- Email: [email protected]
Organ Sharing in the Management of Acute Liver Failure
Organ Sharing in the Management of Acute Liver Failure D. Pezzati, D. Ghinolfi, P. De Simone, G. Tincani, G. Fiorenza, and F. Filipponi ABSTRACT Background. Liver transplantation (OLT) for acute liver failure (ALF) is associated with high morbidity and mortality rates in the early posttransplant course. An efficient organ-sharing organization may grant favorable results. Methods. This is a retrospective analysis of prospectively collected data on patients wait listed for ALF at a single center. Patients were listed for OLT when matching King’s College Criteria. Based on patients’ clinical status, ABO-incompatible grafts were used. Results. From January 2001 to December 2010, 37 patients were wait listed for ALF. Two patients were de-listed (5.4%) for improvement of their clinical conditions; two patients (5.4%) died on the list and 33 (89.2%) underwent OLT. Among these latter, 21 (63.6%) were Italian and 12 (36.4%) were foreign citizens, with four referred from their home country on the basis of international agreements on ALF management. Donors were procured in our region in 10 cases (30.3%), nationally in 22 (66.6%), and outside Italy in 1 (3.1%). Mean time from wait listing to OLT was 1 day (range 0 – 6), and seven patients received an ABO-incompatible graft. Graft and patient survivals at 1 month, 1 year, and 3 years were 78.8%, 72.7%, 66.5%, and 81.8%, 75.8%, and 72.7%, respectively. Five patients underwent retransplantation: two on postoperative day (POD) 2 for primary nonfunction of the liver graft, two on POD 8 and 95 for hepatic artery thrombosis, and one at 18 months for nonanastomotic biliary stenosis. Conclusions. Prompt referral to a OLT center and efficient organ-sharing system play a fundamental role in optimizing the outcome of the patient with ALF. Development of international organ exchange programs might further improve the results for this category of patients. In very selected cases, ABO-incompatible grafts may be a valuable resource. CUTE LIVER FAILURE (ALF) is characterized by the development of severe liver injury with impaired synthetic capacity and encephalopathy in the absence of previous liver disease.1 Etiologies are different worldwide and related to geographical areas.2,3 In the absence of liver transplantation (OLT), survival rates can range from over 60% in patients with acetaminophen-induced ALF to less than 30% in those with nonacetaminophen ALF.4 Management includes intensive care support and specific treatments according to the aetiology, but OLT remains the standard of care for patients with low chance of spontaneous recovery.5 Survival after OLT is between 60% and 80% and not different from other indications for OLT.6 Different prognostic markers have been introduced to allow differentiation of patients likely to survive with medical therapy from those for whom OLT should not be delayed. At present, King’s College7 and Clichy criteria8 are
A
considered to be the most valuable tools to assess prognosis in patient with ALF, even though some authors have recently demonstrated that MELD and PELD scores are superior.9 Prompt recognition of the cause of ALF, early referral to an OLT center and an efficient organ-sharing system are keys to prevent potential complications, to identify patients eligible to transplantation and to improve survivals.10 The aim of the study is to analyze the impact of an efficient organ-sharing organization in transplant accessibility and survival for patients with ALF. From the Hepatobiliary Surgery and Liver Transplantation, University of Pisa School of Medicine, Pisa, Italy. Address reprint requests to Davide Ghinolfi, MD, Hepatobiliary Surgery and Liver Transplantation, University of Pisa School of Medicine, Pisa, Italy. E-mail: [email protected]
0041-1345/13/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.02.022
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1270
Transplantation Proceedings, 45, 1270 –1272 (2013)
ORGAN SHARING IN ACUTE LIVER FAILURE
1271
METHODS
RESULTS
This is a retrospective analysis of prospectively collected data about patients wait listed at a single center as United Network for Organ Sharing (UNOS) status 1 for ALF from January 2001 to December 2010. Based on our regional organizational model, all the patients with ALF in Tuscany are referred to our center. Moreover, based on international agreement,11 also foreign citizens living in a country of the European Union and matching ALF criteria may be referred. Before being transferred to our unit, patients’ history, clinical conditions, lab tests, and preliminary instrumental evaluation when available are reviewed by a transplant surgeon and an hepatologist. Based on this preliminary screening and the workup on arrival, patients may be admitted to the regular floor or to the liver intensive care unit for further investigations and treatments, according to our internal protocol. Patients matching King’s College Criteria are wait listed and granted national priority (UNOS status 1). To assess the potential development of cerebral edema and intracranial hypertension, all patients undergo a baseline head computed tomography scan and transcranial Doppler sonography twice a day to monitor intracranial arterial flow and variations in blood flow velocity.12 In case of severely increased pulsatility index or decreased blood flow velocity, patients are considered for ABO-incompatible grafts. Grafts are procured with aortic perfusion using Celsior solution and OLT performed with cava-replacement technique using venovenous bypass. Posttransplant immunosuppressive regimen consists of tacrolimus, steroids, and mycophenolate mophetil. In case of ABO-incompatible transplant, recipients are treated with intravenous immunoglobulins and total plasma exchange for 14 days.13
