LIVER TRANSPLANTATION 21:761–767, 2015
ORIGINAL ARTICLE
Liver Transplantation in Patients With End-Stage Liver Disease Requiring Intensive Care Unit Admission and Intubation Goldaracena,1 Vinzent Spetzler,1 Jan Knaak,1 Mark McVey,3 Fateh Bazerbachi,4 Nicolas 2 1 1 2 Nazia Selzner, Mark Cattral, Paul Greig, Les Lilly, Ian McGilvray,1 Gary Levy,2 Anand Ghanekar,1 Eberhard Renner,2 David Grant,1 Laura Hawryluck,3 and Markus Selzner1 1 Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Canada; 2 Multiorgan transplant program, Department of Medicine, Toronto General Hospital, Toronto, Canada; 3 Critical Care Medicine, Toronto General Hospital, Toronto, Canada; and 4Department of Medicine, University of Minnesota. Minneapolis, Minneapolis, MN
Data regarding transplantation outcomes in ventilated intensive care unit (ICU)–dependent patients with end-stage liver disease (ESLD) are conflicting. This single-center cohort study investigated the outcomes of patients with ESLD who were intubated with mechanical support before liver transplantation (LT). The ICU plus intubation group consisted of 42 patients with decompensated cirrhosis and mechanical ventilation before transplantation. LT was considered for intubated ICU patients if the fraction of inspired oxygen was 40% with a positive end-expiratory pressure 10, low pressor requirements, and the absence of an active infection. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and to 126 matched non–ICU-bound patients. Patients requiring ICU care with intubation and ICU care alone had more severe postoperative complications than non–ICU-bound patients. Intubation before transplantation was associated with more postoperative pneumonias (15% in intubated ICU transplant candidates, 5% in ICU-bound but not intubated patients, and 3% in control group patients; P 5 0.02). Parameters of reperfusion injury and renal function on postoperative day (POD) 2 and POD 7 were similar in all groups. Bilirubin levels were higher in the ICU plus intubation group at POD 2 and POD 7 after transplantation but were normalized in all groups within 3 months. The ICU plus intubation group versus the ICU-only group and the non-ICU group had decreased 1-, 3-, and 5-year graft survival (81% versus 84% versus 92%, 76% versus 78% versus 87%, and 71% versus 77% versus 84%, respectively; P 5 0.19), but statistical significance was not reached. A Glasgow coma scale score of 7 before transplantation was associated with high postoperative mortality in ICU-bound patients requiring intubation (38% versus 23%; P 5 0.01). In conclusion, ICU admission and mechanical ventilation should not be considered contraindications for LT. With careful patient selection, acceptable long-term outcomes can be achieved despite C 2015 AASLD. increased postoperative complications. Liver Transpl 21:761-767, 2015. V Received August 6, 2014; accepted January 27, 2015.
See Editorial on Page 716
Liver transplantation (LT) is the only potential cure for patients with end-stage liver disease (ESLD) or advanced hepatocellular cancer. The success of LT has increased the demand for this lifesaving
Abbreviations: ALD, alcoholic liver disease; ALT, alanine aminotransferase; APACHE, Acute Physiology and Chronic Health Evaluation; AST, aspartate aminotransferase; BMI, body mass index; CI, confidence interval; CNI, calcineurin inhibitors; ESLD, endstage liver disease; FiO2, fraction of inspired oxygen; GCS, Glasgow coma scale; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; ICU, intensive care unit; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PEEP, positive end-expiratory pressure; POD, postoperative day; PSC, primary sclerosing cholangitis; SD, standard deviation; SOFA, Sequential Organ Failure Assessment; VAP, ventilator-associated pneumonia. Potential conflict of interest: Nothing to report. Address reprint requests to Markus Selzner, M.D., Toronto General Hospital, NCSB 11C-1244, 585 University Avenue, Toronto, ON M5G2N2, Canada. Telephone: 1-416-340-5230; FAX: 1-416-340-5242; E-mail: [email protected] DOI 10.1002/lt.24115 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 2015 American Association for the Study of Liver Diseases. V
762 KNAAK ET AL.
procedure. As a result, the number of patients listed for LT far exceeds the number of available grafts, and 20% to 30% of patients waiting for LT will die on the waiting list or are delisted because of disease progression. The severe organ shortage has made donor livers a rare resource, and transplant physicians need to consider the likely outcome of each potential recipient to ensure reasonable utility for each donor liver. This has resulted in the development of strict listing criteria, and a projected 5-year patient survival of 50% is required by most centers to accept candidates on the LT waiting list.1,2 Mechanically ventilated patients with cirrhosis often progress to multiorgan failure, and their mortality in the absence of LT remains high.3-5 The effects of intensive care unit (ICU) hospitalization and, more specifically, mechanical ventilation on outcome and recovery following LT have not been well investigated.6 Because of the shortage of liver grafts, it is important to determine if ICU admission plus ventilation results in an adequate outcome after transplantation. We investigated short- and long-term outcomes as well as the risk factors predicting outcomes in ICUdependent, mechanically ventilated ESLD patients who underwent LT at our institution.
