  Only a small number of clinical trials, all with a limited number of patients, were available.  The overall data suggested that there is no improvement in survival for burn patients suffering acute hypoxemic respiratory failure, with the use of ECMO.  Extra-corporeal membrane oxygenation run times of less than 200 hours correlate with higher survival compared to 200 hours or more.  Scald burns show a tendency of higher survival than flame burns.  The authors concluded that the presently available literature is based on insufficient patient numbers; and the data obtained as well as the level of evidence generated are limited.  They stated that the role of ECMO in burn and smoke inhalation injury is therefore unclear; further research on ECMO in burn and smoke inhalation injury is warranted.

Combes et al (2014) stated that the use of ECMO for severe acute respiratory failure (ARF) in adults is growing rapidly given recent advances in technology, even though there is controversy regarding the evidence justifying its use.  Because ECMO is a complex, high-risk, and costly modality, at present it should be conducted in centers with sufficient experience, volume, and expertise to ensure it is used safely.  On behalf of the International ECMO Network, these investigators presented a position paper, which represented the consensus opinion of an international group of physicians and associated health-care workers who have expertise in therapeutic modalities used in the treatment of patients with severe ARF, with a focus on ECMO.  These researchers provided physicians, ECMO center directors and coordinators, hospital directors, health-care organizations, and regional, national, and international policy makers a description of the optimal approach to organizing ECMO programs for ARF in adult patients.  They noted that this position paper will help ensure that ECMO is delivered safely and proficiently, such that future observational and randomized clinical trials assessing this technique may be performed by experienced centers under homogeneous and optimal conditions.  The authors concluded that given the need for further evidence, they encourage restraint in the widespread use of ECMO until there is a better appreciation for both the potential clinical applications and the optimal techniques for performing ECMO.

In a Cochrane review, Tramm et al (2015) examined if the use of veno-venous (VV) or venous-arterial (VA) ECMO in adults is more effective in improving survival compared with conventional respiratory and cardiac support.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and EMBASE (Ovid) on August 18, 2014.  They searched conference proceedings, meeting abstracts, reference lists of retrieved articles and databases of ongoing trials and contacted experts in the field.  They imposed no restrictions on language or location of publications.  These researchers included RCTs, quasi-RCTs and cluster-RCTs that compared adult ECMO versus conventional support.  Two review authors independently screened the titles and abstracts of all retrieved citations against the inclusion criteria.  They independently reviewed full-text copies of studies that met the inclusion criteria.  They entered all data extracted from the included studies into Review Manager.  Two review authors independently performed risk of bias assessment.  All included studies were appraised with respect to random sequence generation, concealment of allocation, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias.  The authors included 4 RCTs that randomly assigned 389 participants with acute respiratory failure.  Risk of bias was low in 3 RCTs and high in 1 RCT.  These researchers found no statistically significant differences in all-cause mortality at 6 months (2 RCTs) or before 6 months (during 30 days of randomization in 1 trial and during hospital stay in another RCT).  The quality of the evidence was low to moderate, and further research is very likely to impact the confidence in the estimate of effects because significant changes have been noted in ECMO applications and treatment modalities over study periods to the present.  Two RCTs supplied data on disability.  In 1 RCT survival was low in both groups but none of the survivors had limitations in their daily activities 6 months after discharge.  The other RCT reported improved survival without severe disability in the intervention group (transfer to an ECMO center ± ECMO) 6 months after study randomization but no statistically significant differences in health-related quality of life.  In 3 RCTs, participants in the ECMO group received greater numbers of blood transfusions.  One RCT recorded significantly more non-brain hemorrhage in the ECMO group.  Another RCT reported 2 serious adverse events in the ECMO group, and another reported 3 adverse events in the ECMO group.  Clinical heterogeneity between studies prevented meta-analyses across outcomes.  These investigators found no completed RCT that had investigated ECMO in the context of cardiac failure or arrest.  They found 1 ongoing RCT that examined patients with acute respiratory failure and 2 ongoing RCTs that included patients with acute cardiac failure (arrest).  The authors concluded that ECMO remains a rescue therapy.  Since the year 2000, patient treatment and practice with ECMO have considerably changed as the result of research findings and technological advancements over time.  Over the past 4 decades, only 4 RCTs have been published that compared the intervention versus conventional treatment at the time of the study.  Clinical heterogeneity across these published studies prevented pooling of data for a meta-analysis.  The authors recommended combining results of ongoing RCTs with results of trials conducted after the year 2000 if no significant shifts in technology or treatment occur.  They stated that until these new results become available, data on use of ECMO in patients with acute respiratory failure remain inconclusive.  For patients with acute cardiac failure or arrest, outcomes of ongoing RCTs will assist clinicians in determining what role ECMO and ECPR can play in patient care.

Noly and colleagues (2014) stated that right ventricular failure (RVF) after implantation of left ventricular assist device (LVAD) is a dramatic complication.  These researchers compared retrospectively 2 techniques of temporary right ventricular support after LVAD (HeartMate II, Thoratec Corp, Pleasonton, CA) implantation.  From January 1, 2006 to December 31, 2012, a total of 78 patients [mean age of 52 ± 1.34 years; 15 women (19 %)] received a HeartMate II at the authors’ institution.  Among these, 18 patients (23 %) suffered post-implant RVF treated by peripheral temporary right ventricular support.  Etiology of heart failure was ischemic in 12 (67 %) and dilated cardiomyopathy in 6 (33 %) patients.  The pre-implant RV risk-score averaged 5.1 ± 0.59.  Ten patients were treated using a femoro-femoral veno-arterial ECLS and 8 patients were treated using ECMO as a right ventricular assist device (RVAD) established between a femoral vein and the pulmonary artery via a Dacron prosthesis (RVAD).  Duration of RV support was 7.12 ± 5.4 days and 9.57 ± 3.5 days in veno-arterial ECLS and vein and the pulmonary artery RVAD groups, respectively (p = 0.32).  Three patients (17 %) died while under RV support (veno-arterial ECLS, n = 2; and vein and the pulmonary artery RVAD, n = 1, p = 0.58).  In the veno-arterial ECLS group, 6 (60 %) patients suffered major thromboembolic complications including thrombosis of the ECLS arterial line (n = 2), ischemic stroke (n = 2) and thrombosis of the ascending aorta (n = 2).  No major complication was observed in the vein and the pulmonary artery RVAD group (p = 0.01).  Right ventricular support was successfully weaned in 8 (80 %) patients of the veno-arterial ECLS group and in 7 (87.5 %) of the vein and the pulmonary artery RVAD group (p = 0.58).  The duration of post-implant intensive care unit stay was not different (respectively, 27.5 ± 18.7 days and 20.0 ± 12.0 days; p = 0.38) between both groups.  The authors concluded that temporary support of the failing RV after LVAD implantation using temporary vein and the pulmonary artery RVAD is a promising therapeutic option.

Furthermore, an UpToDate review on “Extracorporeal membrane oxygenation (ECMO) in adults” (Haft and Bartlett, 2015) states that “Future -- Applications for ECMO may expand in the future to include percutaneous temporary left ventricular assistance and low flow ECMO for CO2 removal (ECOOR)”.

Acute Massive Pulmonary Embolism

Yusuff et al (2015) stated that massive pulmonary embolism (PE) can present with extreme physiological dysfunction, characterized by acute right ventricular failure, hypoxemia unresponsive to conventional therapy and cardiac arrest. Consensus regarding the management of patients with persistent shock following thrombolysis is lacking.  These investigators described the application of ECMO in the treatment of acute massive PE.  They were unable to identify any RCTs comparing ECMO with other support systems in the setting of massive PE.  They reviewed case reports and case series published in the past 20 years to evaluate the mortality rate and any poor prognostic factors.  Overall survival was 70.1 % and none of the definitive treatment modalities was associated with a higher mortality (thrombolysis - OR - 0.99, p - 0.9, catheter embolectomy - OR - 1.01, p - 0.99, surgical embolectomy - OR - 0.44, p - 0.20).  Patients who had ECMO instituted while in cardio-respiratory arrest had a higher risk of death (OR - 16.71, p - 0.0004).

Furthermore, an UpToDate review on “Overview of acute pulmonary embolism in adults” (Thompson, 2016) does not mention ECMO as a therapeutic option; and an UpToDate review on “Extracorporeal membrane oxygenation (ECMO) in adults” (Haft and Bartlett, 2016) does not mention pulmonary embolism as an indication of ECMO.

Pozzi and colleagues (2020) noted that high-risk PE requires hemodynamic and respiratory support along with re-perfusion strategies.  Recently updated European guidelines assigned a low class of recommendation to ECMO for high-risk PE.  In a systematic review, these researchers examined clinical outcomes after ECMO in high-risk PE.  They searched electronic data-bases including PubMed, Embase and Web of Science from January 2000 to April 2020.  Efficacy outcomes included in-hospital survival with good neurological outcome and survival at follow-up.  Safety outcomes included lower limb ischemia and hemorrhagic and ischemic stroke.  Where possible (absence of high heterogeneity), meta-analyses of outcomes were performed using a random-effects model.  These investigators included 16 uncontrolled case-series (533 subjects).  In-hospital survival with good neurological outcome ranged between 50 % and 95 % while OS at follow-up ranged from 35 % to 95 %, both with a major degree of heterogeneity (I2 > 70 %).  The prevalence of lower limb ischemia was 8 % (95 % CI: 3 % to 15 %).  The prevalence of stroke (either hemorrhagic or ischemic) was 11 % (95 % CI: 3 % to 23 %), with notable heterogeneity (I² = 63.35 %).  The authors concluded that based on currently available literature, it is not possible to draw definite conclusions on the usefulness of ECMO for high-risk PE.  These researchers stated that large, prospective, multi-center studies or nationwide registries are needed to best define the role of ECMO for high-risk PE.

