First described in 1967, acute respiratory distress syndrome (ARDS) continues to have high rates of mortality.1,2 Despite advances in care including low-tidal volume ventilation, neuromuscular blockade, and prone positioning, some patients continue to deteriorate and require salvage therapy with veno-venous extracorporeal membrane oxygenation (VV ECMO).3–5 During the 1970s, 1980s, and 1990s, the use of ECMO support for respiratory failure demonstrated poor outcomes.6,7 As a result, most authors recommended against its use in respiratory failure because of the lack of survival benefit and the significant resources required to perform. However, in 2009, the Conventional Ventilation versus ECMO for Severe Adult Respiratory Failure (CESAR) trial demonstrated a survival benefit in patients with ARDS when referred to an ECMO center for care.8 At the same time, reports from Italy, Australia, New Zealand, and France demonstrated increase survival using VV ECMO in-patients with H1N1 influenza.9–11 Since 2009, the number of centers and annual VV ECMO runs has increased both in the United States and worldwide.12,13
According to a national registry, since 2009, the mean time for adult patients on VV ECMO for respiratory failure is 260 hours (standard deviation [SD] ±30) with the longest run recorded at 6,248 hours (260 days).12 In the CESAR trial, patients treated with VV ECMO had a median time of 9 days on ECMO.8 These results are similar to reports from Australia, New Zealand, and Italy during the 2009 H1N1 pandemic.10,11 In France’s H1N1 outbreak, patients had a mean time of 23 days on VV ECMO; however, there was a large SD in their cohort.9 A number of reports in the pediatric literature demonstrate that longer ECMO runs for respiratory failure have lower survival to discharge rates.14–16 Recent reports in adults evaluating the outcomes of longer VV ECMO runs have had variable results.17–21 The purpose of this study was to evaluate outcomes between patients requiring short ECMO (sECMO) runs and those with extended ECMO (eECMO) runs at a tertiary care center with a dedicated multidisciplinary intensive care unit (ICU) for VV ECMO.
Materials and Methods
A retrospective review of all patients on VV ECMO admitted to the lung rescue unit (LRU) at the R Adams Cowley Shock Trauma Center/University of Maryland Medical Center between August 2014 and February 2017 was performed. Table 1 lists the guidelines for ECMO consideration at our institution. For the purpose of this study, patients who were on VV ECMO as a bridge to transplant, post-cardiac surgery, or post-lung transplant were excluded. Patients were stratified by duration of ECMO with short-run ECMO defined as ≤504 hours (21 days) on ECMO, while an extended run ECMO defined as >504 hours on ECMO.
The extracorporeal device consisted of a Rotaflow centrifugal pump (Maquet Cardiopulmonary AG, Hirrlingen, Germany). Venous drainage was obtained using a 55 cm long, 23 or 25 Fr (typically) cannula (Maquet Cardiopulmonary AG) while a 23 cm 19, 21, or 23 Fr arterial cannula (Maquet Cardiopulmonary AG) was used for reinfusion through the right internal jugular vein. When a bifemoral cannulation approach was used, a Bio-Medicus venous return cannula was used.