PATIENTS AND METHODS Study Design The study was approved by the research ethics board at the University of Toronto. Between January 2000 and January 2013, 1003 patients underwent deceased donor LT at the Toronto General Hospital (University of Toronto). Patients with acute liver failure were excluded from the study. LT was considered in ICU patients if the fraction of inspired oxygen (FiO2) was 40% with a positive end-expiratory pressure (PEEP) 10, low pressor requirements (levophed at 0.10 mg/kg/minute, vasopressin at 2.4 U/hour), and the absence of active infection. Forty-two patients with ESLD who were intubated in the ICU on the day of LT were identified. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and respiratory support; in addition, they were also compared to 126 non–ICU-bound control patients with cirrhosis who were matched according to the medical Model for End-Stage Liver Disease (MELD) status (63 MELD points), donor age (65 years), recipient age (65 years), hepatitis C virus (HCV) status, and presence of hepatocellular carcinoma (HCC).
Immunosuppression Protocol LT was performed with the standard techniques as previously described.7 The immunosuppression regimen consisted of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) and steroids for the first 3 months. Antimetabolite drugs were used in a CNI-sparing regimen when there was concern about CNI-induced neurotoxicity or nephrotoxicity and for candidates who were considered at high risk for rejection. In our protocol,
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steroids were tapered during the first 3 months after transplantation and were then stopped.
Recipient Data Recipient variables before transplantation were prospectively collected from our database and retrospectively analyzed for short- and long-term outcomes. Outcomes were measured by patient and graft survival, biochemical markers of graft reperfusion injury [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], and function (international normalized ratio and bilirubin). Renal function was assessed by serum creatinine and the requirement for dialysis in the first week after transplantation. All complications within the same hospitalization were recorded and graded according to the Clavien-Dindo score.8 ICU parameters were used to evaluate prognostic factors predicting a poor outcome. The Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE) score, Glasgow coma scale (GCS), MELD score, serum sodium concentration, FiO2 requirement before transplantation, and need for intravenous pressors at the time of the procedure were assessed in all intubated ICU patients.
Statistical Analysis Statistical analysis was performed with SPSS 20 (SPSS, Chicago, IL). Fisher’s exact test and an analysis of variance were used to compare categorical and continuous variables, respectively. The Mann-Whitney U test was performed for nonparametric continuous endpoints. Graft survival and patient survival were determined with the Kaplan-Meier method, and survival curves were compared with the log-rank test. A P value < 0.05 was considered statistically significant.
RESULTS Donor and Recipient Characteristics Three groups were compared in this study. First, 42 mechanically ventilated ICU patients with ESLD underwent LT at our institution between January 2000 and January 2013 (group 1). Second, 80 additional patients were identified who were in the ICU before transplantation with no need for intubation and respiratory support (group 2). Third, a matched-control group of 126 non– ICU-dependent patients were identified and matched to the ICU-bound patients (group 3; Table 1). When we compared patients under ICU care with intubation, patients under ICU care alone, and non-ICU patients, the matching parameters consisted of the MELD score, donor age, recipient age, and HCC (Table 1). In addition, no difference was observed between the 3 groups with respect to the cold ischemia time, donor body mass index (BMI), recipient BMI, or male sex. LT indications were similar between all groups and consisted of hepatitis B virus (HBV), HCV, primary sclerosing cholangitis (PSC), and alcoholic liver disease (ALD; Table 1).
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TABLE 1. Donor and Recipient Characteristics of the Patients Who Were ICU-Bound and Ventilated (Intubated), the Patients Who Were ICU-Bound and Not Ventilated, and the Non–ICU-Bound Control Group ICU Group, Intubated n 5 40
ICU Group, Not Intubated n 5 80
Control Group n 5 126
P Value
32 6 2 42 6 15 25 6 3 42 6 12 25 6 4 962
31 6 2 43 6 15 26 6 3 49 6 11 26 6 6 963
31 6 2 42 6 15 26 6 3 42 6 10 26 6 3 863
0.7 0.6 0.8 0.8 0.4 0.6
10 21 19 14 7
7 20 13 10 8
16 16 11 23 16
0.3 0.9 0.3 0.3 0.3
Parameter, mean 6 SD MELD score Donor age, years Donor BMI, kg/m2 Recipient age, years Recipient BMI, kg/m2 Cold ischemia time, hours LT indication, % HBV HCV PSC ALD HCC
The duration of intubation was 7 6 7 days in intubated ICU patients, whereas none of the nonintubated patients needed respiratory support. The length of ICU support before transplantation was significantly shorter in nonintubated transplant candidates versus intubated patients (7 6 7 versus 1 6 2 days; P < 0.001).
