- Email: [email protected]
Impact of Postoperative Liver Dysfunction on Survival After Left Ventricular Assist Device Implantation
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Impact of Postoperative Liver Dysfunction on Survival After Left Ventricular Assist Device Implantation Kaustav Majumder, MBBS, John R. Spratt, MD, MA, Christopher T. Holley, MD, Samit S. Roy, MSPH, Rebecca J. Cogswell, MD, Kenneth Liao, MD, and Ranjit John, MD Department of Surgery, University of Minnesota, Minneapolis, Minnesota; Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; and Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
Background. Liver dysfunction in left ventricular assist device (LVAD) recipients is common both before and after implantation. Postoperative liver dysfunction (PLD) develops in some LVAD recipients without preoperative liver dysfunction. The aim of this study was to assess clinical outcomes in such patients. Methods. Records of all patients undergoing implantation of a HeartMate II (HM II, St. Jude Medical, Inc, Minneapolis, MN) LVAD at a single center at the University of Minnesota from January 2005 through June 2014 were analyzed. PLD was defined by hypertransaminasemia or hyperbilirubinemia, or both, during the hospitalization for LVAD implantation. Results. During the study period, 284 patients underwent HM II implantation. Excluded from analysis were 14 recipients with preoperative liver dysfunction. In the final cohort (n [ 270), there were no major difference in preoperative characteristics among those patients with versus without PLD. PLD developed in 129 (47.8%) recipients: 16 (12.4%) had isolated hypertransaminasemia (group I),
76 (58.9%) had isolated hyperbilirubinemia (group II), and 37 (28.7%) had combined hypertransaminasemia and hyperbilirubinemia (group III). Group III LVAD recipients had significantly greater rates of 30-day, 90-day, and 1-year mortality, along with significantly higher transfusion requirements and higher rates of renal replacement therapy, prolonged ventilation, and vasopressor use. Moreover, their mortality risk was significantly higher than that of PLD-free LVAD recipients (hazard ratio, 4.6; 95% confidence interval, 2.1 to 10.1; p < 0.001). Conclusions. Isolated hyperbilirubinemia is common after LVAD implantation. In this study, it was not associated with an increase in early or midterm postoperative mortality. However, postoperative combined transaminasemia and hyperbilirubinemia was associated with a significant increase in early and midterm morbidity and mortality. Further research into the pathogenesis of post-LVAD PLD is necessary.
H
Postoperative liver dysfunction (PLD) is associated with increased in-hospital mortality rates after cardiac surgical procedures, including LVAD implantation [6–15]. Heart failure–related liver dysfunction has been attributed to hepatocellular ischemia resulting from poor antegrade perfusion and to passive venous congestion secondary to right ventricular dysfunction [16, 17]. PLD after LVAD implantation has been attributed to perioperative hemodynamic changes and preexisting liver dysfunction [18]. The negative postoperative effects of preoperative liver dysfunction in LVAD recipients have been reported, but the impact of isolated PLD is poorly characterized [5, 14, 18–23]. The aims of this study were use a large, single-center cohort to characterize the incidence and forms of PLD and to determine the relationship of PLD with major morbidity and mortality after LVAD
eart failure is a significant public health concern [1]. Left ventricular assist devices (LVADs) have become important components of heart failure management, both as a bridge to transplantation (BTT) and as destination therapy (DT), and they are associated with improved quality of life [2–4]. Continuous-flow LVADs (CF-LVADs), such as the HeartMate II (HM II, St. Jude Medical, Inc, Minneapolis, MN) and HeartWare HVAD (HeartWare, Framingham, MA), have greater durability and a more favorable complication profile than earlier pulsatile-flow devices [4]. However, device-related complications, including stroke, gastrointestinal bleeding, infection, and end-organ dysfunction, remain common [5]. Accepted for publication April 18, 2017.
(Ann Thorac Surg 2017;104:1556–63) Ó 2017 by The Society of Thoracic Surgeons
Presented at the Thirty-fifth Annual Meeting of the International Society for Heart and Lung Transplantation, Nice, France, April 15, 2015. Address correspondence to Dr John, Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota Medical School, Mayo Mail Code 207, 420 Delaware St SE, Minneapolis, MN 55455; email: [email protected].
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
Drs Cogswell and John disclose a financial relationship with St Jude Medical and Medtronic.
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2017.04.048
MAJUMDER ET AL LIVER DYSFUNCTION AFTER LVAD IMPLANTATION
Abbreviations and Acronyms BTT CABG CF HM II INTERMACS
= = = = =
LVAD MELD PLD POD RRT
= = = = =
bridge to transplantation coronary artery bypass grafting continuous-flow HeartMate II Interagency Registry for Mechanically Assisted Circulatory Support left ventricular assist device Model for End-stage Liver Disease postoperative liver dysfunction postoperative day renal replacement therapy
implantation, specifically common postoperative complications, survival, and rates of cardiac transplantation.
Patients and Methods In this retrospective study, all patients who underwent HM II implantation from January 1, 2005, through June 30, 2014 were identified in the University of Minnesota LVAD database. This analysis was approved by the local Institutional Review Board (IRB #1403M48521).
Patient Care, Device Management, and Anticoagulation Patients received standard heart failure care, including antiarrhythmic therapy, before and after LVAD implantation. Pump speed is optimized to provide adequate cardiac output and optimal left ventricular decompression while maintaining a good pulsatility index greater than 3.5 to 4.0 and intermittent aortic valve opening. Anticoagulation consisted of oral aspirin and warfarin with a low-dose heparin bridge, usually starting on postoperative days (POD) 1 to 2.
Clinical Outcomes Demographics, clinical characteristics, and outcomes data were evaluated in each of the HM II recipients in this cohort. Preoperative liver dysfunction and PLD were both defined as serum levels of aspartate transferase or alanine transferase greater than five times the upper limit of normal (normal range for aspartate transferase, 0 to 45 U/L; for alanine transferase, 0 to 50 U/L) or total serum bilirubin of 5 mg/dL or higher between LVAD implantation and hospital discharge. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria were used to define other postoperative complications [24]. Baseline characteristics, including documented cirrhosis, chronic hepatitis, and a history of heavy alcohol use (considered surrogates for subclinical liver disease), were assessed to determine risk factors for development of PLD. Survival data were evaluated in all recipients.
Statistical Analysis For between-group comparisons, two-sample Student’s t testing was used for normally distributed continuous
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variables, and the Wilcoxon rank-sum test was used for other continuous variables. For categorical variables, c2 testing was used. Univariable and multivariable logistic regression was used to determine predictors of PLD. Survival analysis was performed using the Kaplan-Meier method, and log-rank testing was used to compare and assess unadjusted all-cause mortality rates for PLD versus non-PLD recipients, as well as PLD subgroup analyses. For all analyses, Stata release 13 (StataCorp LP, College Station, TX) was used, and a two-tailed p < 0.05 was considered significant.
Results Baseline Characteristics and Incidence of Postoperative Liver Dysfunction During the 9.5-year study period, 284 patients underwent HM II implantation (547 person-years of total follow-up). Excluded from analysis were 14 HM II recipients with preoperative liver dysfunction. The baseline characteristics of the final cohort of 270 HM II recipients are shown in Table 1. The mean age at implantation was 57 14 years, 219 (81.1%) of the patients were male, and 208 (77%) recipients were considered as having BTT therapy at implantation. Rates of potential subclinical liver disease did not differ between patients with PLD and those without it. Of the 270 HM II recipients, PLD developed in 129 (47.8%): 16 (12.4%) had isolated hypertransaminasemia (group I), 76 (58.9%) had isolated hyperbilirubinemia (group II), and 37 (28.7%) had combined hypertransaminasemia and hyperbilirubinemia (group III).
