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, lung or heart-lung transplantation; or
3. Following heart surgery to ease transition from cardiopulmonary bypass to ventilation; or
4. Non-necrotizing pneumonias (both bacterial and viral); or
5. Primary graft failure after heart, lung or heart-lung transplantation; or
6. Pulmonary contusion; or
7. Refractory pediatric septic shock; or 
8. Other reversible causes of respiratory or cardiac failure (e.g., myocarditis) that is unresponsive to all other measures.
   

Aetna considers ECMO/ECLS for children and adults experimental and investigational for all other indications because of insufficient evidence of its safety and effectiveness.

See also CPB 0518 - Nitric Oxide, Inhalational (INO).

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.  Such a system provides excellent oxygen saturation and carbon dioxide removal.  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.