Short-Term Outcomes Following LT Estimated blood loss during surgery was comparable between ICU patients with intubation, patients with ICU care alone, and non–ICU-bound patients. Median posttransplant ICU stays were longer for the intubation group than the ICU-only group. Similarly, the
median lengths of hospital stays were longer for the ICU plus intubation group (Table 2). There was a trend toward higher postoperative complication rates in the ICU plus intubation group, although this did not reach statistical significance. Patients in both ICU groups had a higher severity of postoperative complications, as demonstrated by higher Clavien-Dindo scores, in comparison with the non-ICU group. In particular, pneumonia rates were higher after LT in the ICU plus intubation group (Table 2). Similarly, severe complications (Clavien-Dindo 3b or higher) were more frequent in the ICU intubated group and the ICU nonintubated group in comparison with the non–ICU-bound group. Additionally, there was a tendency toward higher 30-day postoperative mortality in
TABLE 2. Short-Term Outcomes After Transplantation
Estimated blood loss, mean 6 SD, cc Post-LT ICU stay, median (range), days Post-LT hospital stay, median (range), days Post-LT complications (%) Clavien-Dindo score, mean 6 SD, points Clavien-Dindo > 3b (%) Pneumonia within first 30 days (%) Rejection within first year (%) Relaparotomy within 30 days (%) 30-day mortality (%) Peak AST within 48 hours, mean 6 SD, U/L Peak ALT within 48 hours, mean 6 SD, U/L Creatinine and bilirubin levels, mean 6 SD, lmol/L Creatinine, POD 2 Creatinine, POD 7 Creatinine, 3 months Bilirubin, POD 2 Bilirubin, POD 7 Bilirubin, 3 months
ICU Group,
ICU Group, Not
Intubated
Intubated
4430 6 3057 7 (1-56) 39 (1-279) 55 2.9 6 1.3 35% 15 17 10 11 1257 6 1461 561 6 580 177 6 85 152 6 71 105 6 46 312 6 235 208 6 163 25 6 34
Control
P
Group Value
4530 6 4258 4689 6 5324 0.5 2 (1-55) 2 (1-61) 0.02 25 (1-210) 17 (1-239) 0.01 48 42 0.008 3.5 6 2.4 1.7 6 1.1 0.007 42% 13% 7 (38% versus 23%; P 5 0.01; P < 0.01, McNemar’s test). In addition, we performed a Cox regression analysis to determine the risk factors for poor long-term survival. The following parameters were included in the analysis: MELD score before transplantation, ICU admission before transplantation, intubation before transplantation, duration of intubation, donor age, recipient age, and low GCS score before transplantation. None of the parameters were significant in the Cox regression analysis. In particular, ICU admission before transplantation [hazard ratio (HR), 1.06; 95% confidence interval (CI), 0.91.09] and intubation plus ICU admission (HR, 1.91; 95% CI, 0.69-3.13) had no significant impact on survival.
DISCUSSION In this study, we demonstrate that patients with liver cirrhosis requiring ICU admission and intubation before transplantation had increased postoperative complications but achieved acceptable long-term graft and patient survival rates in comparison with ICU patients without intubation and a non–ICU-bound MELD-matched control group. The waiting-list mortality for LT increased from 11% in 2002 to 16% in 2011. Moreover, the proportion of candidates with MELD scores > 15 doubled between 2009 and 2011, and the number of candidates removed from the waiting list because of increased pretransplant morbidity also doubled within the same time period9,10; this indicates an overall higher demand for LT among sicker recipients. However, because of the well-recognized organ shortage, liver allocation requires careful consideration of the risks/ benefits to the recipients. Ideally, organs would be allocated to recipients who are expected to have a 5year survival rate of 50% or higher after LT.11 Therefore, it is important to identify patients who are considered too sick to undergo LT. Indeed, patients with decompensated ESLD requiring ICU admission and intubation compose a group considered critically ill and have been shown to have a poor prognosis without LT.5,12-14 The short-term outcomes of LT for nonintubated ICU patients were not different from the outcomes for matched non-ICU patients in a small study reported by Aggarwal et al.15 in 2001. The authors reported that an APACHE III score > 90, the use of
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Figure 1.
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(A) Patient survival after transplantation. (B) Graft survival after transplantation.