Preoperative Risk Factors and Postoperative Complications Between patients with PLD and those without it, baseline demographic characteristics did not significantly differ in terms of age, sex, BTT versus destination therapy, comorbidities, past tobacco use, or prior interventions. Patients with group III PLD were more likely to have a lower preoperative serum albumin level (p ¼ 0.001) and a lower INTERMACS profile (p ¼ 0.044) (Table 1). Postoperatively, the need for renal replacement therapy (RRT), prolonged (>7 days) ventilation, prolonged vasopressor use, increased early (POD 0 to 1) and late (POD >2) transfusion requirements, and increased inpatient length of stay were all associated with PLD generally (p < 0.001 for all) and with group III PLD specifically (Tables 2 and 3). Serum albumin was significantly associated with any PLD and group III PLD on univariate and multivariable logistic regression, and levels were higher in recipients with minor (group I or II) or no PLD (Table 4). Postoperatively, RRT, prolonged ventilation and vasopressor use, and increased transfusion requirements were significantly associated with PLD on univariate analysis, but only elevated early transfusion requirements proved significant on multivariate analysis (odds ratio, 1.10; 95% confidence interval, 1.03 to 1.17; p ¼ 0.004). Examining
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Table 1. Baseline Demographics of Patients Undergoing HeartMate II Implantation Between 2005 and 2014 (n ¼ 270) Variable, n (%) Age, years Males BTT Preoperative albumin, mg/dL Hypertension Diabetes mellitus Chronic kidney disease Coronary artery disease Current tobacco use Past tobacco use Prior CT surgery History of MI Prior CABG Prior PCI INTERMACS [IQR] Cirrhosis Chronic hepatitis Prior heavy alcohol use a
No PLD (n ¼ 141)
Any PLD (n ¼ 129)
Group I (n ¼ 16)
Group II (n ¼ 76)
Group III (n ¼ 37)
p Valuea
56.5 14.3 115 (82.1) 112 (79.4) 3.56 0.53 65 (46.1) 54 (38.3) 46 (32.6) 88 (62.4) 40 (29.2) 46 (34.1) 2 (4.2) 64 (45.7) 39 (27.7) 42 (30.0) 4 [3, 5] 4 (2.8) 1 (0.7) 19 (13.5)
57.4 14.2 104 (81.3) 96 (74.4) 3.34 0.65 48 (37.8) 45 (35.4) 50 (39.4) 80 (63.0) 38 (30.7) 48 (39.0) 1 (1.6) 47 (37.0) 46 (36.2) 27 (21.3) 4 [2, 5] 6 (4.7) 1 (0.8) 17 (13.2)
55.1 10.1 9 (56.3) 14 (87.5) 3.58 0.77 5 (31.3) 7 (43.8) 6 (37.5) 8 (50.0) 9 (60.0) 4 (26.7) 0 5 (31.3) 5 (31.3) 2 (12.5) 5 [3, 6] 2 (12.5) 0 0
58.9 13.9 65 (85.5) 56 (73.7) 3.39 0.61 28 (37.3) 23 (30.7) 34 (45.3) 46 (61.3) 20 (27.4) 30 (41.7) 0 29 (38.7) 24 (32.0) 19 (25.3) 4 [2, 5] 2 (2.6) 0 10 (13.2)
55.2 16.1 30 (83.3) 26 (70.3) 3.15 0.64 15 (41.7) 15 (41.7) 10 (27.8) 26 (72.2) 9 (25.0) 14 (38.9) 1 (4.8) 13 (36.1) 17 (47.2) 6 (16.7) 3 [2, 4] 2 (5.4) 1 (2.7) 7 (18.9)
0.49 0.051 0.43 0.001 0.51 0.56 0.2 0.46 0.067 0.62 0.61 0.5 0.17 0.25 0.044 0.18 0.43 0.33
p values refer to comparison of “No PLD” and groups I to III.
Statistically significant values are listed in bold. BTT ¼ bridge to transplantation; CABG ¼ coronary artery bypass graft; Mechanically Assisted Circulatory Support; IQR ¼ interquartile range; vention; PLD ¼ postoperative liver dysfunction.
group III PLD separately, prior coronary artery bypass grafting, serum albumin, and INTERMACS score were found to be significant preoperative predictors on univariate and multivariable logistic analysis (p ¼ 0.051 for INTERMACS). The postoperative outcomes associated with group III PLD were similar to those of PLD of any kind (Table 5).
Survival Of the 270 HM II recipients, 94 died during the follow-up period. The overall survival rate was 94% at 30 days, 89% at 90 days, and 77% at 1 year after implantation. Postoperative survival in patients with (vs without) PLD was
CT ¼ cardiothoracic; INTERMACS ¼ Interagency Registry for MI ¼ myocardial infarction; PCI ¼ percutaneous coronary inter-
worse at 30 days (88% vs 99%), at 90 days (82% vs 90%), and at 1 year (71% vs 82%). The survival rate at each of those intervals in groups I and II was similar and did not significantly differ from the survival rate in HM II recipients without PLD (p > 0.05). However, group III (combined hypertransaminasemia and hyperbilirubinemia) had a significantly decreased survival rate at 30 days (65%), 90 days (42%), and 1 year (39%) (p < 0.0001 vs groups I and II) (Fig 1). Logistic regression adjusted for age, sex, hypertension, diabetes mellitus, chronic kidney disease, coronary artery disease, past or current tobacco use, prior myocardial infarction, prior coronary artery bypass grafting,
Table 2. Postoperative Complications Among All Patients Who Underwent HeartMate II Implantation Variable Arrhythmias, n (%) Stroke, n (%) Gastrointestinal bleeding, n (%) Renal replacement therapy, n (%) Prolonged ventilation, n (%) Pneumonia, n (%) Prolonged vasopressor use, n (%) #PRBC units transfused, POD 0–1 (median [IQR]) #PRBC units transfused, POD >2 (median [IQR]) Length of stay, days (median [IQR])
No PLD (n ¼ 141)
Any PLD (n ¼ 129)
p Value
47 (35.6) 18 (13.4) 25 (18.9) 4 (3.0) 5 (3.8) 20 (14.9) 4 (3.0) 2 [9, 6] (n ¼ 120) 0 [0, 1] (n ¼ 121) 13 [10–18]
41 (35.7) 17 (13.8) 27 (22.7) 23 (18.7) 26 (21.7) 24 (19.7) 21 (17.7) 6 [2, 11] (n ¼ 104) 1 [0, 5] (n ¼ 102) 19 [13–28]
0.99 0.93 0.46 <0.001 <0.001 0.32 <0.001 <0.001 <0.001 <0.001
Statistically significant values are listed in bold. IQR ¼ interquartile range;
PLD ¼ postoperative liver dysfunction;
POD ¼ postoperative day;
PRBC ¼ packed red blood cell.
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Table 3. Postoperative Complications Among Patients With Postoperative Liver Dysfunction After HeartMate II Implantation Variable Arrhythmias, n (%) Stroke, n (%) Gastrointestinal bleeding, n (%) Renal replacement therapy, n (%) Prolonged ventilation, n (%) Pneumonia, n (%) Prolonged vasopressor use, n (%) #PRBC units transfused, POD 0–1 (median [IQR]) #PRBC units transfused, POD >2 (median [IQR]) Length of stay, days (median [IQR])
Group I (n ¼ 16)
Group II (n ¼ 76)
Group III (n ¼ 37)
p Value
5 (35.7) 4 (28.6) 3 (23.1) 3 (21.4) 5 (35.7) 4 (28.6) 3 (23.1) 3 [1, 5] (n ¼ 13) 2 [0, 3] (n ¼ 13) 21.5 [16–30]
25 (35.7) 9 (12.2) 15 (21.1) 6 (8.2) 5 (6.9) 10 (13.7) 4 (5.6) 7 [3, 11] (n ¼ 61) 1 [0, 3] (n ¼ 61) 19 [12–26]
11 (36.7) 4 (11.4) 9 (25.7) 14 (38.9) 16 (47.1) 10 (28.6) 14 (41.2) 8 [4, 15] (n ¼ 30) 4 [1, 10] (n ¼ 28) 22 [15–34]
0.99 0.29 0.85 0.001 <0.001 0.12 <0.001 0.014 0.025 0.48
Statistically significant values are listed in bold. IQR ¼ interquartile range;
POD ¼ postoperative day;
PRBC ¼ packed red blood cell.
and prior percutaneous coronary intervention found that the mortality risk in group III was significantly higher than in HM II recipients without PLD or in groups I and II (odds ratio, 4.6; 95% confidence interval, 2.1 to 10.1; p < 0.001).