Pregnant and Post-Partum Women With H1N1-Related Acute Respiratory Distress Syndrome

Anand and colleagues (2016) stated that ECMO provides complete or partial support of the heart and lungs. Ever since its inception in the 1960s, it has been used across all age groups in the management of refractory respiratory failure and cardiogenic shock.  While it has gained widespread acceptance in the neonatal and pediatric physician community, ECMO remains a controversial therapy for acute respiratory distress syndrome in adults.  Its popularity was revived during the H1N1 pandemic and advancements in technology have contributed to its increasing usage.  Acute respiratory distress syndrome continues to be a potentially devastating condition with significant mortality rates.  Despite gaining more insights into this entity over the years, mechanical ventilation remains the only life-saving, yet potentially harmful intervention available for acute respiratory distress syndrome.  Extracorporeal membrane oxygenation shows promise in this regard by offering less dependence on mechanical ventilation, thereby potentially reducing ventilator-induced injury.  However, the lack of rigorous clinical data has prevented ECMO from becoming the standard of care in the management of acute respiratory distress syndrome.  Therefore, the results of 2 large ongoing randomized trials, which will hopefully throw more light on the role of ECMO in the management of this disease entity, are keenly awaited.  

Post-Operative ECMO for Acute Type A Aortic Dissection

Lin and colleagues (2017) noted that few studies have investigated the use of post-operative ECMO in acute type A aortic dissection (aTAAD).  These investigators identified aTAAD surgical patients at risk of ECMO implantation post-operatively and analyzed the prognosis of these patients.  They retrospectively reviewed 162 consecutive aTAAD patients undergoing operations from January 2008 to December 2015.  Patient data were analyzed for risk factors leading to an ECMO requirement; short-term as well as long-term outcomes in patients who did and did not require ECMO were compared.  Post-operative ECMO was required in 20 patients (12.3 %), and in-hospital mortality was higher in the ECMO group (65.0 % versus 8.5 %, p < 0.001).  Factors predicting post-operative ECMO were pre-operative hemodynamic instability (p = 0.049), aortic cross-clamp time (p = 0.036), and post-operative peak creatinine kinase-MB (p = 0.002); ECMO survivors presented at a younger age (p = 0.036) and had a less post-operative blood transfusion (p = 0.034) than ECMO non-survivors.  The post-discharge survival rate was equivalent in patients with or without ECMO support.  The authors concluded that although post-operative ECMO was an important predictor of in-hospital death, this pilot study showed that aTAAD patients supported with post-operative ECMO who survived to hospital discharge had a long-term survival comparable to patients who did not receive ECMO.

Acute Coronary Syndromes

Pavasini and associates (2017) stated that extracorporeal circulatory support (ECS) is a life-saving technique, and its use is increasing in acute coronary syndromes (ACS).  These investigators performed a meta-analysis on pooled event rate of short-term mortality and complications of ACS patients treated with ECS.  Articles were searched in Medline, Cochrane Library, Google Scholar, and Biomed Central.  Inclusion criteria were observational studies on ACS patients treated with ECS.  Primary outcome was short-term mortality; secondary outcomes were ECS-related complications, causes of death, long-term mortality, and bridge therapy.  A total of 16 articles were selected.  Data about clinical characteristics, ACS diagnosis and treatment, ECS setting, outcome definitions, and event rate were retrieved from the articles.  Random effect meta-analytic pooling was performed reporting results as a summary point estimate and 95 % CI.  A total of 739 patients were included (mean age of 59.8 ± 2.9 years).  The event rate of short-term mortality was 58 % (95 % CI: 51 to 64 %), 6-month mortality was affecting 24 % (95 % CI: 5 to 63 %) of 1-month survivors, and 1-year mortality 17 % (95 % CI: 6 to 40 %) of 6-month survivors.  The event rates of ECS-related complications were acute renal failure 41 %, bleeding 25 %, neurologic damage in survivors 21 %, sepsis/infections 21 %, and leg ischemia 12 %.  Between causes of death, multiple organ failure and brain death affected respectively 40 % and 27 % of patients.  Bridge to VAD was offered to 14 % of patients, and 7 % received a transplant.  The authors concluded that there is still a high rate of short-term mortality and complications in ACS patients treated with ECS.  Moreover, they stated that new studies are needed to optimize and standardize ECS.

Acute Respiratory Distress Syndrome

Munoz et al (2017) evaluated the development of an ECMO program for the treatment of ARDS in adults.  These investigators described a study of 15 cases treated since the program approval from 2010 to 2016, and a case-control study matching the 15 ECMO cases with the 52 severe ARDS treated between 2005 and 2011 in which alternative rescue treatments (prone ventilation, tracheal gas insufflation (TGI) and/or the administration of inhaled nitric oxide (iNO)) were used.  ECMO experience: Mortality 47 % (7/15); 4 patients died due to complications directly related to ECMO therapy.  Intensive care unit (ICU) stay 46.6 ± 45 days (range of 4 to 138).  Hospital stay 72.4 ± 98 days (range of 4 to 320).  Case-control: The mortality in the control group was 77 % (44/52).  The ECMO group practically doubled the mean days of ICU and hospital stay (p < 0.05).  The multi-variate analysis demonstrated an odds ratio (OR) of 0.13 (0.02 to 0.73) for mortality associated with ECMO treatment.  The following were also independent predictors of mortality: age (OR 1.05, 95 % CI: 1 to 11), SOFA score (OR 1.34, 95 % CI: 1.04 to 1.7), and the need for renal replacement therapy (OR 1.3, 95 % CI: 1.04 to 1.7).  Economic analysis: The hospital cost per patient in the ECMO group doubled compared to that of the control group (USD 77,099 versus USD 37,660).  However, the cost per survivor was reduced by 4 % (USD 144,560 versus USD 150,640, respectively).  The authors concluded that these findings endorsed the use of ECMO as a rescue therapy in adults with ARDS, although there are some risks associated with a learning curve as well as an important increase in the days of patient stay.  Moreover, they stated that the justification for the maintenance of an ECMO program in adults should be based on future studies of efficacy and cost effectiveness.

Tillmann et al (2017) evaluated the hospital survival in patients with severe ARDS managed with ECMO and low tidal volume ventilation as compared to patients managed with low tidal volume ventilation alone.  Electronic databases were searched for studies of at least 10 adult patients with severe ARDS comparing the use of ECMO with low tidal volume ventilation to mechanical ventilation with a low tidal volume alone.  Only studies reporting hospital or ICU survival were included.  All identified studies were assessed independently by 2 reviewers.  Of 1,782 citations, 27 studies (n = 1,674) met inclusion criteria.  Hospital survival for ECMO patients ranged from 33.3 to 86 %, while survival with conventional therapy ranged from 36.3 to 71.2 %; 5 studies were identified with appropriate control groups allowing comparison, but due to the high degree of variability between studies (I2 = 63 %), their results could not be pooled; 2 of these studies demonstrated a significant difference, both favoring ECMO over conventional therapy.  The authors concluded that given the lack of studies with appropriate control groups, the confidence in a difference in outcome between the 2 therapies remained weak.  They stated that future studies on the use of ECMO for severe ARDS are needed to clarify the role of ECMO in this disease.

Combes and colleagues (2018) stated that the efficacy of veno-venous extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome (ARDS) remains controversial.  In an international clinical trial, these researchers randomly assigned patients with very severe ARDS, as indicated by 1 of 3 criteria -- a ratio of partial pressure of arterial oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 50 mm Hg for more than 3 hours; a Pao2:Fio2 of less than 80 mm Hg for more than 6 hours; or an arterial blood pH of less than 7.25 with a partial pressure of arterial carbon dioxide of at least 60 mm Hg for more than 6 hours -- to receive immediate veno-venous ECMO (ECMO group) or continued conventional treatment (control group).  Cross-over to ECMO was possible for patients in the control group who had refractory hypoxemia.  The primary end-point was mortality at 60 days.  At 60 days, 44 of 124 patients (35 %) in the ECMO group and 57 of 125 (46 %) in the control group had died (relative risk [RR], 0.76; 95 % confidence interval [CI]: 0.55 to 1.04; p = 0.09).  Cross-over to ECMO occurred a mean (± SD) of 6.5 ± 9.7 days after randomization in 35 patients (28 %) in the control group, with 20 of these patients (57 %) dying.  The frequency of complications did not differ significantly between groups, except that there were more bleeding events leading to transfusion in the ECMO group than in the control group (in 46 % versus 28 % of patients; absolute risk difference, 18 percentage points; 95 % CI: 6 to 30) as well as more cases of severe thrombocytopenia (in 27 % versus 16 %; absolute risk difference, 11 percentage points; 95 % CI:  0 to 21) and fewer cases of ischemic stroke (in no patients versus 5 %; absolute risk difference, −5 percentage points; 95 % CI: −10 to −2).  The authors 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.