vasopressors, mechanical ventilation, and the presence of renal failure were all predictors of increased short-term mortality. Patient survival and graft survival at the 4-year follow-up were similar to the survival of patients who were ambulatory at the time of LT and to the survival of patients who were admitted to the ICU at any time during the hospitalization when they underwent LT. Historically, the mortality rate for patients with cirrhosis in the ICU was high and reached almost 100%. However, this high mortality was not attributable to ESLD per se but rather was due to the de facto perilousness of serious illness in critically ill intubated
patients because a similarly high mortality rate was also observed in intubated patients with other endstage organ failure such as idiopathic pulmonary fibrosis patients who had been admitted to the ICU and required mechanical ventilation.16-19 Kress et al.20 showed that the need for mechanical ventilation was a strong predictor of mortality in patients with liver cirrhosis. The authors studied 524 patients who were admitted to the ICU for decompensated ESLD, among whom 143 were not listed as “not sick enough”; 309 cases underwent listing for LT, and 215 were denied for listing because they had a contraindication, including active alcohol consumption or a
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diagnosed malignancy, or because they were considered “too sick for transplant.” Interestingly, patients who were listed for LT and had an upper gastrointestinal bleed showed a survival rate of 66%. In our study, ICU-dependent patients with intubation had increased posttransplant ICU and hospital stays and had more severe postoperative complications. This was reflected in a trend toward increased 1-year mortality in the intubated ICU group. The most common cause of death in the intubated ICU group in the first year was related to infectious complications, including 3 patients with pneumonia. In contrast, postoperative graft function was similar in all 3 groups. Although the 5-year graft survival rate of the patients in the ICU plus intubation group was decreased in comparison with the nonintubated ICU group or the non–ICU-dependent group (71% versus 77% versus 84%; P 5 0.19), it exceeded the currently endorsed survival cutoffs of 40% to 60% by a wide range. This indicates that with modern ICU treatment, posttransplant complications in the intubated ICU group can be decreased, and this can result in acceptable long-term outcomes. Patients with ESLD have an increased risk of prolonged intubation; this results in ventilator-associated pneumonia (VAP) and contributes to very high mortality.21 In adult LT recipients, Cheng et al.22 investigated a cohort of 50 patients who were intubated after LT. Patients who were intubated for more than 4 days had a higher rate of VAP and a higher mortality rate. Patients intubated with signs of VAP had a 30-day mortality rate of 32%. In the early period after transplantation, bilirubin, a measure of excretory and conjugative function of the graft, was slightly higher in the ICU plus intubation group. This difference disappeared 3 months after transplantation. Other hepatic and renal function markers were similar between the 3 groups 3 months after transplantation. This indicates that despite the poor prognosis of ESLD in patients who are mechanically ventilated and are critically ill, once they are listed and receive a graft, their short- and long-term outcomes could be comparable to those of less critical transplant recipients. In our series, SOFA scores, APACHE scores, requirements for vasopressors before transplantation, and hyponatremia were not predictors of postoperative outcomes. In a subgroup analysis of the intubated ICU patient group, the GCS scores were different between groups. A GCS score < 7 indicated significantly reduced overall survival in LT candidates. Patients suffering with a GCS score < 7 showed a 5-year patient survival rate of 69%. In contrast, normal conscious behavior correlated with a survival rate of 85%. Our study had several limitations, including the small sample size and retrospective nature. We aimed to correct these limitations by using a matchedcontrol study design. In addition, all our patients were derived from a single center with a homogeneous treatment protocol in a modern era of transplantation. In conclusion, LT for patients with ESLD requiring ICU care and intubation has an acceptable long-term
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outcome. The GCS is a readily available clinical tool that could assist in the prognostication of outcomes for these complex patients. Careful selection of transplantation candidates in this setting could provide adequate utilization of scarce organs in select patients who may demonstrate reasonable outcomes following transplantation.
REFERENCES 1. Brown RS Jr, Lake JR. The survival impact of liver transplantation in the MELD era, and the future for organ allocation and distribution. Am J Transplant 2005;5: 203-204. 2. Varma V, Mehta N, Kumaran V, Nundy S. Indications and contraindications for liver transplantation. Int J Hepatol 2011;2011:121862. 3. Goldfarb G, Nouel O, Poynard T, Rueff B. Efficiency of respiratory assistance in cirrhotic patients with liver failure. Intensive Care Med 1983;9:271-273. 4. Moreau R, Hadengue A, Soupison T, Kirstetter P, Mamzer MF, Vanjak D, et al. Septic shock in patients with cirrhosis: hemodynamic and metabolic characteristics and intensive care unit outcome. Crit Care Med 1992;20:746-750. 5. Lee KC, Chiang AA. The outcome of terminal liver cirrhosis patients requiring mechanical ventilation. Zhonghua Yi Xue Za Zhi (Taipei) 1997;59:88-94. 6. Findlay JY, Fix OK, Paugam-Burtz C, Liu L, Sood P, Tomlanovich SJ, Emond J. Critical care of the end-stage liver disease patient awaiting liver transplantation. Liver Transpl 2011;17:496-510. 7. Llad o L, Figueras J. Techniques of orthotopic liver transplantation. HPB (Oxford) 2004;6:69-75. 8. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187-196. 9. Sibulesky L, Heckman MG, Taner CB, Canabal JM, Diehl NN, Perry DK, et al. Outcomes following liver transplantation in intensive care unit patients. World J Hepatol 2013;5:26-32. 10. Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients. OPTN & SRTR 2011 annual report. http://srtr.transplant.hrsa.gov/ annual_reports/2011/pdf/03_%20liver_12.pdf. Accessed August 18, 2013. 11. Olthoff KM, Brown RS Jr, Delmonico FL, Freeman RB, McDiarmid SV, Merion RM, et al. Summary report of a national conference: evolving concepts in liver allocation in the MELD and PELD era. December 8, 2003, Washington, DC, USA. Liver Transpl 2004;10(suppl 2):A6-A22. 12. Zimmerman JE, Wagner DP, Seneff MG, Becker RB, Sun X, Knaus WA. Intensive care unit admissions with cirrhosis: risk-stratifying patient groups and predicting individual survival. Hepatology 1996;23:1393-1401. 13. Rabe C, Schmitz V, Paashaus M, Musch A, Zickermann H, Dumoulin FL, et al. Does intubation really equal death in cirrhotic patients? Factors influencing outcome in patients with liver cirrhosis requiring mechanical ventilation. Intensive Care Med 2004;30:1564-1571. 14. Cholongitas E, Senzolo M, Patch D, Kwong K, Nikolopoulou V, Leandro G, et al. Risk factors, sequential organ failure assessment and Model for End-Stage Liver Disease scores for predicting short term mortality in cirrhotic patients admitted to intensive care unit. Aliment Pharmacol Ther 2006;23:883-893.