Rate of Cardiac Transplantation Of the 208 BTT HM II recipients, 72 (34.6%) subsequently underwent heart transplantation. The transplant rate among HM II recipients without PLD was 0.17 transplants per person-year; among recipients with PLD, the rate was
Table 4. Logistic Regression Assessing Predictors of Any Postoperative Liver Dysfunctiona Univariate Analysis Variable Preoperative Age, years Sex Serum albumin, mg/dL Hypertension Diabetes mellitus Chronic kidney disease Coronary artery disease Current tobacco use Past tobacco use History of MI Prior CABG Prior PCI INTERMACS Postoperative Arrhythmias Stroke Gastrointestinal bleeding Renal replacement therapy Prolonged ventilation Pneumonia Prolonged vasopressor use #PRBC units transfused, POD 0–1 #PRBC units transfused, POD >2 Length of stay, days a
OR (95% CI)
Multivariate Analysis p Value
OR (95% CI)
p Value
1.00 0.94 0.53 0.71 0.88 1.34 1.03 1.07 1.24 0.70 1.49 0.63 0.94
(0.98–1.02) (0.51–1.75) (0.34–0.81) (0.44–1.16) (0.54–1.45) (0.81–2.21) (0.62–1.68) (0.63–1.82) (0.75–2.06) (0.43–1.14) (0.89–2.49) (0.36–1.10) (0.80–1.09)
0.62 0.85 0.003 0.17 0.63 0.25 0.92 0.8 0.41 0.15 0.13 0.11 0.4
1.00 0.76 0.38 0.70 1.04 1.27 1.16 1.49 1.28 0.66 1.82 0.74 0.99
(0.98–1.02) (0.38–1.54) (0.23–0.63) (0.39–1.23) (0.57–1.90) (0.72–2.26) (0.50–2.67) (0.82–2.68) (0.73–2.25) (0.29–1.47) (0.89–3.73) (0.33–1.63) (0.82–1.20)
0.81 0.45 <0.001 0.21 0.9 0.41 0.72 0.19 0.39 0.31 0.1 0.46 0.92
1.04 1.13 1.26 7.59 7.14 1.42 7.02 1.12 1.22 1.01
(0.62–1.75) (0.57–2.24) (0.68–2.31) (2.54–22.6) (2.64–19.3) (0.74–2.72) (2.33–21.1) (1.06–1.18) (1.10–1.35) (0.99–1.02)
0.88 0.74 0.47 <0.001 <0.001 0.29 0.001 <0.001 <0.001 0.059
0.81 1.15 0.53 1.19 1.31 0.69 3.57 1.10 1.10 1.03
(0.41–1.61) (0.45–2.94) (0.22–1.27) (0.25–5.60) (0.28–6.08) (0.27–1.73) (0.80–15.9) (1.03–1.17) (0.98–1.24) (0.99–1.07)
0.55 0.77 0.15 0.83 0.73 0.43 0.096 0.004 0.099 0.12
Regressions of preoperative and postoperative variables performed separately.
Statistically significant values are listed in bold. CABG ¼ coronary artery bypass graft; CI ¼ confidence interval; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support; IQR ¼ interquartile range; MI ¼ myocardial infarction; OR ¼ odds ratio; PCI ¼ percutaneous coronary intervention; POD ¼ postoperative day; PRBC ¼ packed red blood cell.
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Table 5. Logistic Regression Assessing Predictors of Combined Elevation of Both Transaminases and Bilirubina Univariate Analysis Variable Preoperative Age Sex Serum albumin Hypertension Diabetes mellitus Chronic kidney disease Coronary artery disease Current tobacco use Past tobacco use History of MI Prior CABG Prior PCI INTERMACS Postoperative Arrhythmias Stroke Gastrointestinal bleeding Renal replacement therapy Prolonged ventilation Pneumonia Prolonged vasopressor use #PRBC units transfused, POD 0–1 #PRBC units transfused, POD >2 Length of stay, days a
OR (95% CI)
Multivariate Analysis p Value
OR (95% CI)
p Value
0.99 1.14 0.38 0.98 1.26 0.65 1.65 0.75 1.13 0.77 2.16 0.53 0.75
(0.97–1.01) (0.45–2.90) (0.21–0.67) (0.48–1.99) (0.62–2.57) (0.30–1.42) (0.76–3.58) (0.34–1.69) (0.55–2.33) (0.37–1.59) (1.06–4.40) (0.21–1.34) (0.60–0.95)
0.42 0.79 0.001 0.95 0.53 0.28 0.21 0.49 0.74 0.48 0.034 0.18 0.018
0.98 1.08 0.35 0.81 1.70 0.54 2.71 1.04 0.99 0.54 2.80 0.50 0.73
(0.95–1.01) (0.37–3.13) (0.18–0.67) (0.35–1.88) (0.71–4.07) (0.22–1.31) (0.81–9.10) (0.43–2.52) (0.44–2.21) (0.19–1.51) (1.02–7.64) (0.15–1.64) (0.53–1.00)
0.13 0.88 0.002 0.63 0.24 0.17 0.11 0.93 0.98 0.24 0.045 0.25 0.051
1.06 0.72 1.39 10.3 12.1 2.22 13.3 1.08 1.15 1.01
(0.48–2.34) (0.24–2.17) (0.61–3.19) (4.29–24.6) (5.17–28.5) (0.98–5.04) (5.34–33.1) (1.03–1.14) (1.06–1.23) (0.99–1.02)
0.89 0.56 0.43 <0.001 <0.001 0.056 <0.001 0.001 0.001 0.092
0.66 1.49 0.85 3.48 1.60 1.29 0.93 1.08 1.07 1.00
(0.22–1.99) (0.36–6.10) (0.22–3.25) (0.76–16.0) (0.26–9.90) (0.34–4.87) (0.11–8.01) (1.01–1.15) (0.97–1.18) (0.97–1.03)
0.46 0.58 0.81 0.11 0.61 0.70 0.94 0.030 0.19 0.94
Regressions of preoperative and postoperative variables performed separately.
Statistically significant values are listed in bold. CABG ¼ coronary artery bypass graft; CI ¼ confidence interval; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support; IQR ¼ interquartile range; MI ¼ myocardial infarction; OR ¼ odds ratio; PCI ¼ percutaneous coronary intervention; POD ¼ postoperative day; PRBC ¼ packed red blood cell.
0.11 (group I), 0.16 (group II), and 0.03 (group III) transplants per person-year. The transplant rate in group III was significantly lower than among HM II recipients without PLD (p < 0.05) or in group II (p < 0.05).
Comment CF-LVAD support has become standard therapy for patients with end-stage heart failure. Some HM II recipients have multisystem organ dysfunction, including hepatic dysfunction, after device implantation [5]. The pathophysiologic mechanisms responsible for post-LVAD PLD remain unclear. Despite advances in surgical technique and postoperative care, liver dysfunction after cardiac surgery remains common and is associated with poor outcomes [6–13, 15]. Some investigators examined the effect of preoperative liver dysfunction on subsequent PLD and post-LVAD survival [19, 22, 25, 26]. Deo and colleagues [26] assessed the trend of hepatorenal laboratory parameters in 61 LVAD recipients over 1 year. Overall, a significant improvement in hepatic and renal function was observed. Analysis of a separate high-risk cohort
Fig 1. Kaplan-Meier survival estimates for patients undergoing HeartMate II (St. Jude Medical, Inc, St. Paul, MN) left ventricular assist device implantation, January 2005 through June 2014, stratified by severity of postoperative liver dysfunction (PLD).