Once stabilized after cannulation, patient care in the LRU is protocolized to standardize care. Pressure-controlled ventilation with a total pressure of 20 cm H2O and a positive end-expiratory pressure (PEEP) of 10 cm H2O is used. Fractional inspired oxygenation on the ventilator is initially set at 0.4. All patients, without signs of active hemorrhage, have a set hemoglobin goal of 8 g/dl and platelet count of 50 K/mcL. Anticoagulation is achieved with a heparin infusion titrated to a partial thromboplastin time (PTT) of 45–55 seconds unless there is an indication for full systemic anticoagulation (PTT 60–80 s). Patients who require prone positioning, based on radiographic evidence of recruitable lung disease, are prone for 8 hours for their initial session to monitor and evaluate for skin breakdown and hemodynamic stability. All subsequent sessions are 16 hours. Ventilator settings used for prone patients are total pressure control of 25 cm H2O with PEEP of 15 cm H2O. Flow on the ECMO circuit is titrated to pulse oximetry saturation of >88%. For patients who are unable to maintain a saturation of 88% despite maximal flow and a hemoglobin of 8 g/dl, fractional inspired oxygenation on the ventilator and hemoglobin goals are increased at the discretion of the bedside clinical team. Sweep gas (not ventilator settings) is titrated to a partial pressure of carbon dioxide (pCO2) of 35–45 mm Hg if normal right ventricular (RV) function is present on transthoracic echocardiogram. If there is any evidence of RV dysfunction, then the pCO2 is maintained at 35–40 mm Hg and epoprostenol inhalation at 50 ng/kg/min and a nontitrating inotropic dose of epinephrine at 0.04 μg/kg/min are started/continued and maintained until RV function normalizes. Once decannulated, patients have planned surveillance venous duplex at cannula sites, including the abdominal inferior vena cava, at 24 hours after decannulation. All cannula-associated deep vein thrombosis (CaDVT) are treated with full systemic anticoagulation. Any positive study is repeated in 2 weeks and if thrombus remains, patients are treated with 3 months of therapy, otherwise anticoagulation is stopped. Demographics, pre-ECMO data, ECMO data, and survival to discharge were collected. Medians (interquartile range [IQR]) were reported. A p value ≤0.05 was considered statistically significant. Wilcoxon’s rank sum test and Pearson’s χ2 were used when applicable and corresponding 95% confidence intervals of the difference between groups were computed. This study was approved by the institutional review board at the University of Maryland School of Medicine.
One hundred and thirty-nine patients were admitted to the LRU on VV ECMO during the study period (Table 2). Median age was 44 [31–54] years, days on the ventilator before ECMO cannulation was 1 [0–4], PaO2/FiO2 (P/F) before ECMO cannulation 67 [54–79], respiratory extracorporeal membrane oxygenation survival prediction (RESP) score was 4 [2–5], and time on ECMO was 309 [174–452] hours. Aspiration, bacterial and viral pneumonia were the indications for 51% of the patients (Table 3). One hundred and twenty-three (88.5%) patients had a separate return and drainage cannula using the right internal jugular and right/left femoral vein. Thirteen (9.5%) patients had bifemoral cannulation and three (2%) patients require central cannulation (right atrium and pulmonary artery). No dual lumen catheters were used during the study period. Overall survival to hospital discharge was 76%.
One hundred and eight (78%) patients had an ECMO run less than 504 hours and were classified as sECMO, while 31 (22%) patients had an ECMO run >504 and were classified as eECMO. There was no difference in median age, P/F ratio before ECMO cannulation, or RESP score. Extended ECMO patients had a significantly increased median days of ventilation before ECMO cannulation as compared with sECMO and as expected, longer time on ECMO. There was no difference in the rate of survival to hospital discharge between the two groups (Table 4).
Thirteen patients in the sECMO group died within the first 5 days of ECMO cannulation. Eight additional sECMO patients died after decannulation but before hospital discharge. Four patients in the eECMO group died before decannulation; three from multisystem organ failure and one patient and family elected to stop ECMO support. All patients in the eECMO group who were decannulated survived to hospital discharge. Overall, 29 (23 sECMO, six eECMO) patients were discharged directly home without the need for inpatient rehabilitation. The remaining 76 patients required in-patient rehabilitation after discharge.
Sixty-four patients required continuous renal replacement therapy (CRRT) while on VV ECMO. There was no difference in rates of CRRT when stratified by short and eECMO runs (Table 4). Of the 64 patients, 22 (35%) were on CRRT at the time of their death before hospital discharge. Of the 42 patients who were discharged alive, only one (2.3%) required intermittent hemodialysis on discharge. All others had return of renal function.
Of the 112 patients who were decannulated, 96 (85.7%) were found to have at least one CaDVT. Postdecannulation CaDVT formation did not differ between the sECMO and eECMO groups (p = ns). Fifty-six (58%) patients with CaDVT had a planned 2 week follow-up duplex of whom 17 (30%) had complete thrombus resolution and did not require systemic anticoagulation on discharge.
Since 2009, the use of VV ECMO for respiratory failure has increased in the United States and worldwide.12,13 Although Extracorporeal Life Support Organization’s (ELSO) registry average ECMO run time, 260 (±30) hours, has not changed drastically during the past 5 years, the longest run each year has increased over time and varied from 1487 to 6248 hours with a median of 3,177 [IQR 2067–4734] hours.12 One reason for longer ECMO runs may be technological advances including long-term oxygenators and centrifugal pumps.17 These improvements have allowed for lower hemolysis rates, ability to run ECMO without anticoagulation, and decrease transfusion needs.17 However, the answer to how long is too long for an ECMO run remains unknown.