Millar and colleagues (2019) carried out a systematic literature review of animal models combining features of experimental ARDS with ECMO to better understand this situation. Medline and Embase were searched between January 1996 and December 2018. Inclusion criteria: animal models combining features of experimental ARDS with ECMO. Clinical studies, abstracts, studies in which the model of ARDS and ECMO has been reported previously, and studies not employing veno-venous, veno-arterial, or central ECMO were excluded from this analysis. Data were extracted to fully characterize models. Variables related to 4 key features: study design, animals and their peri-experimental care, models of ARDS and mechanical ventilation, and ECMO and its intra-experimental management. A total of 17 models of ARDS and ECMO were identified; 12 were published after 2009. All were performed in large animals, the majority (n = 10) in pigs. The median number of animals included in each study was 17 (12 to 24), with a median study duration of 8 hours (5 to 24). Oleic acid infusion was the commonest means of inducing ARDS. Most models employed peripheral veno-venous ECMO (n = 12). The reporting of supportive measures and the practice of mechanical ventilation were highly variable. Descriptions of ECMO equipment and its management were more complete. The authors concluded that a limited number of models combined the features of experimental ARDS with ECMO. Among those that do, there was significant heterogeneity in both design and reporting. These researchers stated that there is a need to standardize the reporting of pre-clinical studies in this area and to develop best practice in their design.

An American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline on Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome (Fan, et al., 2017) concluded: "There is insufficient evidence to make a recommendation regarding the use of ECMO in patients with ARDS. The only recent RCT considered had limitations including:

1. the use of a composite primary endpoint (i.e., disability-free survival at 6 mo),
2. incomplete application of the intervention (24% of patients randomized to the intervention group did not receive ECMO),
3. the lack of standardized LTV in the control group, and
4. cointervention with transfer to a high-volume referral center.

In the interim, we recommend evidence-based use of lung-protective ventilation and early medical management for patients with severe ARDS before use of ECMO.. . . Further research is needed to clarify the potential efficacy of ECMO for patients with severe ARDS as well as the role of extracorporeal support in patients with mild/moderate ARDS. More data will be coming from an international, multicenter RCT comparing VV ECMO to conventional mechanical ventilation (EOLIA [Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome]; ClinicalTrials.gov NCT01470703)."

Furthermore, an UpToDate review on “Acute respiratory distress syndrome: Supportive care and oxygenation in adults” (Siegel, 2019) does not mention extracorporeal membrane oxygenation as a therapeutic option.

Veno-Venous ECMO for the Treatment of Acute Respiratory Distress Syndrome (ARDS)

Vaquer and colleagues (2017) noted that veno-venous ECMO for refractory ARDS is a rapidly expanding technique.  These researchers performed a systematic review and meta-analysis of the most recent literature to analyze complications and hospital mortality associated with this technique.  Using the PRISMA guidelines for systematic reviews and meta-analysis, Medline and Embase were systematically searched for studies reporting complications and hospital mortality of adult patients receiving veno-venous ECMO for severe and refractory ARDS.  Studies were screened for low bias risk and assessed for study size effect.  Meta-analytic pooled estimation of study variables was performed using a weighted random effects model for study size.  Models with potential moderators were explored using random effects meta-regression.  A total of 12 studies fulfilled inclusion criteria, representing a population of 1,042 patients with refractory ARDS.  Pooled mortality at hospital discharge was 37.7 % (95 % CI: 31.8 to 44.1; I2 = 74.2 %).  Adjusted mortality including 1 imputable missing study was 39.3 % (95 % CI: 33.1 to 45.9).  Meta-regression model combining patient age, year of study realization, mechanical ventilation (MV) days and prone positioning before veno-venous ECMO was associated with hospital mortality (p < 0.001; R2 = 0.80).  Patient age (b = 0.053; p = 0.01) and maximum cannula size during treatment (b = -0.075; p = 0.008) were also independently associated with mortality.  Studies reporting H1N1 patients presented inferior hospital mortality (24.8 versus 40.6 %; p = 0.027).  Complication rate was 40.2 % (95 % CI: 25.8 to 56.5), being bleeding the most frequent 29.3 % (95 % CI: 20.8 to 39.6).  Mortality due to complications was 6.9 % (95 % CI: 4.1 to 11.2).  Mechanical complications were present in 10.9 % of cases (95 % CI: 4.7 to 23.5), being oxygenator failure the most prevalent (12.8 %; 95 % CI: 7.1 to 21.7).  The authors concluded that these findings suggested that despite high initial severity, patients treated with veno-venous ECMO for refractory ARDS presented reduced mortality ratios.  Patient age, H1N1-related ARDS and cannula size were independently associated with hospital mortality, and the combined effect of patient age, year of study realization, MV days and prone positioning before extracorporeal support were also associated with better outcomes.  Medical complications wee commonly present in veno-venous ECMO but have limited impact on patient outcome.  When compared with veno-arterial ECMO for cardiovascular support, veno-venous ECMO presents a different pattern of complications and outcomes, probably due to differences in technical and patient characteristics.

These researchers noted that mechanical complications were present in 11 % of patients.  These findings contrasted with historical reports in which high number of both oxygenator and pump failures were observed.  However, 2 recent evaluations of complications associated with ECMO use in ARDS found that acute replacements of the ECMO system were required in 14.4 and 16.1 % of cases.  These results fall within the observed range of failures found in this meta-analysis.  Nevertheless, the reduced number of studies reporting on technical and mechanical complications included in the present meta-analysis made the interpretation of the above-mentioned results difficult and should be evaluated cautiously.  In addition, more technically oriented evaluations are needed to provide a definitive answer on the technical improvement of veno-venous ECMO systems.  In addition to the already mentioned limitations of this study, some further aspects which may limit the interpretation of present results must be discussed.  The highest statistical quality of systematic reviews and meta-analysis was obtained when RCT are used to estimate pooled outcomes.  Indeed, this minimized the risk of multiple biases and enhanced the quality of information obtained from the analysis.  However, in the present report, the only recent RCT available on the use of ECMO for respiratory failure was combined with non-randomized studies.  In order to reduce bias in the results of this study, strict inclusion criteria were implemented and care was taken to minimize the impact of confounding factors.  In addition, specific statistical methods to identify publication bias and to quantify the impact of study size on results were implemented in the present report.  None of the implemented evaluations suggested unreliability of present analyses, and results were adjusted to include potentially missing reports.  Nevertheless, as new RCT become available, new meta-analyses should be performed to include newest data and improve reliability of present estimations.  Another limitation of the present report was that not all studies provided information in all variables.  While the main study variables were widely covered by most of the reports included, information on certain medical and technical complications was only provided in a few studies.  Thus, the pooled point estimate for certain variables needed to be interpreted cautiously.  Future studies will also be beneficial to provide better estimations of these variables.  The present report was also limited by the fact that only articles written in English were included, which could represent a source of bias.  However, the impact of such idiomatic bias was estimated to be negligible given the low number of reports written in other languages (5.6 %).  Finally, the high heterogeneity levels observed for hospital mortality rates implied increased variance among the included studies.  Although these researchers were able to identify one model that could explain a high proportion of the observed variance, additional unexplored factors could be present.  The inclusion of data from upcoming RCTs, with more homogeneous patient characteristics, objectives and methodologies, may help in minimizing heterogeneity and yield more reliable and definitive results.

Munshi and co-workers (2018) the efficacy of veno-venous ECMO in people with ARDS is uncertain according to the most recent data.  These researchers estimated the effect of veno-venous ECMO on mortality from ARDS.  In this systematic review and meta-analysis, these investigators searched Medline (including Medline In-Process and Epub Ahead of Print), Embase and the Wiley search platform in the Cochrane database for RCTS and observational studies with matching of conventional mechanical ventilation with and without veno-venous ECMO in adults with ARDS.  Titles, abstracts, and full-text articles were screened in duplicate by 2 investigators.  Data for study design, patient characteristics, interventions, and study outcomes were abstracted independently and in duplicate.  Studies were weighted with the inverse variance method and data were pooled via random-effects modelling.  These investigators calculated RRs and 95 % CI: to summarize results.  The primary outcome was 60-day mortality across RCTs.  The Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines were used to rate the quality of evidence.  These investigators included 5 studies – 2 RCTs and 3 observational studies with matching techniques (total n = 773 patients).  In the primary analysis, which included 2 RCTs with a total population of 429 patients, 60-day mortality was significantly lower in the veno-venous ECMO group than in the control group (73 [34 %] of 214 versus 101 [47 %] of 215; RR 0.73 [95 % CI: 0·58 to 0·92]; p =0·008; I2 0%).  The GRADE level of evidence for this outcome was moderate; 3 studies included data for the incidence of major hemorrhage in the ECMO group; 48 (19 %) of the 251 patients in these 3 studies had major hemorrhages.  The authors concluded that compared with conventional mechanical ventilation, use of veno-venous ECMO in adults with severe ARDS was associated with reduced 60-day mortality.  However, veno-venous ECMO was also associated with a moderate risk of major bleeding.  These findings have important implications surrounding decision-making for management of severe ARDS at centers providing veno-venous ECMO.