From January 2001 to December 2010, 37 patients were wait listed for ALF at our center. Two patients (5.4%) were de-listed for clinical improvement; 2 (5.4%) died waiting on the list and 33 (89.2%) underwent OLT. Twenty-one patients were Italians (63.6%) and 12 (36.4%) foreign citizens, five being legal residents, three illegal, and four transferred from other countries. Etiology was hepatitis B virus (HBV) infection in 20 cases (54.1%); cryptogenic in 11 (29.7%); amanita intoxication in 1 (2.7%); Epstein-Barr virus in 1 (2.7%); Wilson in 1 (2.7%); autoimmune in 1 (2.7%), and drug-induced in 2 (5.4%). Mean recipients age was 39.8 ⫾ 13.2 years and males were 18 (48.6%). Mean donor age was 49.6 ⫾ 21.0 years and males were 16 (48.5%). Donors were procured in our region (Tuscany) in 10 cases (30.3%), nationally in 22 cases (66.6%), and abroad in 1 case (3.1%). Mean waiting time from waiting list to OLT was 1 day (range 0 – 6). Mean cold ischemia time was 470 minutes (⫾90 minutes). In seven cases, an ABO-incompatible OLT was performed: A¡O in five cases, B¡O in one case and AB¡A in one case. Graft and patient survival at 1 month, 1 year, and 3 years was 78.8%, 72.7%, 66.5%, and 81.8%, 75.8%, 72.7%, respectively (Fig 1). ABO-incompatible patient and graft survival at 3 years was 62.5% and 50%, respectively. Nine patients (27.3%) died due to multiple organ failure; among these, four received an ABO-incompatible graft and three underwent retransplantation. Cause and time of death are summarized in Table 1. Five patients (15.1%) underwent retransplantation: one for primary nonfunction on postoperative day (POD) 2; one for intractable acute rejection on POD 31; one for nonanastomotic biliary strictures at 18 months; two for hepatic artery thrombosis on POD 8 and 106. At univariate analysis, an ABO-incompatible graft, a recipient older than 50 years, and waiting time longer than
Statistical Analysis The descriptive statistics are reported as mean ⫾ standard deviation or median and range, as appropriate. According to their distribution, the Student t-test or the Mann-Whitney U test were used for continuously distributed variables. Survival was computed with the Kaplan Meyer method. A P ⱕ .05 was considered significant. All analyses were performed using SPSS 20.0 software (Chicago, IL, USA).
Fig 1.
Kaplan-Meier graft and patient survival curves.
1272
PEZZATI, GHINOLFI, DE SIMONE ET AL Table 1. Cause and Timing of Death of OLT Patients Patients
POD Cause Re-OLT
1
2
3
4
5
6
7
8
9
8 PNF PNF
1 MOF No
21 MOF HAT
3151 Pneumo No
11 MOF No
18 MOF No
11 MOF No
106 MOF HAT
153 MOF No
POD, postoperative day; PNF, primary graft non function; MOF, multiorgan graft failure; Pneumo, pneumonia; HAT, hepatic artery thrombosis; OLT, liver transplantation.
3 days were associated with a worse patient survival, while HBV infection was associated with better outcome (Table 2). DISCUSSION
ALF is a major concern for OLT surgeons, hepatologists and intensivists as it is characterized by a high mortality rate. The decision to list for OLT is never easy: patients meeting the listing criteria may survive without transplant in a small percentage of cases. In a recent work from the Birmingham group, 23.4% of patients matching King’s College criteria survived on the transplant wait list without OLT.14 Undoubtedly, ALF patients should be promptly referred to experienced centers as delay in referral and lack of lifesaving procedure like OLT may result in a poor outcomes.15 In the United States, the median waiting time for UNOS status 1 patients—including ALF—is 7 days and a 70% posttransplant survival rate at 5 years is reported.16 It is our opinion that an efficient network for organ sharing plays a crucial role. The Italian National Center for Transplantation has stated that every OLT center with a waitlisted UNOS status one patient be offered each potential donor across the country. This organization allows to reduce wait-list time and to get the chance of more than one graft offer per day. In our series, the mean waiting time from listing to OLT was 1 day and 89% of patients listed for ALF were transplanted with a 5% mortality only on the list. International cooperation and organ exchange programs can Table 2. Univariate Analysis of Donor and Recipient Parameters With Correlation With Graft and Patient Survivals P Value
Donor Hemodynamic instability Age ⬎ 70 y Gender BMI ⬎ 26 Na ⬎ 155 mEq/mL Regional Recipient ABO incompatible Gender Age ⬎50 years Alb ⬍ 2.5 g/dL Waiting time ⬎ 3 d HBV etiology
NS NS NS NS NS NS (P ⫽ .06) .0346 NS .0034 NS .028 .0273
BMI, body mass index; HBV, hepatitis B virus; NS, not significant.