In this study, we evaluated survival outcomes in patients on VV ECMO for respiratory failure when stratified by time on ECMO. Based on previous publications, 504 hours (21 days) was used as the cut off for sECMO versus eECMO.17,18 No difference in survival to discharge was detected between the two cohorts. Previous publications have had mixed results. In 2011, Camboni et al.17 reported outcomes based on support time in 127 patients more than 4 years that required VV ECMO for respiratory failure. The authors stratified by three durations of ECMO support, <10, 10–20, and >20 days. The authors demonstrated a significant difference in survival for those on ECMO <10 days as compared with those whose support was maintained for 10–20 days (59% vs. 31%; p = 0.005). However, there was no survival difference between those on support for <10 or 10–20 days as compared with those on ECMO >20 days (59% vs. 52%, p = 0.39; 31% vs. 52%, p = 0.17). In 2015, Kon et al.18 evaluated outcome in 55 patients more than 4 years using 3 weeks to define long-term ECMO support. The authors found no difference in hospital or 30 day mortality between the two groups and concluded that duration of ECMO support alone should not be used to determine withdrawing ECMO support. In contrast, Posluszny et al.19 performed a retrospective review of the ELSO international multiinstitutional registry to evaluate the outcome for prolonged ECMO (pECMO) in adults with acute respiratory failure (ARF). The authors defined pECMO as ≥14 days and divided the analysis into two time periods, 1989–2006 and 2007–2013. Overall, the median time of pECMO was 504 [336–5014] hours and more than two-thirds of all the cases were in the later time period. Despite an increase in survival for pECMO in the later period, overall, the authors found that pECMO was associated with a lower hospital survival rate compared with prior survival rates of sECMO. However, the authors supported the use of pECMO.
The longest ECMO run survivor in our study was 4,372 hours (182 days). The patient had intraabdominal sepsis that was complicated by ARF requiring VV ECMO. The patient had multiple bouts of bacteremia and cutaneous mucor, all of which were successfully treated. Additionally, the patient received a prolonged course of methylprednisolone for respiratory failure. Despite the eECMO course, the patient remained single system failure, never developing renal failure requiring CRRT or liver failure, and remained neurologically intact the entire hospital course. After decannulation, the patient was transferred to rehabilitation center to continue weaning off mechanical ventilation. Unfortunately, the patient passed away 7 months later still requiring mechanical ventilatory support. The next two longest runs were 2,736 (114 days) and 2,504 (104 days) hours, respectively. Both patients are now home off the ventilator, not requiring supplemental oxygen and have returned to pre-ECMO status. The longest published ECMO run is 265 days.20 Although this patient was successfully decannulated, the patient died before hospital discharge. In Posluszny et al.’s19 25 year review of the ELSO registry, the longest survivor was 2,750 hours (114.6 days). Two patients had longer runs, but neither survived to discharge.
The increased number of reports of eECMO runs begs the question of “how long is too long?.” This is obviously a very difficult question to answer and one that has moral, ethical, and financial implications. The decision process for patients who are in multisystem organ failure, neurologically incapacitated, or have a very low likelihood of survival is relatively straightforward. In those situations, it is the providers’ responsibility to communicate with families, the gravity of the patient’s condition. This process often involves pastoral care, social workers, and palliative care. The situation becomes more difficult when patients have single system respiratory failure despite eECMO runs. Although the discussion of lung transplant may be entertained, many patients are not candidates while others do not wish to pursue the option. How does one tell a neurologically intact, single system failure patient and their family that based on an arbitrary duration of ECMO, the machine will be turned off? The short answer is not very easy. It would seem intuitive that a longer ICU stay and a likelihood of bridge to recovery would decrease over time. However, there is a moderate amount of literature that would contradict this notion and suggest prolonged ICU care may be appropriate in certain patients.22–25 Our group’s practice is to continue care until the patient is decannulated, dies of multisystem organ failure, overwhelming sepsis or the patient and family decide to discontinue ECMO support. Of the four patients who died in the eECMO group, three developed multisystem organ failure and transitioned to comfort care. The fourth patient and family elected to terminate care after 1,837 hours despite being neurologically intact with single system failure.