(serum creatinine and bilirubin higher than the 75th percentile) demonstrated a higher 30-day mortality rate but also a 30% decrease in serum bilirubin at 30 days, which persisted over the study period. Demirozu and associates [19] reported improvements in serum transaminase, bilirubin, and creatinine levels in 23 LVAD recipients with advanced liver dysfunction (excluding three early deaths). Yang and colleagues [22] analyzed Model for EndStage Liver Disease (MELD) and MELD-XI (MELD eXcluding international normalized ratio) scores to assess the impact of liver dysfunction on outcomes in a cohort of 255 HM XVE (pulsatile-flow) or HM II recipients. Recipients with low (<17) preoperative scores had greater survival rates than those with higher scores. Among those patients who subsequently underwent heart transplantation, improvement of MELD-XI scores during LVAD support conferred posttransplant survival rates similar to those observed in patients without preoperative liver dysfunction. Finally, Nishi and colleagues [14] reported a high (36%) 90-day mortality rate in LVAD recipients (n ¼ 167 total) with early (<14 days) postoperative hyperbilirubinemia. Furthermore, early postoperative elevations in central venous pressure predicted poor recovery from PLD. No distinction was made between LVAD recipients with versus without preexisting liver dysfunction. The few studies on PLD risk factors and outcomes in LVAD recipients include patients with preoperative liver dysfunction. Given that preoperative liver dysfunction is itself an important contributor to both PLD and death, we investigated the incidence of PLD among patients without this comorbidity. We report several findings. First, PLD developed in 47.8% of all LVAD recipients during our 9.5-year study period, a finding consistent with previous studies examining PLD after cardiac surgical procedures (including LVAD implantation), but most studies define PLD by hyperbilirubinemia alone [6–15]. In our study, among the patients in whom PLD developed, 28.7% (13.7% of the overall cohort) had combined hypertransaminasemia and hyperbilirubinemia (group III), whereas 58.9% (28.9% of the overall cohort) had isolated hyperbilirubinemia (group II). On further subgroup analysis, only group III recipients had worse survival rates at 30 and 90 days and 1 year compared with other recipients. The effect of combined hypertransaminasemia and hyperbilirubinemia on survival was corroborated by adjusted logistic regression analysis, which revealed a 4.6-fold higher risk of mortality for group III. Second, LVAD recipients with any PLD and group III PLD had significantly higher rates of RRT, prolonged ventilation, and prolonged vasopressor use and greater transfusion requirements, findings consistent with the critical illness common in patients with severe liver dysfunction after cardiac operations. An increased transfusion requirement was predictive of any PLD and group III PLD on multivariate analysis. Third, group III recipients who had undergone BTT LVAD implantation were less likely to undergo heart
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transplantation than were LVAD recipients without severe PLD. The transplantation rate was 0.03 transplants per person-year among BTT recipients in group III, a lower rate than in recipients without PLD or recipients in groups I and II (p < 0.0014). The exact mechanisms responsible for PLD after LVAD implantation are unclear, but several explanations have been offered. Masai and colleagues [27] showed, in a small cohort of LVAD recipients, that preoperative liver dysfunction and an increased preoperative inflammatory profile resulted in a higher incidence of postoperative hyperbilirubinemia and an increased postoperative inflammatory cytokine profile after implantation, despite adequate hemodynamic support. These investigators proposed that the persistent inflammatory response resulted in the derangement of the hepatic microcirculation, thereby aggravating hepatic dysfunction. The finding of Nishi and colleagues [14] of the negative effect of elevated central venous pressure on PLD recovery suggests that new or residual hepatic congestion (eg, post-LVAD right ventricular failure) likely also plays a role. Finally, Yang and associates [22] observed increases in serum bilirubin and alkaline phosphatase concentrations in the first 30 days after initiation of LVAD support. Bilirubin concentration normalized over time, but alkaline phosphatase levels did not, particularly in CF-LVAD recipients, a finding suggesting that CF-LVAD support may be responsible for long-term cholestasis. Our findings suggest that the post-LVAD development of isolated hypertransaminasemia or isolated hyperbilirubinemia may represent a relatively benign form of PLD. However, development of combined hypertransaminasemia and hyperbilirubinemia may represent a significant disruption of hepatic perfusion or an underlying systemic issue, such as right-sided heart failure. In our study, these patients required an increased duration of ventilation and vasopressor use and increased transfusion requirements, and they had poor rates of survival and eventual heart transplantation. Our analysis did not reveal a specific marker that reliably predicts post-LVAD group III PLD before it occurs. However, we believe that our findings mandate aggressive evaluation and management of post-LVAD right-sided heart failure, which can be associated with prolonged vasopressor and ventilator requirements and multiorgan dysfunction, particularly in patients who are critically ill before LVAD implantation. Although our data are insufficient to support such a recommendation, the liberal use of early right ventricular assist device therapy may be beneficial in patients with post-LVAD right-sided heart failure, particularly in the setting of combined hypertransaminasemia and hyperbilirubinemia. This therapy may be facilitated by the proliferation of percutaneous right-sided support devices [28].
Limitations Because this is a retrospective database study, the integrity of our findings depends on accurate prior documentation. Our institutional experience may not completely reflect that of other heart failure programs.
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However, these limitations are offset by the large number of patients reported, and the single-center design ensures some consistency regarding preoperative and postoperative management strategies.
Conclusions Isolated hyperbilirubinemia is common after LVAD implantation. In our study of HM II recipients, it was not associated with an increase in early or midterm postoperative mortality. However, postoperative combined hypertransaminasemia and hyperbilirubinemia were associated with a statistically significant increase in early and midterm morbidity and mortality. Further research into the pathogenesis of PLD is essential to improve outcomes among LVAD recipients. The authors acknowledge Mary Knatterud, PhD, for assistance with manuscript editing. Dr John receives grant support from St. Jude Medical and Medtronic.
References 1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update. Circulation 2013;127:e6–245. 2. Marcel R, Meyer DM. An overview of approved and investigational left ventricular assist devices. Proc (Bayl Univ Med Cent) 2004;17:407–10. 3. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345:1435–43. 4. John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86:1227–35. 5. Yuan N, Arnaoutakis GJ, George TJ, et al. The spectrum of complications following left ventricular assist device placement. J Card Surg 2012;27:630–8. 6. An Y, Xiao YB, Zhong QJ. Hyperbilirubinemia after extracorporeal circulation surgery: a recent and prospective study. World J Gastroenterol 2006;12:6722–6. 7. Collins JD, Bassendine MF, Ferner R, et al. Incidence and prognostic importance of jaundice after cardiopulmonary bypass surgery. Lancet 1983;1:1119–23. 8. Hosotsubo KK, Nishimura M, Nishimura S. Hyperbilirubinaemia after major thoracic surgery: comparison between open-heart surgery and oesophagectomy. Crit Care 2000;4:180–7. 9. Lockey E, McIntyre N, Ross DN, Brookes E, Sturridge MF. Early jaundice after open-heart surgery. Thorax 1967;22:165–9. 10. Mastoraki A, Karatzis E, Mastoraki S, Kriaras I, Sfirakis P, Geroulanos S. Postoperative jaundice after cardiac surgery. Hepatobiliary Pancreat Dis Int 2007;6:383–7. 11. Wang MJ, Chao A, Huang CH, et al. Hyperbilirubinemia after cardiac operation. Incidence, risk factors, and clinical significance. J Thorac Cardiovasc Surg 1994;108:429–36.
