Venovenous extracorporeal membrane oxygenation for acute lung failure in adults

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1 Venovenous extracorporeal membrane oxygenation for acute lung failure in adults Christof Schmid, MD, a Alois Philipp, a Michael Hilker, MD, a Leopold Rupprecht, MD, a Matthias Arlt, MD, b Andreas Keyser, MD, a Matthias Lubnow, MD, c and Thomas Müller, MD c From the a Department of Cardiothoracic Surgery, the b Department of Anesthesiology, and the c Department of Internal Medicine II, University Medical Center, Regensburg, Germany. KEY WORDS: acute lung failure; mechanical lung support; acute respiratory distress syndrome (ARDS); lung transplantation BACKGROUND: Acute lung failure (ALF) is an increasing problem that can be treated with venovenous extracorporeal membrane oxygenation (vv-ecmo). This report summarizes prospectively collected data of an institutional experience with vv-ecmo. METHODS: From January 2007 to December 2010, 176 patients (mean age, 48 16; range, years) with ALF refractory to conventional therapy were supported with vv-ecmo. The general indication for vv-ecmo was a partial oxygen pressure/fraction of inspired oxygen (FIO 2 ) 80 mm Hg under a FIO 2 of 1.0, a positive end-expiratory pressure of 18 cm H 2 O, and refractory respiratory acidosis (ph 7.25), despite optimization of conservative therapy. RESULTS: All patients underwent peripheral cannulation. In 59 cases, vv-ecmo was placed in another facility with ECMO transport by helicopter or ambulance. The mean vv-ecmo support interval was days (range, 1 67 days). During ECMO, 12 patients (7%) could be extubated and stepwise mobilized. Cannula-related complications during long-term support occurred in 14%, which was mostly minor bleeding. Overall survival was 56%: 58 patients (33%) died during mechanical support, and 20 (11%) died after weaning from the system. The best outcome was noted in trauma patients. Risk factors were mainly advanced age and multiorgan failure. CONCLUSION: Modern vv-ecmo is an excellent treatment in patients with severe ALF and should be more liberally used. J Heart Lung Transplant 2012;31: International Society for Heart and Lung Transplantation. All rights reserved. Reprint requests: Christof Schmid, MD, Department of Cardiothoracic Surgery, University Medical Center, Franz-Josef-Strauss-Allee 11, D Regensburg, Germany. Telephone: Fax: address: christof.schmid@klinik.uni-regensburg.de /$ -see front matter 2012 International Society for Heart and Lung Transplantation. All rights reserved. doi: /j.healun Acute lung failure (ALF) is an increasing problem in our society. Recent estimates indicate approximately 190,000 cases of ALF in the United States each year. 1 It is characterized by a life-threatening impairment of the gas exchange, resulting in hypoxia, hypercapnia, and respiratory acidosis. 2 Underlying diseases are of pulmonary origin, including bilateral pneumonia and aspiration, or secondarily affect the lung, such as sepsis, trauma, and massive transfusion. The clinical picture is mostly an acute respiratory distress syndrome (ARDS) but may also be related to a cardiac disease. 3 Causal therapeutic options are sparse. Aggressive ventilation is usually the first step. However, high inspiratory pressure and oxygen tension may worsen pulmonary function and irreversibly damage the lung. 4 The idea of extracorporeal membrane oxygen (ECMO) rose in the 1960s. All clinical attempts failed until 1971, when Hill successfully treated a patient with ECMO after a motorcycle accident. In 1976, Bartlett et al 5,6 reported the first successful use of a bedside heart-lung machine in a neonate. During the following decades, a few other gas exchange devices have been devised, but no one finally convinced the community and got anchored in the respective treatment protocols. 7 9 In the ensuing decades, the venovenous ECMO (vv- ECMO) has been mostly used for neonates and only in few specialized centers. This technology has not been exten-

2 10 The Journal of Heart and Lung Transplantation, Vol 31, No 1, January 2012 sively applied in adults. A dramatic boost in the use of vv-ecmo arose when air transportation of critically ill patients with ECMO became more popular. 10,11 This report summarizes prospectively collected data of an institutional experience, where ECMO in all its technical variations is routine and was performed more than 100 times per year. Patients and methods ECMO indication From January 2007 to December 2010, vv-ecmo was initiated in 176 patients who were a mean age of years (range, years) with ALF refractory to all conventional therapeutic modalities. The underlying diseases were divided in 4 categories: 1. primary lung failure in 102, including bacterial, viral, fungal, and aspiration pneumonia, with H1N1 infection in 9 patients; 2. sepsis with secondary lung failure in 43; 3. trauma with ARDS in 14; and 4. other pathologies not fitting into the former groups, including postsurgical status, in 17. In all cases, a potentially reversible disease was assumed and patient recovery intended. The analysis excluded patients with acute exacerbation of end-stage lung disease and a bridge-totransplantation setting. The general indication for vv-ecmo was partial oxygen pressure (PO 2 )/fraction of inspired oxygen (FIO 2 ) 80 mm Hg under a FiO 2 of 1.0, a positive end-expiratory pressure of 18 cm H 2 O, and a refractory respiratory acidosis (ph 7.25), despite optimization of conservative therapy. Optimization of gas exchange followed an institutional protocol, including initial recruitment maneuvers, prone positioning, inhalation of nitric oxide or iloprost, and high-frequency oscillatory ventilation, as has been reported earlier. 12 Pre-ECMO ventilation lasted up to 72 days, with a mean of days (Table 1). ECMO systems All ECMO systems were composed only of a membrane oxygenator and a pump. The ECMO circuit did not include a venous reservoir, a separate venous bubble trap, or an arterial filter. Components of different companies were used to assemble the systems. In most cases, the PLS system from Maquet (Hirrlingen, Germany), consisting of a centrifugal (Rotaflow) pump (77%) and a Quadrox D polymethyl pentene oxygenator (75%) was used (Figure 1). The entire PLS system, including the tubing, was tip-to-tip heparin-coated. The pump and oxygenator were stored on a small mobile table or fixed to the bed frame. In 2010, the newly released Cardiohelp system, the successor of the PLS, was added to the therapeutic armamentarium and used in 20 patients since. The Cardiohelp is an integrated, small, portable system, also containing a centrifugal pump and an oxygenator, designed for temporary cardiopulmonary support 11 (Figure 1). The Deltastream 3 (Medos, Aachen, Germany) diagonal pump was implemented in 24 patients in combination with a membrane oxygenator (Hilite 7000LT). An average of 1.4 systems were run per patient (Table 2). Cannulation In 90% of patients, 2 separate cannulas were inserted via Seldinger s percutaneous technique. After vessel puncture, a guidewire was inserted and its proper placement controlled by echocardiography. For drainage, a 35-cm long-cannula (Maquet) was advanced via the femoral vein to the inferior caval vein. Venous return was achieved via the jugular, subclavian, or rarely, the femoral vein (Maquet). The predominant (median) cannula sizes were 21F to 23F for the venous drainage and 15F to 17F for the arterial return. Since 2009, patients were also provided with a single dual-lumen cannula (Avalon Lab, Rancho Dominguez, CA) inserted into the right internal jugular vein and into the superior and inferior caval vein. Cannula insertion was always accompanied by transesophageal and transthoracic echocardiography to ensure correct placement, with the orifices directed to the right atrium and inferior caval vein. All cannulas were sutured to the skin. The femoral cannulas were additionally fixed with a special retainer taped to the skin, Table 1 Patient Characteristics and Causes of Acute Lung Failure Variable a All patients (n 176) Primary ALF (n 102) Sepsis (sec ALF) (n 43) Trauma with ARDS (n 14) Others (n 17) Age, years Body mass index, kg/m Pre-ECMO ventilation, days PaO 2 /FIO PaCO 2,mmHg ph PIP max, cm H 2 O PEEP, cm H 2 O Resp minute volume, liters/min Lung Injury Score SOFA Score ALF, acute lung failure; ARDS, acute respiratory distress syndrome; PaCO 2, partial pressure of arterial carbon dioxide; PaO 2, partial pressure of arterial oxygen; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; SOFA, sequential organ failure assessment. a Data for all variables are shown as mean standard deviation.

3 Schmid et al. VV-ECMO for ALF in Adults 11 Figure 1 Overview of patients supported with the MiniECC (left) and Cardiohelp (right) systems. and the dual-lumen cannulas were additionally fixed to the patient s head (Figure 1). Anticoagulation The anticoagulation protocol was based on intravenous heparin application. In patients without an elevated bleeding risk, a partial thromboplastin time of 60 seconds was maintained. A moderately increased bleeding risk was encountered with a lower PTT of 40 to 50 seconds. In trauma patients with severe or multiple bone fractures, the ECMO was started without administering heparin, just relying on the heparin coating of the system for up to 3 days. Partial thromboplastin time was controlled and readjusted twice daily. In patients with heparin-induced thrombocytopenia type II, a heparin-free Softline system (Maquet) and anticoagulation with argatroban (Argatra, Mitsubishi Pharma, Düsseldorf, Germany) were used. The pump and oxygenator were monitored for thrombus deposits daily and exchanged if deemed necessary. Platelet transfusion after implant was not routinely necessary because the 3 pumps that were used caused little trauma. Only if the underlying disease (eg, sepsis) led to significant platelet consumption and significant bleeding the latter were substituted. To prevent thrombus deposition in the oxygenator, we even treated the patients without contraindications with 100 mg aspirin daily. Statistical analysis The statistical analysis was performed with SPSS 16.0 software (SPSS, Chicago, IL). Continuous data are presented as mean standard deviation; categoric variables are presented as frequency (n) and simple percentages (%). A value of p 0.05 was considered statistically significant. Differences between two continuous normally distributed variables were tested with Student s t-test, and the Mann-Whitney test was used for 2 non-normally distributed variables. Results Cannulation Generally, a surgeon was always involved in the decision to initiate vv-ecmo, and all patients underwent peripheral cannulation. In 160 patients, the drainage cannula was inserted into a femoral vein. In 155 patients, a long cannula was used with a non-femoral return cannula. A short venous drainage cannula was only used in 5 patients, who had a (long) femoral return cannula. The predominant location for the return cannula was the right internal jugular vein (standard location), which could

4 12 The Journal of Heart and Lung Transplantation, Vol 31, No 1, January 2012 Table 2 Composition of Extracorporeal Membrane Oxygenation System (A) Pumps Component No. Pump flow (liters/min) RPM Rotaflow (Maquet) ,000 5,000 DP3 (Medos) ,000 (B) Oxygenators a Component No. Gas exchange (m 2 ) Heparin coating Oxygenator PLS (Maquet) Bioline Hilite 7000 LT (Medos) Rheoparin Novalung (Novalung) Heparin Quadrox Pediatric (Maquet) Bioline (C) Pump and oxygenator system Component Cardiohelp (Maquet) No. Pump flow (liters/min) Gas exchange (m 2 ) Heparin coating and 1.8 Bioline RPM, revolutions per minute. a The membrane in all oxygenators was polymethylpentene. be used in 121 patients (75%). Alternative sites were approached in 25%, including the subclavian vein in 34 and the 5 patients with a femoral return cannula. Because the skin incision was kept rather small and vessel access was gradually increased with several dilators, bleeding at the cannulation site was infrequent. The single double-lumen cannula was placed in 16 patients. The median cannula size was 27F (range, 23F 27F). Cannula placement was uneventful in 15 patients (94%). In 1 patient, a guidewire perforated the right ventricular wall. No perforation of a caval vein occurred. Local bleeding was infrequent and was controlled by mild pressure; no patients required surgical revision. Pump flow was 2.0 to 4.0 liters/min and was adjusted to allow lung protective ventilation and sufficient gas exchange. Patient transport with ECMO Only 4.5% of these ECMO systems were implanted in our cardiothoracic department, 67 vv-ecmos were inserted in the Division of Pulmonary Medicine. In 2 patients, a vv- ECMO was implanted immediately after cardiopulmonary resuscitation for hypoxemia in the hospital emergency department, whereas 33 patients had undergone resuscitation within the previous 24 hours. In 59 patients, vv-ecmo was placed in a remote hospital by our team. After the ECMO request came by telephone call, the ECMO team rushed to the institution and briefly assessed the patient s condition. If further conservative treatment did not seem promising, cannulas were immediately placed and the ECMO was connected. After a brief period of hemodynamic stabilization, 22 patients were transported to our institution by ambulance and 37 by helicopter. No severe complications (cannula dislocation, ECMO malfunction, cardiovascular collapse) had to be managed during ground or air transport. The average transport distance was km, the farthest distance was 405 km (252 miles; Figure 2). Support interval and outcome The mean vv-ecmo support interval was days (range, 1 67 days). During ECMO, 12 patients (7%) were extubated and stepwise mobilized. The best mobilization was achieved in patients with the single double-lumen cannula because there were no groin incisions. Cannula-related complications occurred in 14% of patients during long-term support and were mostly minor bleeding. However, no bleeding event developed after careful mobilization of a patient. The average need for blood products included 8 10 units of packed red blood cells and 8 18 units of fresh frozen plasma. Twenty patients (11.3%) had no transfusion requirements. ECMO flows in the 4 groups were not statistically different. The flows indexed to body surface were maintained between 1.2 and 1.4 liters/min m 2 (Figure 3). Overall survival was 56%: 58 patients (33%) died during mechanical support and 20 (11%) died after weaning from the system. The best outcome was noted in trauma patients Figure 2 Implant location within the hospital. CV, cardiovascular; GI, gastrointestinal.

5 Schmid et al. VV-ECMO for ALF in Adults 13 Figure 3 Extracorporeal membrane oxygenation flows indexed to body surface area. ALF, acute lung failure. (71%). Leading causes of death were sepsis/multiorgan failure and unresponsive respiratory failure with no option for lung transplantation (Figure 4). Interestingly, out-of-hospital vv-ecmo implantation yielded superior results compared with local implants, probably related to patient selection and liberal in-hospital use of ECMO. Patients who underwent out-of-hospital implant were younger (44 16 vs years) and had a shorter period of artificial respiration before ECMO placement (mean 4 vs 7 days). Risk factors affecting survival were advanced age, multiple organ failure assessed by the sequential organ failure assessment score, renal failure, and minute ventilation, whereas sex, body mass index, duration of mechanical ventilation before ECMO, and the degree of impaired gas exchange (hypoxia, hypercapnia) were not significantly different between survivors and non-survivors (Table 3). Discussion VV-ECMO is the ultimate treatment option in patients with lung failure. It is easy to install and to maintain, but widespread use has not occurred, except for neonates. In adult patients, the efficacy of vv-ecmo is still controversially discussed because convincing results have never been demonstrated in a large patient cohort The recent Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) trial was conducted in 70 centers in the United Kingdom and recruited 180 patients, who were monitored for 6 months. 16,17 This study compared conventional ventilation methods with ECMO for the treatment of severe acute respiratory failure in adults. Patients were included when they suffered potentially reversible respiratory failure, with a Murray score of 3.0 or uncompensated hypercapnia (ph 7.2). Prolonged high-pressure ventilation with a Figure 4 Survival to discharge. ALF, acute lung failure; ECMO, extracorporeal membrane oxygenation.

6 14 The Journal of Heart and Lung Transplantation, Vol 31, No 1, January 2012 Table 3 Risk Factors for Survival After Venovenous Extracorporeal Membrane Oxygenation Placement Factor a All patients Survivors Non-survivors Age, years 49.1 ( ) 44.6 ( ) 52.6 ( ) b SOFA score 13 (10 15) 11 (9 15) 14 (11 16) c Renal failure 64 (37) 21 (23) 43 (53) c Ventilation, liters/min 11.7 ( ) 11.0 ( ) 12.2 ( ) b SOFA, sequential organ failure assessment. a Continuous data are expressed as mean (range), and categoric data as number (%). b p c p FIO for 7 days and any contraindication for ECMO treatment were exclusion criteria. Even if it has been stated that ECMO will result in 1 additional survivor for every 6 patients treated, the study did not change the attitude of most skeptics. The presented data show that it may be worthwhile to expand the use of vv-ecmo systems. Our results demonstrate quite acceptable results, with more than 50% survival after a mean support interval of 12 days. The longest ECMO support lasted 67 days and confirms that longer support intervals may still be successful. Because our patients were more or less all-comers who were not preselected by study criteria, the results are even more remarkable when they are compared with historical data. Patients were only rejected if they were older than 75 years and were in severe treatmentrefractory multiorgan failure, including ALF, for more than 10 days. The analysis shows that underlying diseases influenced outcome. The best survival rates were achieved in trauma patients, in those with a short pre-ecmo ventilation interval, and in those with less comorbidity. The worst outcome was seen in patients with H1N1 pneumonia. Risk factors negatively affecting survival were advanced age, renal and multiorgan failure, and the necessity of a high minute ventilation. However, none of the causes of ALF resulted in unacceptable outcome data and thus did not become a contraindication for vv-ecmo placement. Interestingly, the duration of ECMO support did not seem to be a negative predictor, as has been shown previously. 18 Cannulation sites were standardized, with the right femoral vein being used for drainage and the right internal jugular vein serving to return the arterialized blood. 19 Although the femoral vein was almost always accessible, central intravenous catheters or hemodialysis catheters sometimes hindered placement of the return cannula. In these patients, cannulation of the right subclavian vein was an acceptable alternative, whereas the opposite femoral vein was not. The use of bifemoral vein cannulation only allows a short drainage cannula with worse flow properties and is thus less effective. The set-up of the ECMO devices varied with the availability of components. Mainly, a Rotaflow pump and a Quadrox PMP oxygenator or its successor the Cardiohelp were used because both are well-known miniaturized extracorporeal circulation systems and demonstrate only minimal hemolysis and inflammation. The Deltastream diagonal pump runs at a higher speed and offers comparable results (Table 2). Transfer of ECMO patients with critical lung function to specialized tertiary care centers has become routine. The reduction of the standard heart lung machine to the 2 basic components of a circulatory pump and an oxygenator, as it is realized in the PLS system and in the new Cardiohelp device, made patient transport with ECMO easily possible in standard ambulances and helicopters. Accompanied by an emergency physician and a pump technician, the patient s management is straightforward. 20 Complication rates during vv-ecmo were within an acceptable range. Bleeding complications at cannulation sites were usually controlled by gentle pressure, and surgical revision was not necessary. Transfusion requirements were mostly related to the patient s overall condition and not to hemolysis by the rotary pump. Death was predominantly linked to multiorgan failure and sepsis, but not to hypoxemia and hypercapnia. Successful support for ALF can also be the first step toward long-term support of patients in chronic lung failure. As the numbers on the waiting lists for lung transplantation are steadily increasing, along with the waiting time, mechanical lung support by ECMO or artificial lung may become important tools in the near future to keep the respective patients alive. In conclusion, vv-ecmo is an excellent treatment in well-selected patients with severe ALF. Considering the success rates, more ECMO teams should be created, including cardiothoracic surgeons, anesthesiologists, pneumologists, and pump technicians. Moreover, installation of an appropriate ECMO program may allow longterm pulmonary support and may also pave the way for this technology in an era of extreme donor shortage in lung transplantation. Disclosure statement The authors gratefully thank the 2 patients in Figure 1 for their permission to reproduce the photographs. Christof Schmid and Alois Philipp are consultants of Maquet. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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