Rather than “How long is too long?” the more appropriate question may be “What happens to these patients after discharge?” Are ECMO patients returning to their community as pulmonary cripples or recovering to preillness condition? Unfortunately, little data exist on long-term follow-up of patients who required VV ECMO for respiratory failure. In 2009, Lindén et al.26 demonstrated that it is common for ECMO-treated ARDS patients to have lung parenchymal changes on computed tomography (CT) and minor pulmonary function abnormalities detected more than 1 year after ECMO. However, a majority of patients had good physical and social recovery with a large proportion returning to preillness employment status. A 2017 meta-analysis reported a significant decrease in health-related quality of life (HRQL) for those patients treated with VV ECMO compared with conventional mechanical ventilation (CMV).27 However, according to the authors, ECMO patients experienced significantly less psychological (depression and anxiety) morbidity. Additionally, the authors concluded that there was no difference in long-term exercise tolerance between patients receiving ECMO and CMV. As there is more evidence demonstrating improved outcomes with early mobilization and rehabilitation in the critically ill adult, it is imperative that an organized collaborative multidisciplinary rehabilitation approach exists for ECMO patients.28–30 Recent studies have demonstrated that a highly trained multidisciplinary team can provide safe physiotherapy, including standing and ambulation, which may improve ICU mortality.31,32 The LRU has established a structured process with physical therapy for the evaluation and implementation of an aggressive program to facilitate mobility. The collaborative goal is to ambulate all patients while on ECMO. Although this is labor-intensive, it is one we believe benefits the patients.
Limitations to this study include its single-center retrospective design. A second limitation is we did not perform a power calculation. This is because we elected to capture data from a specific time point (opening of the LRU) of standardize care. The included period did not allow sufficient patients for a power calculation. A third limitation is that our primary outcome was survival to hospital discharge. Although that is a very important end-point, it may not be the most crucial end-point. The true question is what happens to these patients once discharged from the hospital and their condition in 6 months or 1 year after discharge. As part of the VV ECMO program, we have created a follow-up clinic for all discharged patients. The structured post-discharge program includes interval pulmonary function testing and quality of life surveys. Additional resources provided include referrals for mental health follow-up because of a high-observed occurrence of symptoms similar to posttraumatic stress disorder.
In conclusion, this study demonstrates that patients who require extended VV ECMO for ARDS/ARF have similar survival rates to those of short of ECMO runs. Based on this data, time on VV ECMO should not be the sole determining factor to stop support. Rather, the overall clinical condition, including the presence of multiple system organ failure and the reversibility of the pulmonary condition must be taken into account. Future studies should focus on long-term follow-up of patients treated with ECMO for ARDS to better elucidate the full effect of the therapy.
1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967.2: 319-323.
2. Ranieri VM, Rubenfeld GD, Thompson BT, et al.; ARDS Definition Task Force: Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012.307: 2526-2533.
3. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A; ARDS Network, Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301-8.
4. Papazian L, Forel JM, Gacouin A, et al.; ACURASYS Study Investigators: Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010.363: 1107-1116.
5. Guérin C, Reignier J, Richard JC, et al.; PROSEVA Study Group: Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013.368: 2159-2168.
6. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 1979.242: 2193-2196.
7. Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994.149(2 Pt 1): 295-305.
8. Peek GJ, Mugford M, Tiruvoipati R, et al.; CESAR Trial Collaboration: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicentre randomised controlled trial. Lancet 2009.374: 1351-1363.
9. Cianchi G, Bonizzoli M, Pasquini A, et al. Ventilatory and ECMO treatment of H1N1-induced severe respiratory failure: Results of an Italian referral ECMO center. BMC Pulm Med 2011.11: 2.
10. Davies A, Jones D, Bailey M, et al.; Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators, Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA. 2009;302:1888-1895.
11. Beurtheret S, Mastroianni C, Pozzi M, et al. Extracorporeal membrane oxygenation for 2009 influenza A (H1N1) acute respiratory distress syndrome: Single-centre experience with 1-year follow-up. Eur J Cardiothorac Surg 2012.41: 691-695.