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12. Hsu RB, Lin FY, Chen RJ, et al. Incidence, risk factors, and prognosis of postoperative hyperbilirubinemia after heart transplantation. Eur J Cardiothorac Surg 2007;32:917–22. 13. Kavarana MN, Pessin-Minsley MS, Urtecho J, et al. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg 2002;73:745–50. 14. Nishi H, Toda K, Miyagawa S, et al. Prediction of outcome in patients with liver dysfunction after left ventricular assist device implantation. J Artif Organs 2013;16:404–10. 15. Nishi H, Sakaguchi T, Miyagawa S, et al. Frequency, risk factors and prognosis of postoperative hyperbilirubinemia after heart valve surgery. Cardiology 2012;122:12–9. 16. Giallourakis CC, Rosenberg PM, Friedman LS. The liver in heart failure. Clin Liver Dis 2002;6:947–67. 17. Bayraktar UD, Seren S, Bayraktar Y. Hepatic venous outflow obstruction: three similar syndromes. World J Gastroenterol 2007;13:1912–27. 18. Wadia Y, Etheridge W, Smart F, Wood RP, Frazier OH. Pathophysiology of hepatic dysfunction and intrahepatic cholestasis in heart failure and after left ventricular assist device support. J Heart Lung Transplant 2005;24:361–70. 19. Demirozu ZT, Hernandez R, Mallidi HR, et al. HeartMate II left ventricular assist device implantation in patients with advanced hepatic dysfunction. J Card Surg 2014;29:419–23. 20. Potthoff A, Schettler A, Attia D, et al. Liver stiffness measurements and short-term survival after left ventricular assist device implantation: a pilot study. J Heart Lung Transplant 2015;34:1586–94. 21. Weymann A, Patil NP, Sabashnikov A, et al. Continuousflow left ventricular assist device therapy in patients with preoperative hepatic failure: are we pushing the limits too far? Artif Organs 2015;39:336–42. 22. Yang JA, Kato TS, Shulman BP, et al. Liver dysfunction as a predictor of outcomes in patients with advanced heart failure requiring ventricular assist device support: use of the Model of End-stage Liver Disease (MELD) and MELD eXcluding INR (MELD-XI) scoring system. J Heart Lung Transplant 2012;31:601–10. 23. Yost GL, Coyle L, Bhat G, Tatooles AJ. Model for end-stage liver disease predicts right ventricular failure in patients with left ventricular assist devices. J Artif Organs 2016;19:21–8. 24. INTERMACS. Adverse Event Definitions. 2013. Available at http://www.uab.edu/medicine/intermacs/protocol-3-archive/ appendices/appendix-a. Accessed May 10, 2017. 25. Deo SV, Daly RC, Altarabsheh SE, et al. Predictive value of the model for end-stage liver disease score in patients undergoing left ventricular assist device implantation. ASAIO J 2013;59:57–62. 26. Deo SV, Sharma V, Altarabsheh SE, et al. Hepatic and renal function with successful long-term support on a continuous flow left ventricular assist device. Heart Lung Circ 2014;23: 229–33. 27. Masai T, Sawa Y, Ohtake S, et al. Hepatic dysfunction after left ventricular mechanical assist in patients with end-stage heart failure: role of inflammatory response and hepatic microcirculation. Ann Thorac Surg 2002;73: 549–55. 28. Spratt JR, Raveendran G, Liao K, John R. Novel percutaneous mechanical circulatory support devices and their expanding applications. Exp Rev Cardiovasc Ther 2016;14: 1133–50.
INVITED COMMENTARY In this study, Majumder and colleagues [1] found that patients with combined hypertransaminasemiahyperbilirubinemia after implantation of a HeartMate II left ventricular assist device (LVAD) experienced Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
significantly greater early and midterm morbidity and mortality and were less likely to undergo subsequent heart transplantation, compared with peers who either did not have postoperative liver dysfunction or had either 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2017.05.058
Impact of Postoperative Liver Dysfunction on Survival After Left Ventricular Assist Device Implantation Kaustav Majumder, MBBS, John R. Spratt, MD, MA, Christopher T. Holley, MD, Samit S. Roy, MSPH, Rebecca J. Cogswell, MD, Kenneth Liao, MD, and Ranjit John, MD Department of Surgery, University of Minnesota, Minneapolis, Minnesota; Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; and Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
Background. Liver dysfunction in left ventricular assist device (LVAD) recipients is common both before and after implantation. Postoperative liver dysfunction (PLD) develops in some LVAD recipients without preoperative liver dysfunction. The aim of this study was to assess clinical outcomes in such patients. Methods. Records of all patients undergoing implantation of a HeartMate II (HM II, St. Jude Medical, Inc, Minneapolis, MN) LVAD at a single center at the University of Minnesota from January 2005 through June 2014 were analyzed. PLD was defined by hypertransaminasemia or hyperbilirubinemia, or both, during the hospitalization for LVAD implantation. Results. During the study period, 284 patients underwent HM II implantation. Excluded from analysis were 14 recipients with preoperative liver dysfunction. In the final cohort (n [ 270), there were no major difference in preoperative characteristics among those patients with versus without PLD. PLD developed in 129 (47.8%) recipients: 16 (12.4%) had isolated hypertransaminasemia (group I),
76 (58.9%) had isolated hyperbilirubinemia (group II), and 37 (28.7%) had combined hypertransaminasemia and hyperbilirubinemia (group III). Group III LVAD recipients had significantly greater rates of 30-day, 90-day, and 1-year mortality, along with significantly higher transfusion requirements and higher rates of renal replacement therapy, prolonged ventilation, and vasopressor use. Moreover, their mortality risk was significantly higher than that of PLD-free LVAD recipients (hazard ratio, 4.6; 95% confidence interval, 2.1 to 10.1; p < 0.001). Conclusions. Isolated hyperbilirubinemia is common after LVAD implantation. In this study, it was not associated with an increase in early or midterm postoperative mortality. However, postoperative combined transaminasemia and hyperbilirubinemia was associated with a significant increase in early and midterm morbidity and mortality. Further research into the pathogenesis of post-LVAD PLD is necessary.
H
Postoperative liver dysfunction (PLD) is associated with increased in-hospital mortality rates after cardiac surgical procedures, including LVAD implantation [6–15]. Heart failure–related liver dysfunction has been attributed to hepatocellular ischemia resulting from poor antegrade perfusion and to passive venous congestion secondary to right ventricular dysfunction [16, 17]. PLD after LVAD implantation has been attributed to perioperative hemodynamic changes and preexisting liver dysfunction [18]. The negative postoperative effects of preoperative liver dysfunction in LVAD recipients have been reported, but the impact of isolated PLD is poorly characterized [5, 14, 18–23]. The aims of this study were use a large, single-center cohort to characterize the incidence and forms of PLD and to determine the relationship of PLD with major morbidity and mortality after LVAD
eart failure is a significant public health concern [1]. Left ventricular assist devices (LVADs) have become important components of heart failure management, both as a bridge to transplantation (BTT) and as destination therapy (DT), and they are associated with improved quality of life [2–4]. Continuous-flow LVADs (CF-LVADs), such as the HeartMate II (HM II, St. Jude Medical, Inc, Minneapolis, MN) and HeartWare HVAD (HeartWare, Framingham, MA), have greater durability and a more favorable complication profile than earlier pulsatile-flow devices [4]. However, device-related complications, including stroke, gastrointestinal bleeding, infection, and end-organ dysfunction, remain common [5]. Accepted for publication April 18, 2017.
(Ann Thorac Surg 2017;104:1556–63) Ó 2017 by The Society of Thoracic Surgeons
Presented at the Thirty-fifth Annual Meeting of the International Society for Heart and Lung Transplantation, Nice, France, April 15, 2015. Address correspondence to Dr John, Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota Medical School, Mayo Mail Code 207, 420 Delaware St SE, Minneapolis, MN 55455; email: [email protected].
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
Drs Cogswell and John disclose a financial relationship with St Jude Medical and Medtronic.
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MAJUMDER ET AL LIVER DYSFUNCTION AFTER LVAD IMPLANTATION
Abbreviations and Acronyms BTT CABG CF HM II INTERMACS
= = = = =
LVAD MELD PLD POD RRT
= = = = =
bridge to transplantation coronary artery bypass grafting continuous-flow HeartMate II Interagency Registry for Mechanically Assisted Circulatory Support left ventricular assist device Model for End-stage Liver Disease postoperative liver dysfunction postoperative day renal replacement therapy
implantation, specifically common postoperative complications, survival, and rates of cardiac transplantation.
Patients and Methods In this retrospective study, all patients who underwent HM II implantation from January 1, 2005, through June 30, 2014 were identified in the University of Minnesota LVAD database. This analysis was approved by the local Institutional Review Board (IRB #1403M48521).
Patient Care, Device Management, and Anticoagulation Patients received standard heart failure care, including antiarrhythmic therapy, before and after LVAD implantation. Pump speed is optimized to provide adequate cardiac output and optimal left ventricular decompression while maintaining a good pulsatility index greater than 3.5 to 4.0 and intermittent aortic valve opening. Anticoagulation consisted of oral aspirin and warfarin with a low-dose heparin bridge, usually starting on postoperative days (POD) 1 to 2.