Extra-Corporeal Membrane Oxygenation during Lung Transplantation

Magouliotis and colleagues (2018) reviewed the available literature on patients undergoing lung transplantation supported by cardio-pulmonary bypass (CPB) or ECMO.  These investigators performed a systematic literature search in 3 databases, in accordance with the PRISMA guidelines.  Meta-analyses were used to compare the outcomes of ECMO and CPB procedures.  A total of 7 observational studies met the inclusion criteria incorporating 785 patients.  ECMO support showed lower rate of primary graft dysfunction, bleeding, renal failure requiring dialysis, tracheostomy, intra-operative transfusions, intubation time, and hospital stay.  Total support time was greater for the ECMO-supported group.  No difference was reported between operative and ischemic time.  The authors concluded that the present study indicated that the intra-operative use of ECMO is associated with increased efficacy and safety, regarding short-term outcomes, compared to CPB.  Moreover, they stated that well-designed, randomized studies, comparing ECMO to CPB, are needed to evaluate their clinical outcomes further.

Veno-Arterial ECMO after Coronary Artery Bypass Grafting

Aso and colleagues (2016) stated that the mortality rate of severely ill patients treated with veno-arterial ECMO (VA-ECMO) remains unknown because of differences in patient background, clinical settings, and sample sizes between studies.  These investigators determined the in-hospital mortality of VA-ECMO patients and the proportion weaned from VA-ECMO using a national inpatient database in Japan.  Patients aged 19 years and older who received VA-ECMO during hospitalization for cardiogenic shock, pulmonary embolism, hypothermia, poisoning, or trauma between July 1, 2010 and March 31, 2013 were identified, using The Japanese Diagnosis Procedure Combination national inpatient database.  The primary outcome was in-hospital mortality and the secondary outcome was the proportion weaned from VA-ECMO.  A total of 5,263 patients received VA-ECMO during the study period.  The majority of patients had cardiogenic shock (n = 4,658).  The number of patients weaned from VA-ECMO was 3,389 (64.4 %) and in-hospital mortality after weaning from VA-ECMO was 1,994 (37.9 %).  In-hospital mortality without cardiac arrest in the cardiogenic shock group was significantly lower than that in patients with cardiac arrest (70.5 % versus 77.1 %, p < 0.001).  In the multi-variable logistic regression including multiple imputation, higher age and greater or smaller body mass index (BMI) were significantly associated with in-hospital mortality, whereas hospital volume was not associated with such mortality.  The authors concluded that the present nationwide study showed high mortality rates in patients who received VA-ECMO, and in particular in patients with cardiogenic shock and in patients with cardiac arrest.  Moreover, they noted that weaning from VA-ECMO did not necessarily result in survival.  They stated that further studies are needed to investigate the effects of VA-ECMO and clarify risk-adjusted mortality of VA-ECMO using more detailed data on patient background.

Biancari and associates (2017) stated that the evidence of the benefits of using VA-ECMO after coronary artery bypass grafting (CABG) is scarce.  These investigators analyzed the outcomes of patients who received VA-ECMO therapy due to cardiac or respiratory failure after isolated CABG in 12 centers between 2005 and 2016.  Patients treated pre-operatively with ECMO were excluded from this study; VA-ECMO was employed in 148 patients following CABG for median of 5.0 days (mean of 6.4, SD = 5.6 days).  In-hospital mortality was 64.2 %.  Pooled in-hospital mortality was 65.9 % without significant heterogeneity between the centers (I2 8.6 %).  The proportion of VA-ECMO in each center did not affect in-hospital mortality (p = 0.861).  No patients underwent heart transplantation and 6 patients received a LVAD.  Logistic regression showed that creatinine clearance (p = 0.004, OR 0.98, 95 % CI: 0.97 to 0.99), pulmonary disease (p = 0.018, OR 4.42, 95 % CI: 1.29 to 15.15) and pre-VA-ECMO blood lactate (p = 0.015, OR 1.10, 95 % CI: 1.02 to 1.18) were independent baseline predictors of in-hospital mortality; 1-, 2-, and 3-year survival was 31.0 %, 27.9 %, and 26.1 %, respectively.  The authors concluded that 1/3 of patients with need for VA-ECMO after CABG survived to discharge.  Moreover, they stated that in view of the burden of resources associated with VA-ECMO treatment and the limited number of patients surviving to discharge, further studies are needed to identify patients who may benefit the most from this treatment.

Veno-Arterial ECMO in Drug Overdose

Vignesh and co-workers (2018) noted that over-dose of cardiovascular medications such as beta blockers and calcium channel blockers cause impaired cardiac contractility, vasoplegia, and/or rhythm disturbances.  In addition to conventional management of limiting absorption, increasing elimination and hemodynamic support intravenous (IV) calcium infusion, hyperinsulinemia-euglycemia therapy, glucagon infusion, and IV lipid emulsion have been tried.  Extracorporeal circulatory assist device support has been reported as a rescue therapy in over-dose refractory to maximal medical therapy.  These investigators reported the findings of 3 patients with cardiovascular medication over-dose presenting with profound cardiovascular instability refractory to medical therapy.  Veno-arterial ECMO support (VA ECMO) was initiated to provide hemodynamic support.  Despite the occurrence of device-associated complications, the outcome was good and all patients survived.  The authors concluded that based on the limited evidence, there may be a role for the use of VA ECMO in patients with severe cardio-active drug over-dose refractory to the medical therapy.  These preliminary findings need to be validated by well-designed studies.

Intra-Aortic Balloon Pump Combined with Veno-Arterial ECMO for Cardiac Arrest or Cardiogenic Shock

Vallabhajosyula and associates (2018) stated that there are contrasting reports on the effectiveness of a concomitant IABP in cardiogenic shock (CS) patients treated with VA-ECMO.  These researchers compared short-term mortality in patients with CS treated with VA-ECMO with and without IABP.  These investigators reviewed the published literature from 2000 to 2018 for studies evaluating adult patients requiring VA-ECMO for CS with concomitant IABP.  Studies reporting short-term mortality were included.  Meta-analysis of the association of IABP with mortality was performed using Mantel-Haenszel models.  Subgroup analyses were performed in patients with CS complicating acute myocardial infarction (AMI) and post-cardiotomy CS.  A total of 22 observational studies with 4,653 patients were included.  These studies showed high heterogeneity for the total and post-cardiotomy CS cohorts and low heterogeneity for the AMI cohort.  Short-term mortality was not significantly different in patients with and without IABP 42.1 % versus 57.8 %; RR, 0.80; 95 % CI: 0.52 to 1.22; p = 0.30.  However, concomitant IABP with VA-ECMO was associated with lower mortality in patients with AMI (50.8 % versus 62.4 %; RR, 0.56; 95 % CI: 0.46 to 0.67; p < 0.001).  There was no difference in mortality in post-cardiotomy CS and mixed causes for CS.  The authors concluded that in CS patients requiring VA-ECMO support, the use of IABP did not influence mortality in the total cohort.  In patients with AMI, use of IABP with VA-ECMO was associated with 18.5 % lower mortality in comparison to patients on VA-ECMO alone.  Moreover, these researchers stated that further randomized studies are needed to corroborate these observational data.

Li and colleagues (2019) noted that IABP concomitant with VA-ECMO is frequently used to support patients with refractory CS.  Because of the lack of evidence of the adjunctive benefit, the goal of the study was to compare the effect of VA-ECMO plus IABP with that of VA-ECMO alone.  Systematic searches were conducted to identify studies using PubMed, Embase, the Cochrane Library and the International Clinical Trials Registry Platform.  Studies reporting on patients with adult CS treated with VA-ECMO plus IABP or VA-ECMO alone were identified and included.  The primary outcome was in-hospital death.  The secondary outcomes included neurological, gastro-intestinal (GI) and limb-related complications.  A total of 29 studies comprising 4,576 patients were included.  The pooled in-hospital deaths of patients on VA-ECMO were 1,441/2,285 (63.1 %) compared with 1,339/2,291 (58.4 %) for patients with adjunctive IABP.  VA-ECMO plus IABP was associated with decreased in-hospital deaths [RR 0.90; 95 % CI: 0.85 to 0.95; p < 0.0001].  Moreover, IABP was related to decreased in-hospital deaths of patients with extracorporeal cardiopulmonary resuscitation, post-cardiotomy CS and ischemic heart disease (RR 0.78; 95 % CI: 0.64 to 0.95; p = 0.01; RR 0.91; 95 % CI: 0.85 to 0.98; p = 0.008; RR 0.83; 95 % CI: 0.73 to 0.96, p = 0.009).  The authors concluded that neurological, GI and limb-related complications did not differ significantly between patients on ECMO with and without concurrent IABP; VA-ECMO plus IABP was associated with decreased in-hospital deaths in patients with CS.