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15. Aggarwal A, Ong JP, Younossi ZM, Nelson DR, HoffmanHogg L, Arroliga AC. Predictors of mortality and resource utilization in cirrhotic patients admitted to the medical ICU. Chest 2001;119:1489-1497. 16. Blivet S, Philit F, Sab JM, Langevin B, Paret M, Gu erin C, Robert D. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest 2001;120:209-212. 17. Fumeaux T, Rothmeier C, Jolliet P. Outcome of mechanical ventilation for acute respiratory failure in patients with pulmonary fibrosis. Intensive Care Med 2001;27:1868-1874. 18. Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 2002;166:839-842. 19. Stern JB, Mal H, Groussard O, Brugie`re O, Marceau A, Jebrak G, Fournier M. Prognosis of patients with
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advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure. Chest 2001;120:213-219. 20. Kress JP, Rubin A, Pohlman AS, Hall JB. Outcomes of critically ill patients denied consideration for liver transplantation. Am J Respir Crit Care Med 2000;162(pt 1):418-423. 21. Viasus D, Garcia-Vidal C, Castellote J, Adamuz J, Verdaguer R, Dorca J, et al. Community-acquired pneumonia in patients with liver cirrhosis: clinical features, outcomes, and usefulness of severity scores. Medicine (Baltimore) 2011;90:110-118. 22. Cheng CH, Lee CF, Soong RS, Wu TH, Chan KM, Chou HS, et al. Risk factors and clinical outcomes of ventilatorassociated pneumonia in patients on the liver transplant waiting list. Transplant Proc 2012;44:762-764.
ORIGINAL ARTICLE
Liver Transplantation in Patients With End-Stage Liver Disease Requiring Intensive Care Unit Admission and Intubation Goldaracena,1 Vinzent Spetzler,1 Jan Knaak,1 Mark McVey,3 Fateh Bazerbachi,4 Nicolas 2 1 1 2 Nazia Selzner, Mark Cattral, Paul Greig, Les Lilly, Ian McGilvray,1 Gary Levy,2 Anand Ghanekar,1 Eberhard Renner,2 David Grant,1 Laura Hawryluck,3 and Markus Selzner1 1 Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Canada; 2 Multiorgan transplant program, Department of Medicine, Toronto General Hospital, Toronto, Canada; 3 Critical Care Medicine, Toronto General Hospital, Toronto, Canada; and 4Department of Medicine, University of Minnesota. Minneapolis, Minneapolis, MN
Data regarding transplantation outcomes in ventilated intensive care unit (ICU)–dependent patients with end-stage liver disease (ESLD) are conflicting. This single-center cohort study investigated the outcomes of patients with ESLD who were intubated with mechanical support before liver transplantation (LT). The ICU plus intubation group consisted of 42 patients with decompensated cirrhosis and mechanical ventilation before transplantation. LT was considered for intubated ICU patients if the fraction of inspired oxygen was 40% with a positive end-expiratory pressure 10, low pressor requirements, and the absence of an active infection. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and to 126 matched non–ICU-bound patients. Patients requiring ICU care with intubation and ICU care alone had more severe postoperative complications than non–ICU-bound patients. Intubation before transplantation was associated with more postoperative pneumonias (15% in intubated ICU transplant candidates, 5% in ICU-bound but not intubated patients, and 3% in control group patients; P 5 0.02). Parameters of reperfusion injury and renal function on postoperative day (POD) 2 and POD 7 were similar in all groups. Bilirubin levels were higher in the ICU plus intubation group at POD 2 and POD 7 after transplantation but were normalized in all groups within 3 months. The ICU plus intubation group versus the ICU-only group and the non-ICU group had decreased 1-, 3-, and 5-year graft survival (81% versus 84% versus 92%, 76% versus 78% versus 87%, and 71% versus 77% versus 84%, respectively; P 5 0.19), but statistical significance was not reached. A Glasgow coma scale score of 7 before transplantation was associated with high postoperative mortality in ICU-bound patients requiring intubation (38% versus 23%; P 5 0.01). In conclusion, ICU admission and mechanical ventilation should not be considered contraindications for LT. With careful patient selection, acceptable long-term outcomes can be achieved despite C 2015 AASLD. increased postoperative complications. Liver Transpl 21:761-767, 2015. V Received August 6, 2014; accepted January 27, 2015.
See Editorial on Page 716
Liver transplantation (LT) is the only potential cure for patients with end-stage liver disease (ESLD) or advanced hepatocellular cancer. The success of LT has increased the demand for this lifesaving
Abbreviations: ALD, alcoholic liver disease; ALT, alanine aminotransferase; APACHE, Acute Physiology and Chronic Health Evaluation; AST, aspartate aminotransferase; BMI, body mass index; CI, confidence interval; CNI, calcineurin inhibitors; ESLD, endstage liver disease; FiO2, fraction of inspired oxygen; GCS, Glasgow coma scale; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; ICU, intensive care unit; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PEEP, positive end-expiratory pressure; POD, postoperative day; PSC, primary sclerosing cholangitis; SD, standard deviation; SOFA, Sequential Organ Failure Assessment; VAP, ventilator-associated pneumonia. Potential conflict of interest: Nothing to report. Address reprint requests to Markus Selzner, M.D., Toronto General Hospital, NCSB 11C-1244, 585 University Avenue, Toronto, ON M5G2N2, Canada. Telephone: 1-416-340-5230; FAX: 1-416-340-5242; E-mail: [email protected] DOI 10.1002/lt.24115 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 2015 American Association for the Study of Liver Diseases. V
762 KNAAK ET AL.
procedure. As a result, the number of patients listed for LT far exceeds the number of available grafts, and 20% to 30% of patients waiting for LT will die on the waiting list or are delisted because of disease progression. The severe organ shortage has made donor livers a rare resource, and transplant physicians need to consider the likely outcome of each potential recipient to ensure reasonable utility for each donor liver. This has resulted in the development of strict listing criteria, and a projected 5-year patient survival of 50% is required by most centers to accept candidates on the LT waiting list.1,2 Mechanically ventilated patients with cirrhosis often progress to multiorgan failure, and their mortality in the absence of LT remains high.3-5 The effects of intensive care unit (ICU) hospitalization and, more specifically, mechanical ventilation on outcome and recovery following LT have not been well investigated.6 Because of the shortage of liver grafts, it is important to determine if ICU admission plus ventilation results in an adequate outcome after transplantation. We investigated short- and long-term outcomes as well as the risk factors predicting outcomes in ICUdependent, mechanically ventilated ESLD patients who underwent LT at our institution.
PATIENTS AND METHODS Study Design The study was approved by the research ethics board at the University of Toronto. Between January 2000 and January 2013, 1003 patients underwent deceased donor LT at the Toronto General Hospital (University of Toronto). Patients with acute liver failure were excluded from the study. LT was considered in ICU patients if the fraction of inspired oxygen (FiO2) was 40% with a positive end-expiratory pressure (PEEP) 10, low pressor requirements (levophed at 0.10 mg/kg/minute, vasopressin at 2.4 U/hour), and the absence of active infection. Forty-two patients with ESLD who were intubated in the ICU on the day of LT were identified. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and respiratory support; in addition, they were also compared to 126 non–ICU-bound control patients with cirrhosis who were matched according to the medical Model for End-Stage Liver Disease (MELD) status (63 MELD points), donor age (65 years), recipient age (65 years), hepatitis C virus (HCV) status, and presence of hepatocellular carcinoma (HCC).
Immunosuppression Protocol LT was performed with the standard techniques as previously described.7 The immunosuppression regimen consisted of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) and steroids for the first 3 months. Antimetabolite drugs were used in a CNI-sparing regimen when there was concern about CNI-induced neurotoxicity or nephrotoxicity and for candidates who were considered at high risk for rejection. In our protocol,
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steroids were tapered during the first 3 months after transplantation and were then stopped.
Recipient Data Recipient variables before transplantation were prospectively collected from our database and retrospectively analyzed for short- and long-term outcomes. Outcomes were measured by patient and graft survival, biochemical markers of graft reperfusion injury [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], and function (international normalized ratio and bilirubin). Renal function was assessed by serum creatinine and the requirement for dialysis in the first week after transplantation. All complications within the same hospitalization were recorded and graded according to the Clavien-Dindo score.8 ICU parameters were used to evaluate prognostic factors predicting a poor outcome. The Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE) score, Glasgow coma scale (GCS), MELD score, serum sodium concentration, FiO2 requirement before transplantation, and need for intravenous pressors at the time of the procedure were assessed in all intubated ICU patients.
Statistical Analysis Statistical analysis was performed with SPSS 20 (SPSS, Chicago, IL). Fisher’s exact test and an analysis of variance were used to compare categorical and continuous variables, respectively. The Mann-Whitney U test was performed for nonparametric continuous endpoints. Graft survival and patient survival were determined with the Kaplan-Meier method, and survival curves were compared with the log-rank test. A P value < 0.05 was considered statistically significant.
RESULTS Donor and Recipient Characteristics Three groups were compared in this study. First, 42 mechanically ventilated ICU patients with ESLD underwent LT at our institution between January 2000 and January 2013 (group 1). Second, 80 additional patients were identified who were in the ICU before transplantation with no need for intubation and respiratory support (group 2). Third, a matched-control group of 126 non– ICU-dependent patients were identified and matched to the ICU-bound patients (group 3; Table 1). When we compared patients under ICU care with intubation, patients under ICU care alone, and non-ICU patients, the matching parameters consisted of the MELD score, donor age, recipient age, and HCC (Table 1). In addition, no difference was observed between the 3 groups with respect to the cold ischemia time, donor body mass index (BMI), recipient BMI, or male sex. LT indications were similar between all groups and consisted of hepatitis B virus (HBV), HCV, primary sclerosing cholangitis (PSC), and alcoholic liver disease (ALD; Table 1).
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TABLE 1. Donor and Recipient Characteristics of the Patients Who Were ICU-Bound and Ventilated (Intubated), the Patients Who Were ICU-Bound and Not Ventilated, and the Non–ICU-Bound Control Group ICU Group, Intubated n 5 40
ICU Group, Not Intubated n 5 80
Control Group n 5 126
P Value
32 6 2 42 6 15 25 6 3 42 6 12 25 6 4 962
31 6 2 43 6 15 26 6 3 49 6 11 26 6 6 963
31 6 2 42 6 15 26 6 3 42 6 10 26 6 3 863
0.7 0.6 0.8 0.8 0.4 0.6
10 21 19 14 7
7 20 13 10 8
16 16 11 23 16
0.3 0.9 0.3 0.3 0.3
Parameter, mean 6 SD MELD score Donor age, years Donor BMI, kg/m2 Recipient age, years Recipient BMI, kg/m2 Cold ischemia time, hours LT indication, % HBV HCV PSC ALD HCC
The duration of intubation was 7 6 7 days in intubated ICU patients, whereas none of the nonintubated patients needed respiratory support. The length of ICU support before transplantation was significantly shorter in nonintubated transplant candidates versus intubated patients (7 6 7 versus 1 6 2 days; P < 0.001).
Short-Term Outcomes Following LT Estimated blood loss during surgery was comparable between ICU patients with intubation, patients with ICU care alone, and non–ICU-bound patients. Median posttransplant ICU stays were longer for the intubation group than the ICU-only group. Similarly, the
median lengths of hospital stays were longer for the ICU plus intubation group (Table 2). There was a trend toward higher postoperative complication rates in the ICU plus intubation group, although this did not reach statistical significance. Patients in both ICU groups had a higher severity of postoperative complications, as demonstrated by higher Clavien-Dindo scores, in comparison with the non-ICU group. In particular, pneumonia rates were higher after LT in the ICU plus intubation group (Table 2). Similarly, severe complications (Clavien-Dindo 3b or higher) were more frequent in the ICU intubated group and the ICU nonintubated group in comparison with the non–ICU-bound group. Additionally, there was a tendency toward higher 30-day postoperative mortality in
TABLE 2. Short-Term Outcomes After Transplantation
Estimated blood loss, mean 6 SD, cc Post-LT ICU stay, median (range), days Post-LT hospital stay, median (range), days Post-LT complications (%) Clavien-Dindo score, mean 6 SD, points Clavien-Dindo > 3b (%) Pneumonia within first 30 days (%) Rejection within first year (%) Relaparotomy within 30 days (%) 30-day mortality (%) Peak AST within 48 hours, mean 6 SD, U/L Peak ALT within 48 hours, mean 6 SD, U/L Creatinine and bilirubin levels, mean 6 SD, lmol/L Creatinine, POD 2 Creatinine, POD 7 Creatinine, 3 months Bilirubin, POD 2 Bilirubin, POD 7 Bilirubin, 3 months
ICU Group,
ICU Group, Not
Intubated
Intubated
4430 6 3057 7 (1-56) 39 (1-279) 55 2.9 6 1.3 35% 15 17 10 11 1257 6 1461 561 6 580 177 6 85 152 6 71 105 6 46 312 6 235 208 6 163 25 6 34
Control
P
Group Value
4530 6 4258 4689 6 5324 0.5 2 (1-55) 2 (1-61) 0.02 25 (1-210) 17 (1-239) 0.01 48 42 0.008 3.5 6 2.4 1.7 6 1.1 0.007 42% 13% 7 (38% versus 23%; P 5 0.01; P < 0.01, McNemar’s test). In addition, we performed a Cox regression analysis to determine the risk factors for poor long-term survival. The following parameters were included in the analysis: MELD score before transplantation, ICU admission before transplantation, intubation before transplantation, duration of intubation, donor age, recipient age, and low GCS score before transplantation. None of the parameters were significant in the Cox regression analysis. In particular, ICU admission before transplantation [hazard ratio (HR), 1.06; 95% confidence interval (CI), 0.91.09] and intubation plus ICU admission (HR, 1.91; 95% CI, 0.69-3.13) had no significant impact on survival.
DISCUSSION In this study, we demonstrate that patients with liver cirrhosis requiring ICU admission and intubation before transplantation had increased postoperative complications but achieved acceptable long-term graft and patient survival rates in comparison with ICU patients without intubation and a non–ICU-bound MELD-matched control group. The waiting-list mortality for LT increased from 11% in 2002 to 16% in 2011. Moreover, the proportion of candidates with MELD scores > 15 doubled between 2009 and 2011, and the number of candidates removed from the waiting list because of increased pretransplant morbidity also doubled within the same time period9,10; this indicates an overall higher demand for LT among sicker recipients. However, because of the well-recognized organ shortage, liver allocation requires careful consideration of the risks/ benefits to the recipients. Ideally, organs would be allocated to recipients who are expected to have a 5year survival rate of 50% or higher after LT.11 Therefore, it is important to identify patients who are considered too sick to undergo LT. Indeed, patients with decompensated ESLD requiring ICU admission and intubation compose a group considered critically ill and have been shown to have a poor prognosis without LT.5,12-14 The short-term outcomes of LT for nonintubated ICU patients were not different from the outcomes for matched non-ICU patients in a small study reported by Aggarwal et al.15 in 2001. The authors reported that an APACHE III score > 90, the use of
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Figure 1.