Clinical Outcomes Demographics, clinical characteristics, and outcomes data were evaluated in each of the HM II recipients in this cohort. Preoperative liver dysfunction and PLD were both defined as serum levels of aspartate transferase or alanine transferase greater than five times the upper limit of normal (normal range for aspartate transferase, 0 to 45 U/L; for alanine transferase, 0 to 50 U/L) or total serum bilirubin of 5 mg/dL or higher between LVAD implantation and hospital discharge. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria were used to define other postoperative complications [24]. Baseline characteristics, including documented cirrhosis, chronic hepatitis, and a history of heavy alcohol use (considered surrogates for subclinical liver disease), were assessed to determine risk factors for development of PLD. Survival data were evaluated in all recipients.
Statistical Analysis For between-group comparisons, two-sample Student’s t testing was used for normally distributed continuous
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variables, and the Wilcoxon rank-sum test was used for other continuous variables. For categorical variables, c2 testing was used. Univariable and multivariable logistic regression was used to determine predictors of PLD. Survival analysis was performed using the Kaplan-Meier method, and log-rank testing was used to compare and assess unadjusted all-cause mortality rates for PLD versus non-PLD recipients, as well as PLD subgroup analyses. For all analyses, Stata release 13 (StataCorp LP, College Station, TX) was used, and a two-tailed p < 0.05 was considered significant.
Results Baseline Characteristics and Incidence of Postoperative Liver Dysfunction During the 9.5-year study period, 284 patients underwent HM II implantation (547 person-years of total follow-up). Excluded from analysis were 14 HM II recipients with preoperative liver dysfunction. The baseline characteristics of the final cohort of 270 HM II recipients are shown in Table 1. The mean age at implantation was 57 14 years, 219 (81.1%) of the patients were male, and 208 (77%) recipients were considered as having BTT therapy at implantation. Rates of potential subclinical liver disease did not differ between patients with PLD and those without it. Of the 270 HM II recipients, PLD developed in 129 (47.8%): 16 (12.4%) had isolated hypertransaminasemia (group I), 76 (58.9%) had isolated hyperbilirubinemia (group II), and 37 (28.7%) had combined hypertransaminasemia and hyperbilirubinemia (group III).
Preoperative Risk Factors and Postoperative Complications Between patients with PLD and those without it, baseline demographic characteristics did not significantly differ in terms of age, sex, BTT versus destination therapy, comorbidities, past tobacco use, or prior interventions. Patients with group III PLD were more likely to have a lower preoperative serum albumin level (p ¼ 0.001) and a lower INTERMACS profile (p ¼ 0.044) (Table 1). Postoperatively, the need for renal replacement therapy (RRT), prolonged (>7 days) ventilation, prolonged vasopressor use, increased early (POD 0 to 1) and late (POD >2) transfusion requirements, and increased inpatient length of stay were all associated with PLD generally (p < 0.001 for all) and with group III PLD specifically (Tables 2 and 3). Serum albumin was significantly associated with any PLD and group III PLD on univariate and multivariable logistic regression, and levels were higher in recipients with minor (group I or II) or no PLD (Table 4). Postoperatively, RRT, prolonged ventilation and vasopressor use, and increased transfusion requirements were significantly associated with PLD on univariate analysis, but only elevated early transfusion requirements proved significant on multivariate analysis (odds ratio, 1.10; 95% confidence interval, 1.03 to 1.17; p ¼ 0.004). Examining
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Table 1. Baseline Demographics of Patients Undergoing HeartMate II Implantation Between 2005 and 2014 (n ¼ 270) Variable, n (%) Age, years Males BTT Preoperative albumin, mg/dL Hypertension Diabetes mellitus Chronic kidney disease Coronary artery disease Current tobacco use Past tobacco use Prior CT surgery History of MI Prior CABG Prior PCI INTERMACS [IQR] Cirrhosis Chronic hepatitis Prior heavy alcohol use a
No PLD (n ¼ 141)
Any PLD (n ¼ 129)
Group I (n ¼ 16)
Group II (n ¼ 76)
Group III (n ¼ 37)
p Valuea
56.5 14.3 115 (82.1) 112 (79.4) 3.56 0.53 65 (46.1) 54 (38.3) 46 (32.6) 88 (62.4) 40 (29.2) 46 (34.1) 2 (4.2) 64 (45.7) 39 (27.7) 42 (30.0) 4 [3, 5] 4 (2.8) 1 (0.7) 19 (13.5)
57.4 14.2 104 (81.3) 96 (74.4) 3.34 0.65 48 (37.8) 45 (35.4) 50 (39.4) 80 (63.0) 38 (30.7) 48 (39.0) 1 (1.6) 47 (37.0) 46 (36.2) 27 (21.3) 4 [2, 5] 6 (4.7) 1 (0.8) 17 (13.2)
55.1 10.1 9 (56.3) 14 (87.5) 3.58 0.77 5 (31.3) 7 (43.8) 6 (37.5) 8 (50.0) 9 (60.0) 4 (26.7) 0 5 (31.3) 5 (31.3) 2 (12.5) 5 [3, 6] 2 (12.5) 0 0
58.9 13.9 65 (85.5) 56 (73.7) 3.39 0.61 28 (37.3) 23 (30.7) 34 (45.3) 46 (61.3) 20 (27.4) 30 (41.7) 0 29 (38.7) 24 (32.0) 19 (25.3) 4 [2, 5] 2 (2.6) 0 10 (13.2)
55.2 16.1 30 (83.3) 26 (70.3) 3.15 0.64 15 (41.7) 15 (41.7) 10 (27.8) 26 (72.2) 9 (25.0) 14 (38.9) 1 (4.8) 13 (36.1) 17 (47.2) 6 (16.7) 3 [2, 4] 2 (5.4) 1 (2.7) 7 (18.9)
0.49 0.051 0.43 0.001 0.51 0.56 0.2 0.46 0.067 0.62 0.61 0.5 0.17 0.25 0.044 0.18 0.43 0.33
p values refer to comparison of “No PLD” and groups I to III.
Statistically significant values are listed in bold. BTT ¼ bridge to transplantation; CABG ¼ coronary artery bypass graft; Mechanically Assisted Circulatory Support; IQR ¼ interquartile range; vention; PLD ¼ postoperative liver dysfunction.
group III PLD separately, prior coronary artery bypass grafting, serum albumin, and INTERMACS score were found to be significant preoperative predictors on univariate and multivariable logistic analysis (p ¼ 0.051 for INTERMACS). The postoperative outcomes associated with group III PLD were similar to those of PLD of any kind (Table 5).
Survival Of the 270 HM II recipients, 94 died during the follow-up period. The overall survival rate was 94% at 30 days, 89% at 90 days, and 77% at 1 year after implantation. Postoperative survival in patients with (vs without) PLD was
CT ¼ cardiothoracic; INTERMACS ¼ Interagency Registry for MI ¼ myocardial infarction; PCI ¼ percutaneous coronary inter-
worse at 30 days (88% vs 99%), at 90 days (82% vs 90%), and at 1 year (71% vs 82%). The survival rate at each of those intervals in groups I and II was similar and did not significantly differ from the survival rate in HM II recipients without PLD (p > 0.05). However, group III (combined hypertransaminasemia and hyperbilirubinemia) had a significantly decreased survival rate at 30 days (65%), 90 days (42%), and 1 year (39%) (p < 0.0001 vs groups I and II) (Fig 1). Logistic regression adjusted for age, sex, hypertension, diabetes mellitus, chronic kidney disease, coronary artery disease, past or current tobacco use, prior myocardial infarction, prior coronary artery bypass grafting,
Table 2. Postoperative Complications Among All Patients Who Underwent HeartMate II Implantation Variable Arrhythmias, n (%) Stroke, n (%) Gastrointestinal bleeding, n (%) Renal replacement therapy, n (%) Prolonged ventilation, n (%) Pneumonia, n (%) Prolonged vasopressor use, n (%) #PRBC units transfused, POD 0–1 (median [IQR]) #PRBC units transfused, POD >2 (median [IQR]) Length of stay, days (median [IQR])
No PLD (n ¼ 141)
Any PLD (n ¼ 129)
p Value
47 (35.6) 18 (13.4) 25 (18.9) 4 (3.0) 5 (3.8) 20 (14.9) 4 (3.0) 2 [9, 6] (n ¼ 120) 0 [0, 1] (n ¼ 121) 13 [10–18]
41 (35.7) 17 (13.8) 27 (22.7) 23 (18.7) 26 (21.7) 24 (19.7) 21 (17.7) 6 [2, 11] (n ¼ 104) 1 [0, 5] (n ¼ 102) 19 [13–28]
0.99 0.93 0.46 <0.001 <0.001 0.32 <0.001 <0.001 <0.001 <0.001
Statistically significant values are listed in bold. IQR ¼ interquartile range;
PLD ¼ postoperative liver dysfunction;
POD ¼ postoperative day;
PRBC ¼ packed red blood cell.