Wang and Xing (2019) stated that the effectiveness of intra-aortic balloon pump (IABP) combined with VA-ECMO in patients with cardiac arrest or cardiogenic shock remains controversial.  In a systematic review and meta-analysis, these investigators examined the short-term clinical outcomes of IABP combined with VA-ECMO versus VA-ECMO alone.  They searched PubMed, Embase, and the Cochrane Library for English language articles published from inception to August 18, 2018.  Observational studies comparing IABP combined with VA-ECMO with VA-ECMO alone were considered eligible for the current study.  A total of 12 observational studies with 3,704 patients were included.  In the IABP combined with VA-ECMO group mortality was 59.7 %, compared with 65.8 % in the VA-ECMO alone group.  The RR for this comparison was 0.90 (95 % CI: 0.80 to 1.02; p = 0.107; 59.7 % versus 65.8 %).  In the 1-way sensitivity analysis for estimating the effect of each study on mortality, omission of each study did not make a significant difference. Furthermore, the proportion of patients weaned from VA-ECMO was significantly higher in IABP combined VA-ECMO group than in the VA-ECMO alone group (RR, 1.28; 95 % CI: 1.21 to 1.35; p < 0.001; 77.9 % versus 61.2 %).  The authors concluded that IABP combined with VA-ECMO could improve success rate of weaning from VA-ECMO, but did not reduce in-hospital mortality in patients with cardiac arrest or cardiogenic shock.

Veno-Venous ECMO for the Treatment of Obesity Hypoventilation Syndrome

Umei and Ichiba (2017) stated that the mortality rate for respiratory failure resulting from obesity hypoventilation syndrome is high if it requires ventilator management.  These researchers described a case of severe acute respiratory failure resulting from obesity hypoventilation syndrome (BMI, 60.2 kg/m2) successfully treated with veno-venous ECMO (VV-ECMO).  During ECMO management, a mucus plug was removed by bronchoscopy daily and 18 L of water was removed using diuretics, resulting in weight loss of 24 kg.  The patient was weaned from ECMO on day 5, extubated on day 16, and discharged on day 21.  The authors concluded that the fundamental treatment for obesity hypoventilation syndrome in morbidly obese patients is weight loss; VV-ECMO can be used for respiratory support until weight loss has been achieved.  The authors noted that the main drawback of this case report was that a pulmonary arterial catheter could not be used because of the high risk induced by extreme obesity; therefore, the pulmonary arterial pressure and cardiac output could not be measured directly.  However, based on its physiological effects, they believed that VV-ECMO effectively reduced the intra-thoracic pressure and pulmonary vascular resistance, which stabilized the patient's hemodynamic status and permitted the removal of large volumes of water from the body.  These researchers stated that it is possible to use VV-ECMO for life-threatening respiratory failure if percutaneous cannulation is possible.   These preliminary findings need to be validated by well-designed studies.

An review on “Clinical use of venovenous extracorporeal membrane oxygenation” (Ng et al, 2017) does not mention obesity hypoventilation syndrome as an indication of VV-ECMO.

Furthermore, an UpToDate review on “Treatment of the obesity hypoventilation syndrome” (Martin, 2017) does not mention VV-ECMO as a therapeutic option.

Extracorporeal Membrane Oxygenation for Sepsis

Sangli and colleagues (2020) retrospectively reviewed all pertinent ECMO studies (January 1995 to September 2017) of adults with sepsis as a primary indication for intervention and its association with morbidity and mortality.  Collected data included study type, ECMO configuration, outcomes, effect size, and other features.  Advanced age was a risk factor for death.  Compared with non-survivors, survivors had a lower median Sepsis-Related Organ Failure Assessment score on day 3 (15 versus 18, p = 0.01).  Biomarkers in survivors and non-survivors, respectively, were peak lactate (from 2 studies: 4.5 versus 15.1 mmol/L, p = 0.03; 3.6 ± 3.7 versus 3.3 ± 2.4 mmol/L, p = 0.850) and procalcitonin levels (41 versus 164 ng/ml, p = 0.008).  Bacteremia was associated with catheter colonization, and 90.5 % of a group without blood-stream infections (BSIs) survived to discharge; ECMO weaning was possible for less than 50 % the BSI group.  Myocarditis portended favorable outcomes for patients with sepsis who received ECMO.  ECMO was used in immunosuppressed patients with refractory cardio-pulmonary insufficiency from severe sepsis with successful weaning from ECMO for most patients.  Overall survival (OS) varied substantially among studies (15.38 to 71.43 %).  The authors concluded that existing studies do not present well-defined patterns supporting use of ECMO in sepsis because of sample sizes and disparate study designs.

Furthermore, an UpToDate review on “Evaluation and management of suspected sepsis and septic shock in adults” (Schmidt and Mandel, 2020) does not mention ECMO as a management option.

Veno-Arterial Extracorporeal Membrane Oxygenation for Ventricular Tachycardia Ablation

In a systematic review, Burrell and associates (2019) systematically investigated the reporting of selection criteria and outcome measures, and examined definitions of complications used in veno-arterial extracorporeal membrane oxygenation studies (VA-ECMO).  Medline, Embase and the Cochrane central register were searched for VA-ECMO studies from January 2005 to July 2017.  Studies with less than or equal to 99 patients or without patient centered outcomes were excluded.  Two reviewers independently assessed search results and undertook data extraction.  A total of 46 studies met the inclusion criteria, and all were retrospective, observational studies.  Inconsistent reporting of selection criteria, ECMO management and outcome measures was common.  In-hospital mortality was the most common primary outcome (41 % of studies), followed by 30-day mortality (11 %).  Bleeding was the most frequent complication reported, most commonly defined as "bleeding requiring transfusion" (median of greater than or equal to 2 units/day).  Significant variation in reporting and definitions was also evident for vascular, neurological renal and infectious complications.  The authors concluded that the findings of this systematic review provided clinicians with the most commonly reported selection criteria, outcome measures and complications used in ECMO practice.  However non-standardized definitions and inconsistent reporting limited their ability to inform practice.  New consensus-driven definitions of complications and patient centered outcomes are urgently needed.

Vallabhajosyula and colleagues (2020) stated that refractory ventricular tachycardia (VT) and electrical storm are frequently associated with hemodynamic compromise requiring mechanical support.  These investigators reviewed the current literature on the use of VA-ECMO for hemodynamic support during VT ablation.  This was a systematic review of all published literature from 2000 to 2019 evaluating patients with VT undergoing ablation with VA-ECMO support.  Studies that reported mortality, safety, and efficacy outcomes in adult (greater than 18 years) patients were included.  The primary outcome was short-term mortality (ICU stay, hospital stay, of less than or equal to 30 days).  The literature search identified 4,802 citations during the study period, of which 7 studies comprising 867 patients met the inclusion criteria.  Peri-procedural VA-ECMO was used in 129 (15 %) patients and all were placed peripherally.  Average inducible VTs were 2 to 3 per procedure and ablation time varied between 34 mins and 4.7 hours.  Median ages were between 61 and 68 years with 93 % men.  Median duration of VA-ECMO varied between 140 mins and 6 days.  Short-term mortality was 15 % (19 patients), with the most frequent causes being refractory VT, cardiac arrest, and acute heart failure.  All-cause mortality at the longest follow-up was 25 %.  Major bleeding, vascular/access complications, limb ischemia, stroke, and acute kidney injury (AKI)  were reported with varying frequency of 1 to 6 %.  The authors concluded that VA-ECMO is used infrequently for hemodynamic support for VT ablation. further data on patient selection, procedural optimization, and clinical outcomes are needed to determine the efficacy of this strategy.

A Journal of the American College of Cardiology Scientific Expert Panel on venoarterial ECMO (VA-ECMO) for adults (Guglin, et al., 2019) concluded that VA-ECMO is successfully used to hemodynamically stabilize patients in refractory ventricular tachycardia or fibrillation, regardless of etiology. Creating a continuous blood flow, ECMO maintains adequate hemodynamics in the setting of ventricular tachycardia, ventricular fibrillation, or electrical storm while antiarrhythmic therapies are administrated or radiofrequency ablation is performed, helping patients to survive, either to stability or to heart transplantation or LVAD implantation.

Argatroban Anti-Coagulation for Adults Undergoing Extracorporeal Membrane Oxygenation

Fisser and associates (2021) stated that during veno-venous ECMO (vvECMO), direct thrombin inhibitors are considered by some potentially advantageous over unfractionated heparin (UFH).  These researchers tested the hypothesis that argatroban is non-inferior to UFH regarding thrombosis and bleeding during vvECMO.  They carried out an observational, non-inferiority, propensity-score matched study of consecutive patients without heparin-induced-thrombocytopenia (HIT) on vvECMO, treated between January 2006 and March 2019 in the ICU at the University Hospital Regensburg.  Anti-coagulation was realized with UFH until August 2017 and with argatroban from September 2017 onwards.  Target activated partial thromboplastin time (aPTT) was 50 ± 5 seconds in both groups.  Primary composite endpoint was major thrombosis and/or major bleeding.  Major bleeding was defined as a drop in hemoglobin of greater than or equal to 2 g/dL/day or in transfusion of greater than or equal to 2 packed red cells/24 hours, or retroperitoneal, cerebral, or pulmonary bleeding.  Major thrombosis was defined as obstruction of greater than 50 % of the vessel lumen diameter by means of duplex sonography.  In addition, these investigators evaluated technical complications such as oxygenator defects or pump head thrombosis, the time-course of platelets, and the cost of anti-coagulation (including HIT-testing).  Out of 465 patients receiving UFH, 78 were matched to 39 patients receiving argatroban.  The primary endpoint occurred in 79 % of patients in the argatroban group and in 83 % in the UFH group (non-inferiority for argatroban, p = 0.026).  The occurrence of technical complications was equally distributed (argatroban 49 % versus UFH 42 %, p = 0.511).  The number of platelets was similar in both groups before ECMO therapy but lower in the UFH group after end of ECMO support (median inter-quartile range [IQR]: 141 [104 to 198]/nl versus 107 [54 to 171]/nl, p = 0.010).  Anti-coagulation costs per day of ECMO were higher in the argatroban group (€26 [13.8 to 53.0] versus €0.9 [0.5 to 1.5], p < 0.001) but not after accounting for blood products and HIT-testing (€63 [42 to 171) versus €40 [17 to 158], p = 0.074).  The authors concluded that in patients without HIT on vvECMO, argatroban was non-inferior to UFH regarding bleeding and thrombosis.  The occurrence of technical complications was similarly distributed.  Argatroban may have less impact on platelet decrease during ECMO, but this finding needs further evaluation.  Direct drug costs were higher for argatroban but comparable to UFH after accounting for HIT-testing and transfusions.