12. Extracorporeal Life Support Organization. ECLS Registry report. United States Summary. July 2017.
13. Extracorporeal Life Support Organization. ECLS Registry report. International Summary. July 2017.
14. Gupta P, McDonald R, Chipman CW, et al. 20-year experience of prolonged extracorporeal membrane oxygenation in critically ill children with cardiac or pulmonary failure. Ann Thorac Surg 2012.93: 1584-1590.
15. Brogan TV, Zabrocki L, Thiagarajan RR, Rycus PT, Bratton SL. Prolonged extracorporeal membrane oxygenation for children with respiratory failure. Pediatr Crit Care Med 2012.13: e249-e254.
16. Prodhan P, Stroud M, El-Hassan N, et al. Prolonged extracorporeal membrane oxygenator support among neonates with acute respiratory failure: A review of the Extracorporeal Life Support Organization registry. ASAIO J 2014.60: 63-69.
17. Camboni D, Philipp A, Lubnow M, et al. Support time-dependent outcome analysis for veno-venous extracorporeal membrane oxygenation. Eur J Cardiothorac Surg 2011.40: 1341-1346; discussion 1346.
18. Kon ZN, Dahi S, Evans CF, et al. Long-term venovenous extracorporeal membrane oxygenation support for acute respiratory distress syndrome. Ann Thorac Surg 2015.100: 2059-2063.
19. Posluszny J, Rycus PT, Bartlett RH, et al.; ELSO Member Centers: Outcome of adult respiratory failure patients receiving prolonged (≥14 days) ECMO. Ann Surg 2016.263: 573-581.
20. Wiktor AJ, Haft JW, Bartlett RH, Park PK, Raghavendran K, Napolitano LM. Prolonged VV ECMO (265 Days) for ARDS without technical complications. ASAIO J 2015.61: 205-206.
21. Moon SM, Lee H, Moon JH, et al. Prolonged maintenance of VV ECMO for 104 days with native lung recovery in acute respiratory failure. ASAIO J 2016.62: e15-e17.
22. Arabi Y, Venkatesh S, Haddad S, Al Shimemeri A, Al Malik S. A prospective study of prolonged stay in the intensive care unit: Predictors and impact on resource utilization. Int J Qual Health Care 2002.14: 403-410.
23. Venker J, Miedema M, Strack van Schijndel RJ, Girbes AR, Groeneveld AB. Long-term outcome after 60 days of intensive care. Anaesthesia 2005.60: 541-546.
24. Friedrich JO, Wilson G, Chant C. Long-term outcomes and clinical predictors of hospital mortality in very long stay intensive care unit patients: A cohort study. Crit Care 2006.10: R59.
25. Rimachi R, Vincent JL, Brimioulle S. Survival and quality of life after prolonged intensive care unit stay. Anaesth Intensive Care 2007.35: 62-67.
26. Lindén VB, Lidegran MK, Frisén G, Dahlgren P, Frenckner BP, Larsen F. ECMO in ARDS: A long-term follow-up study regarding pulmonary morphology and function and health-related quality of life. Acta Anaesthesiol Scand 2009.53: 489-495.
27. Wilcox ME, Jaramillo-Rocha V, Hodgson C, Taglione MS, Ferguson ND, Fan E. Long-term quality of life after extracorporeal membrane oxygenation in ARDS survivors: systematic review and meta-analysis. J Intensive Care Med 2017 [epub ahead of print].
28. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial. Lancet 2009.373: 1874-1882.
29. Burtin C, Clerckx B, Robbeets C, et al. Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med 2009.37: 2499-2505.
30. Omanwa K, Menaker J. The role of rehabilitation leadership in a multidisciplinary intensive care lung rescue unit: our experience at the University of Maryland Medical Center. Abstract. 2017.ATS International Conference. Washington DC.
31. Munshi L, Kobayashi T, DeBacker J, et al. Intensive care physiotherapy during extracorporeal membrane oxygenation for acute respiratory distress syndrome. Ann Am Thorac Soc 2017.14: 246-253.
32. Wells CL, Forrester J, Vogel J, Rector R, Tabatabai A, Herr D. Safety and feasibility of early physical therapy for patients on extracorporeal membraneoxygenator: University of Maryland Medical Center Experience. Crit Care Med 2017 [epub ahead of print].