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Table 3. Postoperative Complications Among Patients With Postoperative Liver Dysfunction After HeartMate II Implantation Variable Arrhythmias, n (%) Stroke, n (%) Gastrointestinal bleeding, n (%) Renal replacement therapy, n (%) Prolonged ventilation, n (%) Pneumonia, n (%) Prolonged vasopressor use, n (%) #PRBC units transfused, POD 0–1 (median [IQR]) #PRBC units transfused, POD >2 (median [IQR]) Length of stay, days (median [IQR])
Group I (n ¼ 16)
Group II (n ¼ 76)
Group III (n ¼ 37)
p Value
5 (35.7) 4 (28.6) 3 (23.1) 3 (21.4) 5 (35.7) 4 (28.6) 3 (23.1) 3 [1, 5] (n ¼ 13) 2 [0, 3] (n ¼ 13) 21.5 [16–30]
25 (35.7) 9 (12.2) 15 (21.1) 6 (8.2) 5 (6.9) 10 (13.7) 4 (5.6) 7 [3, 11] (n ¼ 61) 1 [0, 3] (n ¼ 61) 19 [12–26]
11 (36.7) 4 (11.4) 9 (25.7) 14 (38.9) 16 (47.1) 10 (28.6) 14 (41.2) 8 [4, 15] (n ¼ 30) 4 [1, 10] (n ¼ 28) 22 [15–34]
0.99 0.29 0.85 0.001 <0.001 0.12 <0.001 0.014 0.025 0.48
Statistically significant values are listed in bold. IQR ¼ interquartile range;
POD ¼ postoperative day;
PRBC ¼ packed red blood cell.
and prior percutaneous coronary intervention found that the mortality risk in group III was significantly higher than in HM II recipients without PLD or in groups I and II (odds ratio, 4.6; 95% confidence interval, 2.1 to 10.1; p < 0.001).
Rate of Cardiac Transplantation Of the 208 BTT HM II recipients, 72 (34.6%) subsequently underwent heart transplantation. The transplant rate among HM II recipients without PLD was 0.17 transplants per person-year; among recipients with PLD, the rate was
Table 4. Logistic Regression Assessing Predictors of Any Postoperative Liver Dysfunctiona Univariate Analysis Variable Preoperative Age, years Sex Serum albumin, mg/dL Hypertension Diabetes mellitus Chronic kidney disease Coronary artery disease Current tobacco use Past tobacco use History of MI Prior CABG Prior PCI INTERMACS Postoperative Arrhythmias Stroke Gastrointestinal bleeding Renal replacement therapy Prolonged ventilation Pneumonia Prolonged vasopressor use #PRBC units transfused, POD 0–1 #PRBC units transfused, POD >2 Length of stay, days a
OR (95% CI)
Multivariate Analysis p Value
OR (95% CI)
p Value
1.00 0.94 0.53 0.71 0.88 1.34 1.03 1.07 1.24 0.70 1.49 0.63 0.94
(0.98–1.02) (0.51–1.75) (0.34–0.81) (0.44–1.16) (0.54–1.45) (0.81–2.21) (0.62–1.68) (0.63–1.82) (0.75–2.06) (0.43–1.14) (0.89–2.49) (0.36–1.10) (0.80–1.09)
0.62 0.85 0.003 0.17 0.63 0.25 0.92 0.8 0.41 0.15 0.13 0.11 0.4
1.00 0.76 0.38 0.70 1.04 1.27 1.16 1.49 1.28 0.66 1.82 0.74 0.99
(0.98–1.02) (0.38–1.54) (0.23–0.63) (0.39–1.23) (0.57–1.90) (0.72–2.26) (0.50–2.67) (0.82–2.68) (0.73–2.25) (0.29–1.47) (0.89–3.73) (0.33–1.63) (0.82–1.20)
0.81 0.45 <0.001 0.21 0.9 0.41 0.72 0.19 0.39 0.31 0.1 0.46 0.92
1.04 1.13 1.26 7.59 7.14 1.42 7.02 1.12 1.22 1.01
(0.62–1.75) (0.57–2.24) (0.68–2.31) (2.54–22.6) (2.64–19.3) (0.74–2.72) (2.33–21.1) (1.06–1.18) (1.10–1.35) (0.99–1.02)
0.88 0.74 0.47 <0.001 <0.001 0.29 0.001 <0.001 <0.001 0.059
0.81 1.15 0.53 1.19 1.31 0.69 3.57 1.10 1.10 1.03
(0.41–1.61) (0.45–2.94) (0.22–1.27) (0.25–5.60) (0.28–6.08) (0.27–1.73) (0.80–15.9) (1.03–1.17) (0.98–1.24) (0.99–1.07)
0.55 0.77 0.15 0.83 0.73 0.43 0.096 0.004 0.099 0.12
Regressions of preoperative and postoperative variables performed separately.
Statistically significant values are listed in bold. CABG ¼ coronary artery bypass graft; CI ¼ confidence interval; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support; IQR ¼ interquartile range; MI ¼ myocardial infarction; OR ¼ odds ratio; PCI ¼ percutaneous coronary intervention; POD ¼ postoperative day; PRBC ¼ packed red blood cell.
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Table 5. Logistic Regression Assessing Predictors of Combined Elevation of Both Transaminases and Bilirubina Univariate Analysis Variable Preoperative Age Sex Serum albumin Hypertension Diabetes mellitus Chronic kidney disease Coronary artery disease Current tobacco use Past tobacco use History of MI Prior CABG Prior PCI INTERMACS Postoperative Arrhythmias Stroke Gastrointestinal bleeding Renal replacement therapy Prolonged ventilation Pneumonia Prolonged vasopressor use #PRBC units transfused, POD 0–1 #PRBC units transfused, POD >2 Length of stay, days a
OR (95% CI)
Multivariate Analysis p Value
OR (95% CI)
p Value
0.99 1.14 0.38 0.98 1.26 0.65 1.65 0.75 1.13 0.77 2.16 0.53 0.75
(0.97–1.01) (0.45–2.90) (0.21–0.67) (0.48–1.99) (0.62–2.57) (0.30–1.42) (0.76–3.58) (0.34–1.69) (0.55–2.33) (0.37–1.59) (1.06–4.40) (0.21–1.34) (0.60–0.95)
0.42 0.79 0.001 0.95 0.53 0.28 0.21 0.49 0.74 0.48 0.034 0.18 0.018
0.98 1.08 0.35 0.81 1.70 0.54 2.71 1.04 0.99 0.54 2.80 0.50 0.73
(0.95–1.01) (0.37–3.13) (0.18–0.67) (0.35–1.88) (0.71–4.07) (0.22–1.31) (0.81–9.10) (0.43–2.52) (0.44–2.21) (0.19–1.51) (1.02–7.64) (0.15–1.64) (0.53–1.00)
0.13 0.88 0.002 0.63 0.24 0.17 0.11 0.93 0.98 0.24 0.045 0.25 0.051
1.06 0.72 1.39 10.3 12.1 2.22 13.3 1.08 1.15 1.01
(0.48–2.34) (0.24–2.17) (0.61–3.19) (4.29–24.6) (5.17–28.5) (0.98–5.04) (5.34–33.1) (1.03–1.14) (1.06–1.23) (0.99–1.02)
0.89 0.56 0.43 <0.001 <0.001 0.056 <0.001 0.001 0.001 0.092
0.66 1.49 0.85 3.48 1.60 1.29 0.93 1.08 1.07 1.00
(0.22–1.99) (0.36–6.10) (0.22–3.25) (0.76–16.0) (0.26–9.90) (0.34–4.87) (0.11–8.01) (1.01–1.15) (0.97–1.18) (0.97–1.03)
0.46 0.58 0.81 0.11 0.61 0.70 0.94 0.030 0.19 0.94
Regressions of preoperative and postoperative variables performed separately.