Geli and colleagues (2022) noted that heparin is the widely used anti-coagulation strategy for patients on ECMO; however, HIT and acquired anti-thrombin (AT) deficiency preclude the use of heparin requiring utilization of an alternative anti-coagulant agent.  Direct thrombin inhibitors are being proposed as potential alternatives with argatroban as one of the main agents.  These researchers examined the evidence with regard to safety and efficacy of argatroban as a potential alternative to heparin in the adult patient population undergoing ECMO support.  They carried out a web-based systematic literature search in Medline (PubMed) and Embase from inception until June 18, 2020.  The search identified 13 publications relevant to the target (4 cohort studies and 9 case series).  Case reports and case series with less than 3 cases were not included in the qualitative synthesis.  The aggregate number of argatroban treated patients on ECMO was n = 307.  In the majority of studies, argatroban was used as a continuous infusion without loading dose.  Starting doses on ECMO varied between 0.05 and 2 μg/kg/min and were titrated to achieve the chosen therapeutic target range.  The aPTT was the anti-coagulation parameter used for monitoring purposes in most studies, whereas some employed the activated clotting time (ACT).  Optimal therapeutic targets varied between 43 to 70 and 60 to 100 seconds for aPTT and between 150 to 210 and 180 to 230 seconds for ACT.  Bleeding and thrombo-embolic complication rates were comparable to patients treated with UFH.  The authors concluded that argatroban infusion rates and anti-coagulation target ranges showed substantial variations.  These researchers stated that argatroban appeared to be a potential alternative to UFH in patients requiring ECMO.  Moreover, they stated that to definitively establish its safety, efficacy and ideal dosing strategy, larger prospective studies on well-defined patient populations are needed.

ECMO in Pediatric Abdominal Organ Transplant Patients

Reid and colleagues (2021) noted that advances in ECMO have made it a useful adjunct in critically ill pediatric patients; however, a dearth of evidence exists regarding risks and benefits in pediatric abdominal organs transplantation.  These researchers carried out a qualitative systematic review of outcomes in pediatric patients undergoing ECMO support pre- or post-abdominal organ transplantation.  This review was performed from January 1, 1989, to April 24, 2020, via PubMed, Embase, Scopus, Web of Science, the Cochrane Library, and ClinicalTrials.gov of all pediatric solid abdominal organ transplant recipients (pre- and post-transplant) and donors who underwent veno-arterial ECMO (vaECMO) or vvECMO cannulation.  Death was the primary outcome, with graft function and complications as secondary outcomes.  A total of 14 articles were identified that fit criteria, with 88 % being case reports; 3 patients were donors placed on ECMO, with no mortality among the 8 recipients of organs from these donors; 19 recipients were placed on ECMO.  All were liver transplants.  Most patients experienced at least 1 complication (84 %), with bleeding as the most common cause (44 %).  Mortality was 26 %.  Causes of death included multi-organ system failure (n = 3), heart failure (n = 1), systemic inflammatory response syndrome (n = 1), abdominal compartment syndrome (n = 3), bleeding (n = 1), septic shock from aspergillus (n = 1), and hepatic artery thrombosis (n = 2).  The authors concluded that the data are poor on ECMO usage in pediatric abdominal transplantation.  These investigators stated that while complications were high, mortality did not appear to be related to ECMO usage and was relatively low given the severity of patient illness.

ECMO for the Treatment of Coronavirus Disease 2019 (COVID-19)

In a systematic review, Haiduc and associates (2020) examined the available evidence regarding the use of ECMO in patients with coronavirus disease 2019 (COVID-19).  These researchers carried out a systematic review using PRISMA guidelines.  A comprehensive literature search was conducted on Global Health Medline, Embase, and Cochrane databases using keywords and MeSH terms to identify articles pertaining to ECMO and COVID-19.  A narrative synthesis was then undertaken to identify the key themes.  A total of 25 articles met the inclusion criteria of this systematic review; 3 main themes were identified following the data extraction: First -- evidence against/inconclusive regarding ECMO for COVID-19; second -- evidence supporting ECMO for COVID-19, and third -- vvECMO and vaECMO.  After combining the data, there were 3,428 patients diagnosed with COVID-19 and 95 ECMO-associated deaths (19.83 %).  The authors concluded that the findings of this study highlighted the paucity of evidence and the need for further data to consolidate the efficacy of ECMO in improving patient outcomes.  These researchers stated that although ECMO has been shown to be beneficial in a selected group of patients, the recuperative effects of ECMO remain inconclusive.

Hu and co-workers (2020) noted that COVID-19 can cause severe ARDS; ECMO can support gas exchange in patients failing conventional mechanical ventilation, however, its role is still controversial.  These investigators carried out a systematic review focusing on the use of ECMO in patients with COVID-19.  PubMed/Medline, Google Scholar, Embase, the Cochrane Library, EBSCO and Ovid (updated April 30, 2020) were systematically searched.  Case reports/case series from COVID-19 patients treated with ECMO were included in the study.  A total of 3 reviewers examined, selected, and abstracted data from studies.  All disparate opinions were resolved through discussion.  They included 13 articles for systematic evaluation, including 10 case reports and 3 case series studies, with a total of 72 patients.  They searched for the following information: First author of articles; patient's location; age; gender; BMI; co-morbidities; time on ECMO; mode of ECMO; treatments and clinical outcomes.  As of all reporting times, the data showed that 38 patients (52.8 %) have died, 13 patients (18.0 %) were still receiving ECMO treatment, 12 patients (16.7 %) were alive, 7 patients (9.7 %) were in recovery and 2 patients (2.8 %) remained hospitalized.  The authors concluded that ECMO played an important role in the stabilization and survival critically ill patients with COVID-19; however, the effectiveness of ECMO in reducing the mortality of severe ARDS caused by COVID-19 was limited.  These researchers stated that a larger sample size study and a comprehensive analysis examining the value of ECMO on COVID-19 patients are urgently needed.

Ma et al (2020) stated that the highly contagious COVID-19 has now infected many Chinese and has rapidly become a global pandemic, with health care systems overwhelmed with severe and critically ill patients in less well-resourced countries.  ECMO is a sophisticated life support system supporting respiratory and circulatory failure and has been used in the management of severe infection with MERS and H1N1 influenza, with some evidence showing an additional survival benefit with use of ECMO.  However, these researchers stated that much remains mysterious regarding the virus 2019-ConV, and solid clinical evidence is lacking on the role of ECMO in rescuing critical illness.  Despite the use of ECMO in China and recommendations on ECMO by WHO and Chinese experts in COVID-19, several fundamental questions remain unanswered, including benefit, timing, indications, management, and risks of ECMO, as well as global sharing of evidence from trials.

de Oliveira and colleagues (2021) examined the literature on the use of ECMO in patients with COVID-19.  The research was conducted according to the recommendations of PRISMA.  Studies were selected from PubMed/Medline and LILACS databases between December 2019 and May 17 2020, using the descriptors "ECMO AND COVID-19", "Extracorporeal Membrane Oxygenation AND COVID-19", "ECLS AND COVID-19", and "Extracorporeal Life Support AND COVID-19".  Exclusion criteria were government epidemiological bulletins, comments, literature reviews, and articles without full access to content.  A total of 233 scientific productions were identified; however, only 18 did not meet the exclusion criteria and could be included in this study, resulting in a total of 911 patients -- 624 (68.5 %) men, 261 (28.6 %) women, and 26 (2.8 %) without sex information.  The mean age of the patients was 53.7 years.  ECMO was necessary in 274 (30.1 %) individuals (200 [73 %] submitted to vvECMO, 9 [3.3 %] to vaECMO, and 7 [2.5 %] moved between these 2 types or needed a more specific ECMO according to the disease prognosis).  Five studies did not specify the type of ECMO used, resulting in 57 (20.8 %) patients; 5 patients (1.8 %) were discharged, 77 (28.1 %) died, 125 (45.6 %) remained hospitalized until publication time of their respective studies, and 67 patients (24.4 %) had no outcome information.  The authors concluded that more research, covering larger populations, must be performed to examine the role of ECMO in the treatment of COVID-19.

Putowski and co-workers (2021) noted that the recent development in extra-corporeal life support (ECLS) has created new therapeutic opportunities for critically ill patients.  An interest in ECMO, the pinnacle of ECLS techniques, has recently increased in the past 10 years.  These investigators have observed improvements in the survival of patients suffering from severe ARDS while on ECMO.  The authors concluded that although there is a paucity of conclusive data from clinical research regarding the use of ECMO in COVID-19 patients, the pathophysiology of the disease makes vvECMO a promising option. These researchers stated that there are ongoing studies, which may answer the question whether the reduction of cytokine levels during ECMO therapy would improve survival in patients with COVID-19.