maximize graft resources and provide broader access to OLT for ALF patients. In our series, four patients were referred from foreign countries with low donation rates, and one donor was procured abroad for an Italian recipient. Expansion of the donor pool using ABO-incompatible grafts may be of great importance with regard to those recipients who are rapidly deteriorating. Based on our results, we recommend these grafts only in patients with an increased intracranial pressure and when an ABO-compatible organ is not rapidly available. REFERENCES 1. O’Grady JG, Schalm SW, Williams R: Acute liver failure: redefining the syndromes. Lancet. 1993;342:273. 2. Acharya SK, Batra Y, Hazari S, et al: Etiopathogenesis of acute hepatic failure: eastern versus western countries. J Gastroenterol Hepatol. 2002;17(suppl 3):268. 3. Bernal W: Changing patterns of causation and the use of transplantation in the UK. Semin Liver Dis. 2003;23:227. 4. Lee WM: Etiologies of ALF. Semin Liver Dis. 2008;28:142. 5. Bernal W, Auzinger G, Sizer E, et al: Intensive care management of acute liver failure. Semin Liver Dis. 2008;28:188. 6. Schiodt FV, Lee WM: Liver transplantation for acute liver failure-better safe than sorry. Liver Transpl. 2002;8:1063. 7. O’Grady JG, Graeme JM, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989; 97:439. 8. Bernuau J, Goudeau A, Poynard T, et al: Multivariete analysis of prognostic factors in fulminant hepatitis B. Hepatology. 1986;6:648. 9. Yantorno SE, Kremers WK, Ruf AE, et al: MELD is superior to King’s College and Clichy’s Criteria to assess prognosis in fulminant hepatic failure. Liver Transpl. 2007;13:822. 10. Bernal W, Auzinger G, Dhawan A, et al: Acute liver failure. Lancet. 2010;376:190. 11. Pretagostini R, Peritore D, Di Ciaccio D, et al: Exchange of organs and patients with foreign nations during the first 15 months of activity of the Italian Gate to Europe. Transplant Proc. 2007;39: 1739. 12. Bindi ML, Biancofiore G, Esposito M, et al: Transcranial doppler sonography is useful for the decision making at the point of care in patients with acute hepatic failure: a single centre’s experience. Clin Monit Comput. 2008;22:449. 13. Urbani L, Mazzoni A, Bianco I, et al: The role of immunomodulation in ABO-incompatible adult liver transplant recipients. J Clin Apher. 2008;23:55. 14. Marudanayagam R, Shanmugam V, Gunson B, et al: Aetiology and outcome of acute liver failure. HPB Surg. 2009;11:429. 15. Rossaro L, Lee W: Acute liver failure: early referral is the key. Pract Gastroenterol 2004. 16. Organ Procurement and Transplantation Network. Liver Kaplan Meier waiting times for registrations listed: 1999 –2004. Available at: http://optn.transplant.hrsa.gov
A
considered to be the most valuable tools to assess prognosis in patient with ALF, even though some authors have recently demonstrated that MELD and PELD scores are superior.9 Prompt recognition of the cause of ALF, early referral to an OLT center and an efficient organ-sharing system are keys to prevent potential complications, to identify patients eligible to transplantation and to improve survivals.10 The aim of the study is to analyze the impact of an efficient organ-sharing organization in transplant accessibility and survival for patients with ALF. From the Hepatobiliary Surgery and Liver Transplantation, University of Pisa School of Medicine, Pisa, Italy. Address reprint requests to Davide Ghinolfi, MD, Hepatobiliary Surgery and Liver Transplantation, University of Pisa School of Medicine, Pisa, Italy. E-mail: [email protected]
0041-1345/13/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.02.022
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1270
Transplantation Proceedings, 45, 1270 –1272 (2013)
ORGAN SHARING IN ACUTE LIVER FAILURE
1271
METHODS
RESULTS