Statistically significant values are listed in bold. CABG ¼ coronary artery bypass graft; CI ¼ confidence interval; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support; IQR ¼ interquartile range; MI ¼ myocardial infarction; OR ¼ odds ratio; PCI ¼ percutaneous coronary intervention; POD ¼ postoperative day; PRBC ¼ packed red blood cell.
0.11 (group I), 0.16 (group II), and 0.03 (group III) transplants per person-year. The transplant rate in group III was significantly lower than among HM II recipients without PLD (p < 0.05) or in group II (p < 0.05).
Comment CF-LVAD support has become standard therapy for patients with end-stage heart failure. Some HM II recipients have multisystem organ dysfunction, including hepatic dysfunction, after device implantation [5]. The pathophysiologic mechanisms responsible for post-LVAD PLD remain unclear. Despite advances in surgical technique and postoperative care, liver dysfunction after cardiac surgery remains common and is associated with poor outcomes [6–13, 15]. Some investigators examined the effect of preoperative liver dysfunction on subsequent PLD and post-LVAD survival [19, 22, 25, 26]. Deo and colleagues [26] assessed the trend of hepatorenal laboratory parameters in 61 LVAD recipients over 1 year. Overall, a significant improvement in hepatic and renal function was observed. Analysis of a separate high-risk cohort
Fig 1. Kaplan-Meier survival estimates for patients undergoing HeartMate II (St. Jude Medical, Inc, St. Paul, MN) left ventricular assist device implantation, January 2005 through June 2014, stratified by severity of postoperative liver dysfunction (PLD).
(serum creatinine and bilirubin higher than the 75th percentile) demonstrated a higher 30-day mortality rate but also a 30% decrease in serum bilirubin at 30 days, which persisted over the study period. Demirozu and associates [19] reported improvements in serum transaminase, bilirubin, and creatinine levels in 23 LVAD recipients with advanced liver dysfunction (excluding three early deaths). Yang and colleagues [22] analyzed Model for EndStage Liver Disease (MELD) and MELD-XI (MELD eXcluding international normalized ratio) scores to assess the impact of liver dysfunction on outcomes in a cohort of 255 HM XVE (pulsatile-flow) or HM II recipients. Recipients with low (<17) preoperative scores had greater survival rates than those with higher scores. Among those patients who subsequently underwent heart transplantation, improvement of MELD-XI scores during LVAD support conferred posttransplant survival rates similar to those observed in patients without preoperative liver dysfunction. Finally, Nishi and colleagues [14] reported a high (36%) 90-day mortality rate in LVAD recipients (n ¼ 167 total) with early (<14 days) postoperative hyperbilirubinemia. Furthermore, early postoperative elevations in central venous pressure predicted poor recovery from PLD. No distinction was made between LVAD recipients with versus without preexisting liver dysfunction. The few studies on PLD risk factors and outcomes in LVAD recipients include patients with preoperative liver dysfunction. Given that preoperative liver dysfunction is itself an important contributor to both PLD and death, we investigated the incidence of PLD among patients without this comorbidity. We report several findings. First, PLD developed in 47.8% of all LVAD recipients during our 9.5-year study period, a finding consistent with previous studies examining PLD after cardiac surgical procedures (including LVAD implantation), but most studies define PLD by hyperbilirubinemia alone [6–15]. In our study, among the patients in whom PLD developed, 28.7% (13.7% of the overall cohort) had combined hypertransaminasemia and hyperbilirubinemia (group III), whereas 58.9% (28.9% of the overall cohort) had isolated hyperbilirubinemia (group II). On further subgroup analysis, only group III recipients had worse survival rates at 30 and 90 days and 1 year compared with other recipients. The effect of combined hypertransaminasemia and hyperbilirubinemia on survival was corroborated by adjusted logistic regression analysis, which revealed a 4.6-fold higher risk of mortality for group III. Second, LVAD recipients with any PLD and group III PLD had significantly higher rates of RRT, prolonged ventilation, and prolonged vasopressor use and greater transfusion requirements, findings consistent with the critical illness common in patients with severe liver dysfunction after cardiac operations. An increased transfusion requirement was predictive of any PLD and group III PLD on multivariate analysis. Third, group III recipients who had undergone BTT LVAD implantation were less likely to undergo heart
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transplantation than were LVAD recipients without severe PLD. The transplantation rate was 0.03 transplants per person-year among BTT recipients in group III, a lower rate than in recipients without PLD or recipients in groups I and II (p < 0.0014). The exact mechanisms responsible for PLD after LVAD implantation are unclear, but several explanations have been offered. Masai and colleagues [27] showed, in a small cohort of LVAD recipients, that preoperative liver dysfunction and an increased preoperative inflammatory profile resulted in a higher incidence of postoperative hyperbilirubinemia and an increased postoperative inflammatory cytokine profile after implantation, despite adequate hemodynamic support. These investigators proposed that the persistent inflammatory response resulted in the derangement of the hepatic microcirculation, thereby aggravating hepatic dysfunction. The finding of Nishi and colleagues [14] of the negative effect of elevated central venous pressure on PLD recovery suggests that new or residual hepatic congestion (eg, post-LVAD right ventricular failure) likely also plays a role. Finally, Yang and associates [22] observed increases in serum bilirubin and alkaline phosphatase concentrations in the first 30 days after initiation of LVAD support. Bilirubin concentration normalized over time, but alkaline phosphatase levels did not, particularly in CF-LVAD recipients, a finding suggesting that CF-LVAD support may be responsible for long-term cholestasis. Our findings suggest that the post-LVAD development of isolated hypertransaminasemia or isolated hyperbilirubinemia may represent a relatively benign form of PLD. However, development of combined hypertransaminasemia and hyperbilirubinemia may represent a significant disruption of hepatic perfusion or an underlying systemic issue, such as right-sided heart failure. In our study, these patients required an increased duration of ventilation and vasopressor use and increased transfusion requirements, and they had poor rates of survival and eventual heart transplantation. Our analysis did not reveal a specific marker that reliably predicts post-LVAD group III PLD before it occurs. However, we believe that our findings mandate aggressive evaluation and management of post-LVAD right-sided heart failure, which can be associated with prolonged vasopressor and ventilator requirements and multiorgan dysfunction, particularly in patients who are critically ill before LVAD implantation. Although our data are insufficient to support such a recommendation, the liberal use of early right ventricular assist device therapy may be beneficial in patients with post-LVAD right-sided heart failure, particularly in the setting of combined hypertransaminasemia and hyperbilirubinemia. This therapy may be facilitated by the proliferation of percutaneous right-sided support devices [28].
Limitations Because this is a retrospective database study, the integrity of our findings depends on accurate prior documentation. Our institutional experience may not completely reflect that of other heart failure programs.
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However, these limitations are offset by the large number of patients reported, and the single-center design ensures some consistency regarding preoperative and postoperative management strategies.
Conclusions Isolated hyperbilirubinemia is common after LVAD implantation. In our study of HM II recipients, it was not associated with an increase in early or midterm postoperative mortality. However, postoperative combined hypertransaminasemia and hyperbilirubinemia were associated with a statistically significant increase in early and midterm morbidity and mortality. Further research into the pathogenesis of PLD is essential to improve outcomes among LVAD recipients. The authors acknowledge Mary Knatterud, PhD, for assistance with manuscript editing. Dr John receives grant support from St. Jude Medical and Medtronic.
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INVITED COMMENTARY In this study, Majumder and colleagues [1] found that patients with combined hypertransaminasemiahyperbilirubinemia after implantation of a HeartMate II left ventricular assist device (LVAD) experienced Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
significantly greater early and midterm morbidity and mortality and were less likely to undergo subsequent heart transplantation, compared with peers who either did not have postoperative liver dysfunction or had either 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2017.05.058