Veno-Arterial ECMO in Pulmonary Embolism-Related Cardiac Arrest

Scott and colleagues (2021) stated that management of patients experiencing massive PE-related cardiac arrest is controversial.  Veno-arterial ECMO (VA-ECMO) has emerged as a potential therapeutic option for these patients.  These researchers carried out a systematic review examining survival and predictors of mortality in patients with massive PE-related cardiac arrest with veno-arterial ECMO use. A literature search was started on February 16, 2020, and completed on March 16, 2020, using PubMed, Embase, Cochrane Central, Cinahl, and Web of Science.  These investigators included all available literature that reported survival to discharge in patients managed with veno-arterial ECMO for massive PE-related cardiac arrest.  They extracted patient characteristics, treatment details, and outcomes.  A total of 300 patients were included in this systemic review from 77 selected articles (total screened, n = 1,115); 183 out of 301 patients (61 %) survived to discharge.  Patients (n = 51) who received systemic thrombolysis prior to cannulation had similar survival compared with patients who did not (67 % versus 61 %, respectively; p = 0.48).  There was no significant difference in risk of death if PE was the primary reason for admission or not (OR, 1.62; p = 0.35) and if ECMO cannulation occurred in the emergency department versus other hospital locations (OR, 2.52; p = 0.16); 53 of 60 patients (88 %) were neurologically intact at discharge or follow-up.  Multi-variate analysis demonstrated a 3-fold increase in the risk of death for patients greater than 65 years old (adjusted OR, 3.08; p = 0.03) and a 6-fold increase if cannulation occurred during cardiopulmonary resuscitation (adjusted OR, 5.67; p = 0.03).  The authors concluded that the use of VA-ECMO in management of massive PE-related cardiac arrest has a survival rate of 61 %.  Systemic thrombolysis prior to VA-ECMO did not confer increased odds of death and this review suggested that both modalities can be complimentary to each other with a focus on achieving return of spontaneous circulation.  In this study, age greater than 65 and ECMO cannulation during CPR had increased mortality (3- and 6-fold risks of death, respectively) and may aid in the decision-making process of deploying VA-ECMO for massive PE-related cardiac arrest.

The authors stated that this review had several drawbacks -- reporting bias being the most notable.  This study can only report a survival to discharge without significant comment on short- or long-term survival.  Literature in abstract form was used but often did not often provide additional detail beyond the primary outcome.  Furthermore, there was heterogeneous reporting of important clinical variables (neurologic status at discharge, presence or absence of significant bleed, cannulation during or after CPR, and duration of CPR) among the majority of literature found that made it difficult to comment confidently on all of these variables’ impact on survival.  These researchers  also did not have sufficient detail to comment on co-morbid conditions and other important secondary outcomes: long-term need for dialysis, chronic ventilator dependency, discharge to nursing facilities versus home, need for percutaneous endoscopic gastrostomy and artificial feeding, re-admissions, and long-term PE-related complications like chronic thromboembolic pulmonary hypertension.

ECMO in Liver Transplantation

Hogen et al (2021) reviewed the indications for ECMO in liver transplantation (LT) recipients and their optimal management on ECMO.  Recent studies have reported a 30 % to 40 % survival rate among LT recipients who received ECMO.  Increasingly, case reports have documented successful outcomes of LT performed for patients on pre-operative ECMO.  Outcomes appeared to be superior with patients in the immediate peri-LT period with reversible causes of severe, acute respiratory, and/or cardiovascular collapse.  Mortality is most commonly secondary to infection.  Volume optimization with continuous renal replacement therapy (CRRT) may improve outcomes and perfusion to the graft, especially for patients on VA-ECMO.  There is little consensus on management of anti-coagulation in these patients; however, it can likely be held temporarily when the patient is coagulopathic and/or experiencing bleeding complications.  The authors concluded that ECMO should be considered in the peri-LT period for patients with severe, acute, and reversible causes of respiratory and/or cardiovascular collapse, with acceptable outcomes in patients who would otherwise not be expected to survive.  Management of the post-LT patient on ECMO is challenging with a slowly enlarging body of literature to inform decision-making.

Ziogas et al (2021) stated that ECMO can be used to maintain oxygen delivery and provide hemodynamic support in case of circulatory and respiratory failure.  Although the role of ECMO has emerged in the setting of adult LT, data in children are limited.  These investigators described the characteristics and outcomes of children receiving ECMO support at the time of or following LT.  All pediatric LT recipients (less than or equal to 20 years of age) requiring ECMO support peri-/post-LT were identified from a linked Pediatric Health Information System/Scientific Registry of Transplant Recipients dataset (2002 to 2018).  The Kaplan-Meier method and Cox regression analysis were used to examine post-ECMO survival.  They carried out a systematic literature review in accordance with the PRISMA statement.  A total of 34 children required ECMO peri-/post-LT.  The median time from LT to ECMO was 5 days (IQR of 0.0 to 12.3), and the median ECMO duration was 1 day (IQR of 1.0 to 6.3).  Children started on ECMO within 1 day of LT exhibited superior survival compared with those started on ECMO later (p = 0.03).  When adjusting for recipient weight, increasing time from LT to ECMO initiation was associated with increased risk of mortality (hazard ratio [HR], 1.03; 95 % CI: 1.00 to 1.06; p = 0.049).  Overall, 55.9 % (n = 19 of 34) of the patients survived; 22 children receiving ECMO in the peri-/post-LT period were systematically reviewed, and 15 of them survived (68.2 %).  The authors concluded that with an encouraging of greater than 55 % patient survival at 6 months, ECMO should be considered as a viable option in pediatric LT recipients with potentially reversible severe respiratory or cardiovascular failure refractory to conventional treatment.

Park et al (2021) noted that peri-operative respiratory failure occurs frequently in LT recipients; and VV-ECMO has been employed in patients with acute and potentially reversible life-threatening respiratory failure that is unresponsive to conventional therapies.  VV-ECMO is used as a bridging device for lung transplantation; however, there are few reports on VV-ECMO as bridging therapy in LT patients with respiratory failure.  These researchers examined patient outcomes of VV-ECMO following LT and evaluated its applicability and safety in LT surgery.  From January 2017 to May 2019, VV-ECMO was used in 8 deceased donor LT patients at Pusan National University Yangsan Hospital.  Patients administered pre- or post-operative VV-ECMO showed a 50 % 1-year survival rate and 75 % success rate for ECMO weaning; 6 patients were administered pre-operative VV-ECMO for respiratory failure, of whom 4 patients survived for longer than 1 year; 2 patients who received VV-ECMO for refractory hypoxia during LT died; 1 failed ECMO weaning, and the other was successfully weaned off ECMO but died of other causes.  The authors concluded that VV-ECMO could lower the risk of hypoxemia-related organ failure while awaiting and during LT via better controlled gas exchange without significant acute morbidity.  These researchers stated that VV-ECMO may expand operability in patients with severe respiratory failure awaiting LT.