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(A) Patient survival after transplantation. (B) Graft survival after transplantation.
vasopressors, mechanical ventilation, and the presence of renal failure were all predictors of increased short-term mortality. Patient survival and graft survival at the 4-year follow-up were similar to the survival of patients who were ambulatory at the time of LT and to the survival of patients who were admitted to the ICU at any time during the hospitalization when they underwent LT. Historically, the mortality rate for patients with cirrhosis in the ICU was high and reached almost 100%. However, this high mortality was not attributable to ESLD per se but rather was due to the de facto perilousness of serious illness in critically ill intubated
patients because a similarly high mortality rate was also observed in intubated patients with other endstage organ failure such as idiopathic pulmonary fibrosis patients who had been admitted to the ICU and required mechanical ventilation.16-19 Kress et al.20 showed that the need for mechanical ventilation was a strong predictor of mortality in patients with liver cirrhosis. The authors studied 524 patients who were admitted to the ICU for decompensated ESLD, among whom 143 were not listed as “not sick enough”; 309 cases underwent listing for LT, and 215 were denied for listing because they had a contraindication, including active alcohol consumption or a
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diagnosed malignancy, or because they were considered “too sick for transplant.” Interestingly, patients who were listed for LT and had an upper gastrointestinal bleed showed a survival rate of 66%. In our study, ICU-dependent patients with intubation had increased posttransplant ICU and hospital stays and had more severe postoperative complications. This was reflected in a trend toward increased 1-year mortality in the intubated ICU group. The most common cause of death in the intubated ICU group in the first year was related to infectious complications, including 3 patients with pneumonia. In contrast, postoperative graft function was similar in all 3 groups. Although the 5-year graft survival rate of the patients in the ICU plus intubation group was decreased in comparison with the nonintubated ICU group or the non–ICU-dependent group (71% versus 77% versus 84%; P 5 0.19), it exceeded the currently endorsed survival cutoffs of 40% to 60% by a wide range. This indicates that with modern ICU treatment, posttransplant complications in the intubated ICU group can be decreased, and this can result in acceptable long-term outcomes. Patients with ESLD have an increased risk of prolonged intubation; this results in ventilator-associated pneumonia (VAP) and contributes to very high mortality.21 In adult LT recipients, Cheng et al.22 investigated a cohort of 50 patients who were intubated after LT. Patients who were intubated for more than 4 days had a higher rate of VAP and a higher mortality rate. Patients intubated with signs of VAP had a 30-day mortality rate of 32%. In the early period after transplantation, bilirubin, a measure of excretory and conjugative function of the graft, was slightly higher in the ICU plus intubation group. This difference disappeared 3 months after transplantation. Other hepatic and renal function markers were similar between the 3 groups 3 months after transplantation. This indicates that despite the poor prognosis of ESLD in patients who are mechanically ventilated and are critically ill, once they are listed and receive a graft, their short- and long-term outcomes could be comparable to those of less critical transplant recipients. In our series, SOFA scores, APACHE scores, requirements for vasopressors before transplantation, and hyponatremia were not predictors of postoperative outcomes. In a subgroup analysis of the intubated ICU patient group, the GCS scores were different between groups. A GCS score < 7 indicated significantly reduced overall survival in LT candidates. Patients suffering with a GCS score < 7 showed a 5-year patient survival rate of 69%. In contrast, normal conscious behavior correlated with a survival rate of 85%. Our study had several limitations, including the small sample size and retrospective nature. We aimed to correct these limitations by using a matchedcontrol study design. In addition, all our patients were derived from a single center with a homogeneous treatment protocol in a modern era of transplantation. In conclusion, LT for patients with ESLD requiring ICU care and intubation has an acceptable long-term
LIVER TRANSPLANTATION, June 2015
outcome. The GCS is a readily available clinical tool that could assist in the prognostication of outcomes for these complex patients. Careful selection of transplantation candidates in this setting could provide adequate utilization of scarce organs in select patients who may demonstrate reasonable outcomes following transplantation.
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15. Aggarwal A, Ong JP, Younossi ZM, Nelson DR, HoffmanHogg L, Arroliga AC. Predictors of mortality and resource utilization in cirrhotic patients admitted to the medical ICU. Chest 2001;119:1489-1497. 16. Blivet S, Philit F, Sab JM, Langevin B, Paret M, Gu erin C, Robert D. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest 2001;120:209-212. 17. Fumeaux T, Rothmeier C, Jolliet P. Outcome of mechanical ventilation for acute respiratory failure in patients with pulmonary fibrosis. Intensive Care Med 2001;27:1868-1874. 18. Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 2002;166:839-842. 19. Stern JB, Mal H, Groussard O, Brugie`re O, Marceau A, Jebrak G, Fournier M. Prognosis of patients with
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