This is a retrospective analysis of prospectively collected data about patients wait listed at a single center as United Network for Organ Sharing (UNOS) status 1 for ALF from January 2001 to December 2010. Based on our regional organizational model, all the patients with ALF in Tuscany are referred to our center. Moreover, based on international agreement,11 also foreign citizens living in a country of the European Union and matching ALF criteria may be referred. Before being transferred to our unit, patients’ history, clinical conditions, lab tests, and preliminary instrumental evaluation when available are reviewed by a transplant surgeon and an hepatologist. Based on this preliminary screening and the workup on arrival, patients may be admitted to the regular floor or to the liver intensive care unit for further investigations and treatments, according to our internal protocol. Patients matching King’s College Criteria are wait listed and granted national priority (UNOS status 1). To assess the potential development of cerebral edema and intracranial hypertension, all patients undergo a baseline head computed tomography scan and transcranial Doppler sonography twice a day to monitor intracranial arterial flow and variations in blood flow velocity.12 In case of severely increased pulsatility index or decreased blood flow velocity, patients are considered for ABO-incompatible grafts. Grafts are procured with aortic perfusion using Celsior solution and OLT performed with cava-replacement technique using venovenous bypass. Posttransplant immunosuppressive regimen consists of tacrolimus, steroids, and mycophenolate mophetil. In case of ABO-incompatible transplant, recipients are treated with intravenous immunoglobulins and total plasma exchange for 14 days.13
From January 2001 to December 2010, 37 patients were wait listed for ALF at our center. Two patients (5.4%) were de-listed for clinical improvement; 2 (5.4%) died waiting on the list and 33 (89.2%) underwent OLT. Twenty-one patients were Italians (63.6%) and 12 (36.4%) foreign citizens, five being legal residents, three illegal, and four transferred from other countries. Etiology was hepatitis B virus (HBV) infection in 20 cases (54.1%); cryptogenic in 11 (29.7%); amanita intoxication in 1 (2.7%); Epstein-Barr virus in 1 (2.7%); Wilson in 1 (2.7%); autoimmune in 1 (2.7%), and drug-induced in 2 (5.4%). Mean recipients age was 39.8 ⫾ 13.2 years and males were 18 (48.6%). Mean donor age was 49.6 ⫾ 21.0 years and males were 16 (48.5%). Donors were procured in our region (Tuscany) in 10 cases (30.3%), nationally in 22 cases (66.6%), and abroad in 1 case (3.1%). Mean waiting time from waiting list to OLT was 1 day (range 0 – 6). Mean cold ischemia time was 470 minutes (⫾90 minutes). In seven cases, an ABO-incompatible OLT was performed: A¡O in five cases, B¡O in one case and AB¡A in one case. Graft and patient survival at 1 month, 1 year, and 3 years was 78.8%, 72.7%, 66.5%, and 81.8%, 75.8%, 72.7%, respectively (Fig 1). ABO-incompatible patient and graft survival at 3 years was 62.5% and 50%, respectively. Nine patients (27.3%) died due to multiple organ failure; among these, four received an ABO-incompatible graft and three underwent retransplantation. Cause and time of death are summarized in Table 1. Five patients (15.1%) underwent retransplantation: one for primary nonfunction on postoperative day (POD) 2; one for intractable acute rejection on POD 31; one for nonanastomotic biliary strictures at 18 months; two for hepatic artery thrombosis on POD 8 and 106. At univariate analysis, an ABO-incompatible graft, a recipient older than 50 years, and waiting time longer than
Statistical Analysis The descriptive statistics are reported as mean ⫾ standard deviation or median and range, as appropriate. According to their distribution, the Student t-test or the Mann-Whitney U test were used for continuously distributed variables. Survival was computed with the Kaplan Meyer method. A P ⱕ .05 was considered significant. All analyses were performed using SPSS 20.0 software (Chicago, IL, USA).
Fig 1.
Kaplan-Meier graft and patient survival curves.
1272
PEZZATI, GHINOLFI, DE SIMONE ET AL Table 1. Cause and Timing of Death of OLT Patients Patients
POD Cause Re-OLT
1
2
3
4
5
6
7
8
9
8 PNF PNF
1 MOF No
21 MOF HAT
3151 Pneumo No
11 MOF No
18 MOF No
11 MOF No
106 MOF HAT
153 MOF No
POD, postoperative day; PNF, primary graft non function; MOF, multiorgan graft failure; Pneumo, pneumonia; HAT, hepatic artery thrombosis; OLT, liver transplantation.
3 days were associated with a worse patient survival, while HBV infection was associated with better outcome (Table 2). DISCUSSION
ALF is a major concern for OLT surgeons, hepatologists and intensivists as it is characterized by a high mortality rate. The decision to list for OLT is never easy: patients meeting the listing criteria may survive without transplant in a small percentage of cases. In a recent work from the Birmingham group, 23.4% of patients matching King’s College criteria survived on the transplant wait list without OLT.14 Undoubtedly, ALF patients should be promptly referred to experienced centers as delay in referral and lack of lifesaving procedure like OLT may result in a poor outcomes.15 In the United States, the median waiting time for UNOS status 1 patients—including ALF—is 7 days and a 70% posttransplant survival rate at 5 years is reported.16 It is our opinion that an efficient network for organ sharing plays a crucial role. The Italian National Center for Transplantation has stated that every OLT center with a waitlisted UNOS status one patient be offered each potential donor across the country. This organization allows to reduce wait-list time and to get the chance of more than one graft offer per day. In our series, the mean waiting time from listing to OLT was 1 day and 89% of patients listed for ALF were transplanted with a 5% mortality only on the list. International cooperation and organ exchange programs can Table 2. Univariate Analysis of Donor and Recipient Parameters With Correlation With Graft and Patient Survivals P Value
Donor Hemodynamic instability Age ⬎ 70 y Gender BMI ⬎ 26 Na ⬎ 155 mEq/mL Regional Recipient ABO incompatible Gender Age ⬎50 years Alb ⬍ 2.5 g/dL Waiting time ⬎ 3 d HBV etiology
NS NS NS NS NS NS (P ⫽ .06) .0346 NS .0034 NS .028 .0273
BMI, body mass index; HBV, hepatitis B virus; NS, not significant.
maximize graft resources and provide broader access to OLT for ALF patients. In our series, four patients were referred from foreign countries with low donation rates, and one donor was procured abroad for an Italian recipient. Expansion of the donor pool using ABO-incompatible grafts may be of great importance with regard to those recipients who are rapidly deteriorating. Based on our results, we recommend these grafts only in patients with an increased intracranial pressure and when an ABO-compatible organ is not rapidly available. REFERENCES 1. O’Grady JG, Schalm SW, Williams R: Acute liver failure: redefining the syndromes. Lancet. 1993;342:273. 2. Acharya SK, Batra Y, Hazari S, et al: Etiopathogenesis of acute hepatic failure: eastern versus western countries. J Gastroenterol Hepatol. 2002;17(suppl 3):268. 3. Bernal W: Changing patterns of causation and the use of transplantation in the UK. Semin Liver Dis. 2003;23:227. 4. Lee WM: Etiologies of ALF. Semin Liver Dis. 2008;28:142. 5. Bernal W, Auzinger G, Sizer E, et al: Intensive care management of acute liver failure. Semin Liver Dis. 2008;28:188. 6. Schiodt FV, Lee WM: Liver transplantation for acute liver failure-better safe than sorry. Liver Transpl. 2002;8:1063. 7. O’Grady JG, Graeme JM, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989; 97:439. 8. Bernuau J, Goudeau A, Poynard T, et al: Multivariete analysis of prognostic factors in fulminant hepatitis B. Hepatology. 1986;6:648. 9. Yantorno SE, Kremers WK, Ruf AE, et al: MELD is superior to King’s College and Clichy’s Criteria to assess prognosis in fulminant hepatic failure. Liver Transpl. 2007;13:822. 10. Bernal W, Auzinger G, Dhawan A, et al: Acute liver failure. Lancet. 2010;376:190. 11. Pretagostini R, Peritore D, Di Ciaccio D, et al: Exchange of organs and patients with foreign nations during the first 15 months of activity of the Italian Gate to Europe. Transplant Proc. 2007;39: 1739. 12. Bindi ML, Biancofiore G, Esposito M, et al: Transcranial doppler sonography is useful for the decision making at the point of care in patients with acute hepatic failure: a single centre’s experience. Clin Monit Comput. 2008;22:449. 13. Urbani L, Mazzoni A, Bianco I, et al: The role of immunomodulation in ABO-incompatible adult liver transplant recipients. J Clin Apher. 2008;23:55. 14. Marudanayagam R, Shanmugam V, Gunson B, et al: Aetiology and outcome of acute liver failure. HPB Surg. 2009;11:429. 15. Rossaro L, Lee W: Acute liver failure: early referral is the key. Pract Gastroenterol 2004. 16. Organ Procurement and Transplantation Network. Liver Kaplan Meier waiting times for registrations listed: 1999 –2004. Available at: http://optn.transplant.hrsa.gov