Reid et al (2022) noted that there is a paucity of evidence regarding risks and benefits of ECMO in adult LT.  This was a systematic review conducted from January 1, 2000 to April 24, 2020 of adult LT recipients (pre- or post-transplant) and donors who underwent VA-ECMO or VV-ECMO cannulation.  Death was the primary outcome, with graft function and complications as secondary outcomes.  A total of 41 articles were identified that fit criteria.  A total of 183 donors were placed on ECMO, with recipient complication profiles and mortality that mirrored rates from standard criteria donors; 61 recipients were placed on ECMO intra-operatively or post-operatively.  Most patients experienced at least 1 complication with infections as the most common cause and minimal complications specifically related to ECMO use.  Multi-system organ failure (MSOF) and infections were more common among LT recipients who died compared to those who survived.  Overall mortality at 90 days was 45.9 %.  Causes of death were most commonly MSOF and infections.  The authors concluded that ECMO use in adult LT is a useful adjunct.  Recipient morbidity and mortality from donors placed on ECMO paralleled that of recipients from standard criteria donors, and morbidity and mortality of recipients placed on ECMO were similar to other ECMO populations.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
33946	Extracorporeal membrane oxygenation (ECMO)/extracorporeal life support (ECLS) provided by physician; initiation, veno-venous
33947	initiation, veno-arterial
33948	daily management, each day, veno-venous
33949	daily management, each day, veno-arterial
33951	insertion of peripheral (arterial and/or venous) cannula(e), percutaneous, birth through 5 years of age (includes fluoroscopic guidance, when performed)
33952	insertion of peripheral (arterial and/or venous) cannula(e), percutaneous, 6 years and older (includes fluoroscopic guidance, when performed)
33953	insertion of peripheral (arterial and/or venous) cannula(e), open, birth through 5 years of age
33954	insertion of peripheral (arterial and/or venous) cannula(e), open, 6 years and older
33955	insertion of central cannula(e) by sternotomy or thoracotomy, birth through 5 years of age
33956	insertion of central cannula(e) by sternotomy or thoracotomy, 6 years and older
33957	reposition peripheral (arterial and/or venous) cannula(e), percutaneous, birth through 5 years of age (includes fluoroscopic guidance, when performed)
33958	reposition peripheral (arterial and/or venous) cannula(e), percutaneous, 6 years and older (includes fluoroscopic guidance, when performed)
33959	reposition peripheral (arterial and/or venous) cannula(e), open, birth through 5 years of age (includes fluoroscopic guidance, when performed)
33962	reposition peripheral (arterial and/or venous) cannula(e), open, 6 years and older (includes fluoroscopic guidance, when performed)
33963	reposition of central cannula(e) by sternotomy or thoracotomy, birth through 5 years of age (includes fluoroscopic guidance, when performed)
33964	reposition central cannula(e) by sternotomy or thoracotomy, 6 years and older (includes fluoroscopic guidance, when performed)
33965	removal of peripheral (arterial and/or venous) cannula(e), percutaneous, birth through 5 years of age
33966	removal of peripheral (arterial and/or venous) cannula(e), percutaneous, 6 years and older
33969	removal of peripheral (arterial and/or venous) cannula(e), open, birth through 5 years of age
33984	removal of peripheral (arterial and/or venous) cannula(e), open, 6 years and older
33985	removal of central cannula(e) by sternotomy or thoracotomy, birth through 5 years of age
33986	removal of central cannula(e) by sternotomy or thoracotomy, 6 years and older
33987	Arterial exposure with creation of graft conduit (eg, chimney graft) to facilitate arterial perfusion for ECMO/ECLS (List separately in addition to code for primary procedure)
33988	Insertion of left heart vent by thoracic incision (eg, sternotomy, thoracotomy) for ECMO/ECLS
33989	Removal of left heart vent by thoracic incision (eg, sternotomy, thoracotomy) for ECMO/ECLS
Other CPT codes related to the CPB:
32851	Lung transplant, single; without cardiopulmonary bypass
32852	Lung transplant, single; with cardiopulmonary bypass
32853	Lung transplant, double (bilateral sequential or en bloc); without cardiopulmonary bypass
32854	Lung transplant, double (bilateral sequential or en bloc); with cardiopulmonary bypass
33120	Excision of intracardiac tumor, resection with cardiopulmonary bypass
33305	Repair of cardiac wound; with cardiopulmonary bypass
33315	Cardiotomy, exploratory (includes removal of foreign body, atrial or ventricular thrombus); with cardiopulmonary bypass
33322	Suture repair of aorta or great vessels; with cardiopulmonary bypass
33335	Insertion of graft, aorta or great vessels; with cardiopulmonary bypass
33403	Valvuloplasty, aortic valve; using transventricular dilation, with cardiopulmonary bypass
33405	Replacement, aortic valve, with cardiopulmonary bypass; with prosthetic valve other than homograft or stentless valve
33406	with allograft valve (freehand)
33410	with stentless tissue valve
33422	Valvotomy, mitral valve; open heart, with cardiopulmonary bypass
33425	Valvuloplasty, mitral valve, with cardiopulmonary bypass
33426	with prosthetic ring
33427	radical reconstruction, with or without ring
33430	Replacement, mitral valve, with cardiopulmonary bypass
33460	Valvectomy, tricuspid valve, with cardiopulmonary bypass
33465	Replacement, tricuspid valve, with cardiopulmonary bypass
33474	Valvotomy, pulmonary valve, open heart; with cardiopulmonary bypass
33496	Repair of non-structural prosthetic valve dysfunction with cardiopulmonary bypass (separate procedure)
33500	Repair of coronary arteriovenous or arteriocardiac chamber fistula; with cardiopulmonary bypass
33504	Repair of anomalous coronary artery from pulmonary artery origin; by graft, with cardiopulmonary bypass
33510 - 33536	Coronary artery bypass grafting
33641	Repair atrial septal defect, secundum, with cardiopulmonary bypass, with or without patch
33702	Repair sinus of Valsalva fistula, with cardiopulmonary bypass
33710	with repair of ventricular septal defect
33720	Repair sinus of Valsalva aneurysm, with cardiopulmonary bypass
33736	Atrial septectomy or septostomy; open heart with cardiopulmonary bypass
33814	Obliteration of aortopulmonary septal defect; with cardiopulmonary bypass
33853	Repair of hypoplastic or interrupted aortic arch using autogenous or prosthetic material; with cardiopulmonary bypass
33858	Ascending aorta graft, with cardiopulmonary bypass, includes valve suspension, when performed; for aortic dissection
33859	for aortic disease other than dissection (eg, aneurysm)
33860	Ascending aorta graft, with cardiopulmonary bypass, includes valve suspension, when performed
33864	Ascending aorta graft, with cardiopulmonary bypass with valve suspension, with coronary reconstruction and valve sparing aortic root remodeling (e.g., David Procedure, Yacoub Procedure)
33870	Transverse arch graft, with cardiopulmonary bypass
33871	Transverse aortic arch graft, with cardiopulmonary bypass, with profound hypothermia, total circulatory arrest and isolated cerebral perfusion with reimplantation of arch vessel(s) (eg, island pedicle or individual arch vessel reimplantation)
33875	Descending thoracic aorta graft, with or without bypass
33877	Repair of thoracoabdominal aortic aneurysm with graft, with or without cardiopulmonary bypass
33910	Pulmonary artery embolectomy; with cardiopulmonary bypass
33916	Pulmonary endarterectomy, with or without embolectomy, with cardiopulmonary bypass
33922	Transection of pulmonary artery with cardiopulmonary bypass
33926	Repair of pulmonary artery arborization anomalies by unifocalization; with cardiopulmonary bypass
47133 - 47147	Liver transplantation
Neonates:
ICD-10 codes covered if selection criteria are met:
P22.0	Respiratory distress syndrome of newborn
P24.01	Meconium aspiration with respiratory symptoms
P25.0 - P25.8	Interstitial emphysema and related conditions originating in the perinatal period [uncontrollable air leak]
P28.5	Respiratory failure of newborn
P29.30 - P29.38	Persistent fetal circulation
Q79.0	Congenital diaphragmatic hernia
R65.21	Severe sepsis with septic shock [neonatal and pediatric]
Children and adults:
ICD-10 codes covered if selection criteria are met:
A22.1	Pulmonary anthrax [non-necrotizing]
A36.81	Diphtheritic cardiomyopathy
A37.01 A37.11 A37.81 A37.91	Pneumonia in whooping cough [non-necrotizing]
A39.52	Meningococcal myocarditis
A48.1	Legionnaires' disease [non-necrotizing]
A52.06	Other syphilitic heart involvement
B25.0	Cytomegaloviral pneumonitis [non-necrotizing]
B33.22	Viral myocarditis
B44.0	Invasive pulmonary aspergillosis [non-necrotizing]
B58.81	Toxoplasma myocarditis
B77.81	Ascariasis pneumonia [non-necrotizing]
I01.2	Acute rheumatic myocarditis
I09.0	Rheumatic myocarditis
I40.0 - I40.9	Acute myocarditis
I41	Myocarditis in diseases classified elsewhere
I47.20, I47.21, I47.29	Ventricular tachycardia
I49.01	Ventricular fibrillation
I50.1 - I50.9	Heart failure
I51.4	Myocarditis, unspecified
J10.00 - J18.1 J18.8 - J18.9	Influenza and pneumonia [non-necrotizing]
J70.5	Respiratory conditions due to smoke inhalation
J80	Acute respiratory distress syndrome [adult respiratory distress syndrome]
J95.1 - J95.3 J95.821 - J95.822	Acute and chronic pulmonary insufficiency and postprocedural respiratory failure following thoracic and nonthoracic surgery [adult respiratory distress syndrome associated with trauma and surgery]
J96.00 - J96.02	Acute respiratory failure [reversible] [unresponsive to all other measures]
J96.20 - J96.22	Acute and chronic respiratory failure [reversible] [unresponsive to all other measures]
J96.90 - J96.92	Respiratory failure, unspecified [reversible] [unresponsive to all other measures]
J98.4	Other disorders of lung [adult respiratory distress syndrome]
R57.0	Cardiogenic shock
R65.21	Severe sepsis with septic shock [neonatal and pediatric]
S21.309+ [S27.329+ also required]	Lung contusion with open wound into thorax
S27.321+ - S27.329+	Contusion of lung
T86.20 - T86.298	Complications of heart transplant
Z94.4	Liver transplant status
Z76.82	Awaiting organ transplant status
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive list):
A40.0 - A40.9	Streptococcal sepsis
A41.01 - A41.9	Other sepsis
E66.2	Morbid (severe) obesity with alveolar hypoventilation
I24.0	Acute coronary thrombosis not resulting in myocardial infarction
I24.1	Dressler's syndrome
I24.8	Other forms of acute ischemic heart disease
I24.9	Acute ischemic heart disease, unspecified
I26.01 - I26.09	Pulmonary embolus, with acute cor pulmonale
I26.90 - I26.99	Pulmonary embolus, without acute cor pulmonale
I46.8	Cardiac arrest due to other underlying condition [pulmonary embolism]
I71.00 - I71.03	Dissection of aorta
J12.89	Pneumonia due to coronavirus disease 2019
R06.03	Acute respiratory distress
T20.00x+ - T32.99	Burns
T36.0x1A - T50.996S	Poisoning by, adverse effect of and underdosing of systemic antibiotics
T86.810 - T86.819	Complications of lung transplant
U07.1	COVID-19

The above policy is based on the following references: