LIVER TRANSPLANTATION 20:1141–1144, 2014
LETTER FROM THE FRONTLINE
Extracorporeal Membrane Oxygenation for Refractory Hypoxemia After Liver Transplantation in Severe Hepatopulmonary Syndrome: A Solution With Pitfalls Received April 25, 2014; accepted May 16, 2014.
TO THE EDITORS: According to a recent publication by Nayyar et al.,1 severe hypoxemia after liver transplantation (LT) in patients with hepatopulmonary syndrome (HPS) is not uncommon. According to a review of the literature and the authors’ local institutional experience, the prevalence could be as high as 12% with a mortality rate of 45%. Very severe preoperative hypoxemia, defined as a partial pressure of oxygen 50 mm Hg, and the presence of anatomical shunts were identified as predictors of this complication. Among the possible treatment strategies, the authors reported the use of inhaled vasodilator agents and systemic vasoconstrictors such as methylene blue to improve ventilation perfusion matching. The effectiveness of specific rescue ventilation strategies such as high-frequency oscillatory techniques and ventilation in the prone position remains unproven. We would like to propose another potentially beneficial treatment and bridging strategy: venovenous (V-V) extracorporeal membrane oxygenation (ECMO). Long-term ECMO support in this population after transplantation, solely for treating refractory shunt, has thus far not been reported in adults. Cannulation for ECMO after LT can also pose a significant challenge that depends on the configuration used. We have used ECMO in 6 patients (5 adults and 1 child) before and after LT since December 2012. Three patients required extracorporeal cardiac support, whereas the other 3 patients underwent V-V ECMO for hypoxemic respiratory failure. Ethical approval for the reporting of anonymous data was given by the South East London Research Ethics Committee. CASE A 44-year-old patient with alcoholic cirrhosis and very severe HPS (partial pressure of oxygen on home oxygen 5 35-40 mm Hg) underwent LT via the piggyback
technique. He remained profoundly hypoxemic with severe intrapulmonary shunting for the first 13 days after transplantation. He underwent extensive investigations, including high-resolution and computed tomography pulmonary angiography, but no alternative cause of hypoxemia was identified apart from trivial pleural effusions and some dependent lung collapse. On a bubble echocardiogram, a severe rightto-left shunt persisted. All efforts to ameliorate the shunt flow—positioning maneuvers (including prone ventilation for up to 20 hours/day), the use of flowmodifying medication, nebulized vasodilator therapy, diuresis, and adjustments in ventilator settings— proved unsuccessful. The patient underwent early percutaneous tracheostomy to facilitate weaning; however, all attempts to wean the patient from sedation resulted in profound desaturation (PaO2/FiO2 40–60 mmHg) because of increasing cardiac output and shunt flow and increasing peripheral oxygen consumption. Because of concerns about secondary lung injury, infections, and ischemic (hypoxemic) biliary complications, the decision to use V-V ECMO support was made. A double-lumen bicaval cannula (27-Fr) was placed via the right internal jugular vein under fluoroscopic and echocardiographic guidance, and pump flows of 3-4 L/minute were achieved (Fig. 1). According to our institutional practice, low-level circuit anticoagulation with heparin was performed with an early activated clotting time target of 180 seconds followed by an activated partial thromboplastin time ratio of 1.8 to 2. A sudden rise in venous access pressures and a drop in the pump flow some 24 hours after ECMO initiation were attributed to cannula migration/malpositioning into the blind end of the donor’s inferior vena cava cuff. This was confirmed via transesophageal echocardiography, abdominal sonography, and eventually fluoroscopy when the cannula was repositioned and advanced into the retrohepatic portion of the
Michael A. Heneghan is part of the speakers’ bureau for Falk Pharma. Address reprint requests to Georg Auzinger, M.D., Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, United Kingdom. E-mail: [email protected] DOI 10.1002/lt.23926 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION. DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
1142 LETTER FROM THE FRONTLINE
recipient’s inferior vena cava (Fig. 2B). A possible complication arising from this was hemorrhagic venous infarction and hematoma formation of the left lobe of the graft with an aspartate aminotransferase elevation to 2400 U/L without evidence of graft dysfunction/failure (Fig. 3). On computed tomography imaging on the day before ECMO cannulation, the graft appearance was normal with patent vasculature; urgent abdominal sonography at the time of the venous access pressure rise showed normal right and left hepatic artery Doppler signaling and a patent por-
LIVER TRANSPLANTATION, September 2014
tal vein. It was not possible to reliably identify the left hepatic vein at that stage. The patient was later successfully weaned off sedation and tolerated minimal respiratory and oxygenation support. The graft function remained well preserved, and the pulmonary shunt flow decreased according to a semiquantitative echocardiographic and clinical assessment. He was weaned off ECMO after 21 days of support and was discharged into ward care a week later. He was subsequently transferred to his referring hospital for further rehabilitation and was later discharged home without the need for supplemental oxygen and with excellent graft function.
DISCUSSION
Figure. 1. Sketch of a double-lumen cannula traversing the superior vena cava and the right atrium with the tip positioned in the inferior vena cava. The access lumina are in the superior vena cava and inferior vena cava (blue arrows); the return lumen is in the right atrium with the flow directed toward the tricuspid valve (red arrow).
Although the use of V-V ECMO has previously been reported for the treatment of severe respiratory failure after LT,2 we are aware of only 1 publication on its use in the context of HPS in an adult3; in that particular instance, the patient was primarily supported for the treatment of acute respiratory distress syndrome in order to facilitate transplantation and was taken off ECMO upon the completion of surgery. Another report described the successful use of ECMO in a pediatric patient with autoimmune liver disease and HPS complicated by refractory hypoxemia after LT.4 This was attributed to an increase in the shunt flow in the context of bacteremia. We believe that V-V ECMO should be considered as an early rescue strategy for this small group of patients with severe HPS and persistent posttransplant intrapulmonary shunting. To the best of our knowledge, this is also the first description of the use of the bicaval Wang-Zwische double-lumen cannula for V-V ECMO after LT. The use of this particular type of cannula is in our view preferable because it allows early mobilization and ventilator
Figure. 2. (A) High cannula tip position after cannulation. (B) Fluoroscopy image after the advancement of the cannula into the recipient’s retrohepatic inferior vena cava.
LIVER TRANSPLANTATION, Vol. 20, No. 9, 2014
Figure. 3. Left lobe graft infarction. The ECMO cannula is positioned in the retrohepatic inferior vena cava.
weaning due to its single access and return site (commonly via the right internal jugular vein). The latest generation of ECMO circuits with their compact design, biocompatible polymethylpentene membrane oxygenators, and heparin-bonded circuits also reduce the risk of bleeding and circuit-related complications significantly. In our own institutional experience, we have managed patients on ECMO without systemic anticoagulation for up to 3 weeks and with no circuit clotting. In this particular instance, low-level anticoagulation was continued because there was no evidence of active bleeding after repositioning of the cannula or when the hematoma was diagnosed on repeat computed tomography imaging 2 days later. Despite this, ECMO remains a highly invasive procedure and requires dedicated specialist nursing and medical care, which in our view can be provided only through an established ECMO service. The durability and less complex setup of modern ECMO circuits keep disposable costs low, with the major expenditures related to personnel costs. Recent calculations5 have estimated that the cost of V-V ECMO for patients is on average double the expenditures for conventional advanced respiratory support; this is based on data from a dedicated ECMO unit. We believe that it is possible to contain costs significantly through the incorporation of an ECMO program within a multidisciplinary intensive care unit staffed by the existing nursing and medical workforce, as is the case at our institution. Adequate training according to recognized standards also obviates the 24-hour presence of a perfusionist. Theoretical concerns about ECMO in this particular setting are related to the potential reversal of hypoxic pulmonary vasoconstrictive responses through the
LETTER FROM THE FRONTLINE 1143
return of highly oxygenated blood to the right heart and subsequently pulmonary circulation. Whether this could delay the reversal of shunting is currently unknown. The use of bicaval cannulae after LT may also be challenging. According to the type of caval anastomosis used, great care should be taken during cannula placement. We strongly recommend both transesophageal echocardiography and fluoroscopic guidance because potentially fatal malpositioning of bicaval cannulae in the right ventricle or hepatic veins has been reported. This applies not only to the cannula tip position but also to the direction of the return flow, which needs to be aimed toward the tricuspid valve rather than the right atrial free wall to minimize the risk of atrial perforation. Despite cannulation of the patient under the guidance of both imaging modalities, the cannula in this case was initially probably not inserted far enough and appeared to be placed with its tip at the level of the piggyback anastomosis (Fig. 2A); it may have subsequently slipped into the donor’s inferior vena cava cuff. We think that this ultimately resulted in the venous infarction of the left liver lobe and hematoma formation, although no definitive sonographic diagnosis of an outflow obstruction was made at the time. In conclusion, we advocate the use of ECMO for severe refractory hypoxemia after LT for HPS. It may facilitate early ventilator weaning and, therefore, prevent the need for the prolonged use of sedation and reduce complications associated with these interventions. Early mobilization is feasible, especially with double-lumen cannulae, although great care needs to be taken during the positioning of these devices in the context of LT. Ultimate proof of the effectiveness of this intervention warrants future multicenter trials.
Georg Auzinger, M.D., AFICM1,2 Christopher Willars, MBBS, FRCA, FFICM1,2 Robert Loveridge, MBBS, FRCA, FFICM2 Thomas Best, MBBS, FRCA, FFICM2 Andre Vercueil, MBBS, FRCA, FFICM2 Andreas Prachalias, MBBS, M.D., FRCS1 Michael A. Heneghan, M.D., FRCPI1 Julia Wendon, Prof, FRCP, FFICM1,2 1 Institute of Liver Studies and 2Critical Care/ECMO Service King’s College Hospital London, United Kingdom
REFERENCES 1. Nayyar D, Man HS, Granton J, Gupta S. Defining and characterizing severe hypoxemia after liver transplantation in hepatopulmonary syndrome. Liver Transpl 2014; 20:182-190. 2. Park YH, Hwang S, Park HW, Park CS, Lee HJ, Namgoong JM, et al. Effect of pulmonary support using extracorporeal membrane oxygenation for adult liver transplant recipients with respiratory failure. Transplant Proc 2012;44:757-761.
1144 LETTER FROM THE FRONTLINE
3. Monsel A, Mal H, Brisson H, Luo R, Eyraud D, V ezinet C, et al. Extracorporeal membrane oxygenation as a bridge to liver transplantation for acute respiratory distress syndrome-induced life-threatening hypoxaemia aggravated by hepatopulmonary syndrome. Crit Care 2011;15: R234. 4. Fleming GM, Cornell TT, Welling TH, Magee JC, Annich GM. Hepatopulmonary syndrome: use of extracorporeal
LIVER TRANSPLANTATION, September 2014
life support for life-threatening hypoxia following liver transplantation. Liver Transpl 2008;14:966-970. 5. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, et al.; for CESAR Trial Collaboration. Efficacy and economic assessment of conventional respiratory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351-1363.
LETTER FROM THE FRONTLINE
Extracorporeal Membrane Oxygenation for Refractory Hypoxemia After Liver Transplantation in Severe Hepatopulmonary Syndrome: A Solution With Pitfalls Received April 25, 2014; accepted May 16, 2014.
TO THE EDITORS: According to a recent publication by Nayyar et al.,1 severe hypoxemia after liver transplantation (LT) in patients with hepatopulmonary syndrome (HPS) is not uncommon. According to a review of the literature and the authors’ local institutional experience, the prevalence could be as high as 12% with a mortality rate of 45%. Very severe preoperative hypoxemia, defined as a partial pressure of oxygen 50 mm Hg, and the presence of anatomical shunts were identified as predictors of this complication. Among the possible treatment strategies, the authors reported the use of inhaled vasodilator agents and systemic vasoconstrictors such as methylene blue to improve ventilation perfusion matching. The effectiveness of specific rescue ventilation strategies such as high-frequency oscillatory techniques and ventilation in the prone position remains unproven. We would like to propose another potentially beneficial treatment and bridging strategy: venovenous (V-V) extracorporeal membrane oxygenation (ECMO). Long-term ECMO support in this population after transplantation, solely for treating refractory shunt, has thus far not been reported in adults. Cannulation for ECMO after LT can also pose a significant challenge that depends on the configuration used. We have used ECMO in 6 patients (5 adults and 1 child) before and after LT since December 2012. Three patients required extracorporeal cardiac support, whereas the other 3 patients underwent V-V ECMO for hypoxemic respiratory failure. Ethical approval for the reporting of anonymous data was given by the South East London Research Ethics Committee. CASE A 44-year-old patient with alcoholic cirrhosis and very severe HPS (partial pressure of oxygen on home oxygen 5 35-40 mm Hg) underwent LT via the piggyback
technique. He remained profoundly hypoxemic with severe intrapulmonary shunting for the first 13 days after transplantation. He underwent extensive investigations, including high-resolution and computed tomography pulmonary angiography, but no alternative cause of hypoxemia was identified apart from trivial pleural effusions and some dependent lung collapse. On a bubble echocardiogram, a severe rightto-left shunt persisted. All efforts to ameliorate the shunt flow—positioning maneuvers (including prone ventilation for up to 20 hours/day), the use of flowmodifying medication, nebulized vasodilator therapy, diuresis, and adjustments in ventilator settings— proved unsuccessful. The patient underwent early percutaneous tracheostomy to facilitate weaning; however, all attempts to wean the patient from sedation resulted in profound desaturation (PaO2/FiO2 40–60 mmHg) because of increasing cardiac output and shunt flow and increasing peripheral oxygen consumption. Because of concerns about secondary lung injury, infections, and ischemic (hypoxemic) biliary complications, the decision to use V-V ECMO support was made. A double-lumen bicaval cannula (27-Fr) was placed via the right internal jugular vein under fluoroscopic and echocardiographic guidance, and pump flows of 3-4 L/minute were achieved (Fig. 1). According to our institutional practice, low-level circuit anticoagulation with heparin was performed with an early activated clotting time target of 180 seconds followed by an activated partial thromboplastin time ratio of 1.8 to 2. A sudden rise in venous access pressures and a drop in the pump flow some 24 hours after ECMO initiation were attributed to cannula migration/malpositioning into the blind end of the donor’s inferior vena cava cuff. This was confirmed via transesophageal echocardiography, abdominal sonography, and eventually fluoroscopy when the cannula was repositioned and advanced into the retrohepatic portion of the
Michael A. Heneghan is part of the speakers’ bureau for Falk Pharma. Address reprint requests to Georg Auzinger, M.D., Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, United Kingdom. E-mail: [email protected] DOI 10.1002/lt.23926 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION. DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
1142 LETTER FROM THE FRONTLINE
recipient’s inferior vena cava (Fig. 2B). A possible complication arising from this was hemorrhagic venous infarction and hematoma formation of the left lobe of the graft with an aspartate aminotransferase elevation to 2400 U/L without evidence of graft dysfunction/failure (Fig. 3). On computed tomography imaging on the day before ECMO cannulation, the graft appearance was normal with patent vasculature; urgent abdominal sonography at the time of the venous access pressure rise showed normal right and left hepatic artery Doppler signaling and a patent por-
LIVER TRANSPLANTATION, September 2014
tal vein. It was not possible to reliably identify the left hepatic vein at that stage. The patient was later successfully weaned off sedation and tolerated minimal respiratory and oxygenation support. The graft function remained well preserved, and the pulmonary shunt flow decreased according to a semiquantitative echocardiographic and clinical assessment. He was weaned off ECMO after 21 days of support and was discharged into ward care a week later. He was subsequently transferred to his referring hospital for further rehabilitation and was later discharged home without the need for supplemental oxygen and with excellent graft function.
DISCUSSION
Figure. 1. Sketch of a double-lumen cannula traversing the superior vena cava and the right atrium with the tip positioned in the inferior vena cava. The access lumina are in the superior vena cava and inferior vena cava (blue arrows); the return lumen is in the right atrium with the flow directed toward the tricuspid valve (red arrow).
Although the use of V-V ECMO has previously been reported for the treatment of severe respiratory failure after LT,2 we are aware of only 1 publication on its use in the context of HPS in an adult3; in that particular instance, the patient was primarily supported for the treatment of acute respiratory distress syndrome in order to facilitate transplantation and was taken off ECMO upon the completion of surgery. Another report described the successful use of ECMO in a pediatric patient with autoimmune liver disease and HPS complicated by refractory hypoxemia after LT.4 This was attributed to an increase in the shunt flow in the context of bacteremia. We believe that V-V ECMO should be considered as an early rescue strategy for this small group of patients with severe HPS and persistent posttransplant intrapulmonary shunting. To the best of our knowledge, this is also the first description of the use of the bicaval Wang-Zwische double-lumen cannula for V-V ECMO after LT. The use of this particular type of cannula is in our view preferable because it allows early mobilization and ventilator
Figure. 2. (A) High cannula tip position after cannulation. (B) Fluoroscopy image after the advancement of the cannula into the recipient’s retrohepatic inferior vena cava.
LIVER TRANSPLANTATION, Vol. 20, No. 9, 2014
Figure. 3. Left lobe graft infarction. The ECMO cannula is positioned in the retrohepatic inferior vena cava.
weaning due to its single access and return site (commonly via the right internal jugular vein). The latest generation of ECMO circuits with their compact design, biocompatible polymethylpentene membrane oxygenators, and heparin-bonded circuits also reduce the risk of bleeding and circuit-related complications significantly. In our own institutional experience, we have managed patients on ECMO without systemic anticoagulation for up to 3 weeks and with no circuit clotting. In this particular instance, low-level anticoagulation was continued because there was no evidence of active bleeding after repositioning of the cannula or when the hematoma was diagnosed on repeat computed tomography imaging 2 days later. Despite this, ECMO remains a highly invasive procedure and requires dedicated specialist nursing and medical care, which in our view can be provided only through an established ECMO service. The durability and less complex setup of modern ECMO circuits keep disposable costs low, with the major expenditures related to personnel costs. Recent calculations5 have estimated that the cost of V-V ECMO for patients is on average double the expenditures for conventional advanced respiratory support; this is based on data from a dedicated ECMO unit. We believe that it is possible to contain costs significantly through the incorporation of an ECMO program within a multidisciplinary intensive care unit staffed by the existing nursing and medical workforce, as is the case at our institution. Adequate training according to recognized standards also obviates the 24-hour presence of a perfusionist. Theoretical concerns about ECMO in this particular setting are related to the potential reversal of hypoxic pulmonary vasoconstrictive responses through the
LETTER FROM THE FRONTLINE 1143
return of highly oxygenated blood to the right heart and subsequently pulmonary circulation. Whether this could delay the reversal of shunting is currently unknown. The use of bicaval cannulae after LT may also be challenging. According to the type of caval anastomosis used, great care should be taken during cannula placement. We strongly recommend both transesophageal echocardiography and fluoroscopic guidance because potentially fatal malpositioning of bicaval cannulae in the right ventricle or hepatic veins has been reported. This applies not only to the cannula tip position but also to the direction of the return flow, which needs to be aimed toward the tricuspid valve rather than the right atrial free wall to minimize the risk of atrial perforation. Despite cannulation of the patient under the guidance of both imaging modalities, the cannula in this case was initially probably not inserted far enough and appeared to be placed with its tip at the level of the piggyback anastomosis (Fig. 2A); it may have subsequently slipped into the donor’s inferior vena cava cuff. We think that this ultimately resulted in the venous infarction of the left liver lobe and hematoma formation, although no definitive sonographic diagnosis of an outflow obstruction was made at the time. In conclusion, we advocate the use of ECMO for severe refractory hypoxemia after LT for HPS. It may facilitate early ventilator weaning and, therefore, prevent the need for the prolonged use of sedation and reduce complications associated with these interventions. Early mobilization is feasible, especially with double-lumen cannulae, although great care needs to be taken during the positioning of these devices in the context of LT. Ultimate proof of the effectiveness of this intervention warrants future multicenter trials.
Georg Auzinger, M.D., AFICM1,2 Christopher Willars, MBBS, FRCA, FFICM1,2 Robert Loveridge, MBBS, FRCA, FFICM2 Thomas Best, MBBS, FRCA, FFICM2 Andre Vercueil, MBBS, FRCA, FFICM2 Andreas Prachalias, MBBS, M.D., FRCS1 Michael A. Heneghan, M.D., FRCPI1 Julia Wendon, Prof, FRCP, FFICM1,2 1 Institute of Liver Studies and 2Critical Care/ECMO Service King’s College Hospital London, United Kingdom
REFERENCES 1. Nayyar D, Man HS, Granton J, Gupta S. Defining and characterizing severe hypoxemia after liver transplantation in hepatopulmonary syndrome. Liver Transpl 2014; 20:182-190. 2. Park YH, Hwang S, Park HW, Park CS, Lee HJ, Namgoong JM, et al. Effect of pulmonary support using extracorporeal membrane oxygenation for adult liver transplant recipients with respiratory failure. Transplant Proc 2012;44:757-761.
1144 LETTER FROM THE FRONTLINE
3. Monsel A, Mal H, Brisson H, Luo R, Eyraud D, V ezinet C, et al. Extracorporeal membrane oxygenation as a bridge to liver transplantation for acute respiratory distress syndrome-induced life-threatening hypoxaemia aggravated by hepatopulmonary syndrome. Crit Care 2011;15: R234. 4. Fleming GM, Cornell TT, Welling TH, Magee JC, Annich GM. Hepatopulmonary syndrome: use of extracorporeal
LIVER TRANSPLANTATION, September 2014
life support for life-threatening hypoxia following liver transplantation. Liver Transpl 2008;14:966-970. 5. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, et al.; for CESAR Trial Collaboration. Efficacy and economic assessment of conventional respiratory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351-1363.
